Carbamazepine Extended-release Capsules Research Articles

Adverse event load in bipolar participants receiving either carbamazepine immediate-release or extended-release capsules: a blinded, randomized study

In epilepsy, slow-release formulations of carbamazepine (CBZ) have fewer adverse events (AEs) compared with immediate-release (IR) formulations. As CBZ is used for mania, it is important to determine whether a similar pattern exists for bipolar patients. This was a 3-month, blinded, random-assignment study to an IR formulation or extended-release carbamazepine capsules (ERCC, Equetro) in type I or type II bipolar patients already on CBZ or clinically determined to benefit from it. Dosages were titrated to patients' clinical needs. Mood and AE ratings were performed at baseline and monthly for 3 months. There was no difference in mood ratings or in the total level of AEs in patients receiving IR or ERCC. However, autonomic AEs (5.0+/-1.1 vs. 2.0+/-0.7, P = 0.02) and gastrointestinal AEs (1.6+/-0.4 vs. 0.6+/-0.3, P = 0.05) were significantly less in participants receiving ERCC. CBZ level in patients receiving ERCC were higher (9.2+/-1.7 vs. IR 7.2+/-1.3 microg/ml, P = 0.005). Total AE load was directly related to CBZ level only in participants receiving the IR formulation. In conclusion, ERCC is better tolerated than IR CBZ in bipolar patients.

Safety of Carbamazepine Extended-Release Capsules in Bipolar Disorder Polypharmacy

This analysis is a retrospective chart review evaluating the safety of carbamazepine (CBZ) extended-release capsules (CBZ-ERC) (Shire, Wayne, PA, USA) when used in combination with other agents as part of a polypharmacy regimen in the treatment of patients with bipolar disorder. The safety of CBZ-ERC was determined by comparing the adverse event profiles of patients on monotherapy versus those of patients on polytherapy. The medical records of 300 adult patients (aged 18-70) treated in a private practice setting with CBZ (monotherapy or polytherapy) who met the DSM-IV criteria for bipolar disorder were examined. We found that patients taking CBZ-ERC together with other agents (antipsychotics, antiepileptics, selective serotonin reuptake inhibitors and other antidepressants, anxiolytics, lithium, and attention-deficit/hyperactivity disorder medications) were no more likely to report gastrointestinal, nervous system, or cutaneous adverse events than patients on CBZ-ERC monotherapy. These real-world data suggest that the occurrence of adverse events may not differ significantly between patients on CBZ-ERC monotherapy and those on polytherapy with multiple other agents.

Carbamazepine Extended-Release Capsules Use in Bipolar Disorder: Efficacy and Safety in Adult Patients

Safety, tolerability, and efficacy of carbamazepine (CBZ) have been demonstrated in numerous studies over the last three decades. Until recently, CBZ studies largely involved immediate-release formulations, while long-term studies have been few in number. The recent development of beaded CBZ extended-release capsules (CBZ-ERC) (Shire, Wayne, PA, USA) provides a new formulation with potential advantages in safety, tolerability, and efficacy over earlier formulations. The present study assesses these parameters in patients of various bipolar subtypes (mixed/manic, bipolar I depression, and bipolar II), in a single-site private practice setting. Data were obtained from the charts of 300 patients>or=18 years old who met DSM-IV criteria for bipolar disorder. Clinical response to CBZ-ERC therapy was defined as a score of <or=3 on the Clinical Global Impression-Improvement (CGI-I) scale, while relapse was defined as a change in CGI-I to >or=4 in those subjects who had previously achieved clinical response. Clinical response occurred in 73% of patients, leading to a mean CGI-I score of 2.5 (SD=1.2). Relapse was seen in 33% of responders. Most common adverse events were somnolence, dizziness, and nausea. A high level of treatment response and a low relapse rate were observed in long-term treatment with CBZ-ERC in adults with bipolar disorder. The limited number and nature of the adverse events observed during the course of this study provide evidence of the safety and tolerability of CBZ-ERC. Carbamazepine extended-release capsules appear safe and efficacious for the treatment of bipolar disorder. Controlled studies are warranted to further establish the safety, tolerability, and efficacy of CBZ-ERC for treatment of adult bipolar patients.

Carbamazepine Extended-Release Capsules: A Retrospective Review of Its Use in Children and Adolescents

Bipolar disorder occurs in 1% of children and adolescents, but few clinical trials address treatment of this population. This retrospective chart review evaluated the long-term safety and tolerability of carbamazepine extended-release capsules (CBZ-ERC) (Shire, Wayne, PA, USA) in 300 children and adolescent patients who had been treated for bipolar disorder in a private psychiatric practice. Data were collected from the medical records of all young and adolescent (4-17 years old) patients who met the DSM-IV criteria for a diagnosis of bipolar disorder type I, type II, or bipolar not otherwise specified who had been treated with CBZ-ERC either as add-on or monotherapy between October 1998 and November 2003 at Red Oak Psychiatry Associates, Houston, TX. The severity of illness was assessed using the Clinical Global Impression-Severity scale, and improvement was measured by the Clinical Global Impression-Improvement (CGI-I) scale. A response, defined as a CGI-I score of <or=3, was achieved in 76% of patients, 90% of whom were at least markedly ill (CGI-I>or=5) at CBZ-ERC initiation. Treatment was well tolerated, with the most common adverse events being somnolence (9.7%), nausea (6.3%), dizziness (5.0%), and rash (4.3%). Carbamazepine extended-release capsules appear safe and efficacious for the treatment of bipolar disorders in children and adolescent patients.

Outcomes and Length of Treatment With Carbamazepine Extended-Release Capsules in Bipolar Disorder

This analysis was a retrospective chart review evaluating the relationship between outcomes and length of treatment with carbamazepine extended-release capsules (CBZ-ERC) (Shire, Wayne, PA, USA) in bipolar disorder. The medical records of adult patients (>or=18 years) meeting DSM-IV criteria for bipolar disorder who were treated with CBZ-ERC for 30 days or less, 31 to 180 days, and more than 180 days were reviewed in this study. There were significant differences in mean Clinical Global Impression-Improvement (CGI-I) scores at the best office visit among the three treatment groups. The mean CGI-I scores for the 31- to 180-day (2.3+/-1.1) and >180-day (1.8+/-1.0) groups were significantly lower than the mean score for the <or=30-day treatment group (p<0.0001), and the mean CGI-I score for the >180-day group was significantly lower than that of the 31- to 180-day group (p=0.0027). Significantly fewer patients in the 31- to 180-day (5.4%; p=0.0039) and >180-day groups reported nausea (4.8%; p=0.034) when compared to the <30 day group. The results of this study indicate that future controlled studies are warranted to further explore the safety and efficacy of CBZ-ERC as a long-term therapy for bipolar disorder.

A Retrospective Analysis of Changing From Alternative Agents to Carbamazepine Extended-Release Capsules in Bipolar Disorder

Patients with bipolar disorder do not respond to the same therapy in the same way. This potentially necessitates the trial of various treatment modalities in a patient until the illness can be successfully controlled. Medical histories from 187 patients were reviewed to obtain information on efficacy when patients were switched from their initial drug therapy-immediate-release (IR) or extended-release (ER) carbamazepine (CBZ) tablets, valproic acid, lamotrigine, lithium, olanzapine, and oxcarbazepine-to beaded CBZ extended-release capsules (CBZ-ERC) (Shire, Wayne, PA, USA). Clinical Global Impression-Severity and Clinical Global Impression-Improvement scores were used to assess severity of illness, and response and relapse rates, respectively. The overall response rate was 79.7%. The greatest percentage of responders to CBZ-ERC treatment was seen in patients originally on lithium (90.5%), followed by those initially treated with oxcarbazepine (84.8%), olanzapine (81.5%), lamotrigine (77.8%), valproic acid (75.4%), and IR or ER CBZ tablets (74.2%). The overall relapse rate was 38.2%. Patients on lithium had the highest relapse rate (52.6%), followed by those on olanzapine (50.0%), valproic acid (34.9%), IR or ER CBZ tablets (34.8%), oxcarbazepine (32.1%), and lamotrigine (28.6%). Adverse events were minimal, with nausea, dizziness, and somnolence being the most frequent. The encouraging treatment response and adverse event profile observed in this retrospective analysis suggest that CBZ-ERC is an efficacious agent for the treatment of patients with bipolar disorder switched from other psychotropic agents.

Safety and Efficacy of Carbamazepine Extended-Release Capsules in Patients With Bipolar Disorder: QD vs BID

Adherence to prescribed pharmacotherapy is an important factor in the success of a selected treatment regimen. Because the dosing frequency of a particular medication can affect adherence rates, this important aspect of treatment must be taken into account. This report presents results from a retrospective assessment of the charts of 23 patients who received once-daily (qd) carbamazepine extended-release capsules (CBZ-ERC) (Shire, Wayne, PA, USA) for the treatment of bipolar disorder. The assessment compared qd dosing of CBZ-ERC with twice-daily (bid) dosing by matching the charts of the 23 study subjects to those of 23 similar control patients who had been taking CBZ-ERC dosed bid. In this study, no significant difference was observed in Clinical Global Impression-Improvement (CGI-I) scores between the qd and bid groups. In addition, the percentage of responders (those whose CGI-I score were <or=3) was the same (83%) for both groups. Relapse rates and measures of safety and tolerability were also similar in the two treatment groups. These findings suggest that CBZ-ERC dosed qd is comparable in efficacy, safety, and tolerability to CBZ-ERC dosed bid for patients with bipolar disorder.

Carbamazepine Extended-Release Capsules in the Treatment of Bipolar Disorder

Carbamazepine Extended-Release Capsules in the Treatment of Bipolar Disorder

Predictors of Response to Carbamazepine Extended-Release Capsules Treatment in Bipolar Disorder

Predictors of response to psychoactive drugs are valuable in providing practical guidance and in optimizing a treatment regimen. Here we used linear regression analysis to identify treatment-specific predictors of response to therapy with beaded extended-release carbamazepine capsules (CBZ-ERC) (Shire, Wayne, PA, USA) in 600 outpatients with bipolar disorder. Data were obtained from medical charts of subjects who received CBZ-ERC in a private practice setting. Illness severity and improvement were assessed using the Clinical Global Impression-Severity (CGI-S) and Clinical Global Impression-Improvement (CGI-I) scales. We found that increasing baseline CGI-S scores correlated with lower CGI-I scores (R2=0.01, p=0.009); that is, the higher the baseline CGI-S score, the greater the expected degree of improvement. There was also a correlation between increasing CBZ-ERC dose and improvement in CGI-I scores (R2=0.02; p=0.0004). Moreover, we found that increasing carbamazepine (CBZ) blood concentration correlated with decreases in CGI-I scores (R2=0.12; p=0.025), and that there was a correlation between higher total daily CBZ-ERC dose in mg/kg of body weight and decreases in CGI-I scores (R2=0.01; p=0.038). These findings suggest that bipolar patients with more severe baseline symptoms, on higher CBZ-ERC doses, and with higher CBZ blood levels were more likely to respond to CBZ-ERC treatment.

Extended-Release Carbamazepine Capsules as Monotherapy in Bipolar Disorder

Recently, two large, 3-week, randomised, double-blind, placebo-controlled trials using nearly identical protocols demonstrated that monotherapy with carbamazepine extended-release capsules (CBZ-ERC) was effective for the treatment of acute mania in patients with bipolar I disorder. By pooling data from these two trials, a more highly powered analysis of the efficacy and safety of CBZ-ERC in bipolar I disorder could be conducted. Efficacy was assessed with the Young Mania Rating Scale (YMRS), the Clinical Global Impression (CGI)-Severity (CGI-S) scale, the CGI-Improvement (CGI-I) scale and the Hamilton Depression Rating Scale (HDRS). A sub-analysis of the data based on manic versus mixed presentation was performed, as well as sub-analyses by age, sex and ethnicity. Of the 443 randomised patients in the pooled population, 240 completed the studies. Forty-two percent of CBZ-ERC-treated patients did not complete the studies, compared with 50% of placebo-treated patients (p=0.087). Ten percent of patients given CBZ-ERC withdrew because of lack of efficacy, compared with 22% of patients given placebo (p<0.001). At endpoint, CBZ-ERC compared with placebo was associated with significant improvements in mean YMRS total scores in patients experiencing both manic (p<0.0001) and mixed (p<0.01) episodes, using last-observation-carried-forward analyses. CGI-I and CGI-S scores also showed significant improvements from baseline for both manic and mixed patients at endpoint. In patients with mixed episodes, at endpoint there was a mean improvement in HDRS total score of 4.8 points with CBZ-ERC, compared with 2.3 points with placebo (p<0.05). Ninety percent of patients given CBZ-ERC experienced an adverse event, compared with 64% of those patients given placebo. Discontinuation because of adverse events occurred in 10.8% of patients taking CBZ-ERC, compared with 5.5% of patients taking placebo. These results confirm previous findings that CBZ-ERC is effective in the treatment of bipolar I disorder patients with either acute manic or mixed episodes. These data suggest that further randomised controlled studies are warranted to delineate the effect of CBZ-ERC on depressive symptoms in patients with bipolar disorder.

Clinical use of carbamazepine for bipolar disorders

Two recently completed large, randomised, double-blind, placebo-controlled trials supporting the efficacy of carbamazepine (CBZ) extended-release capsules (ERC) for the treatment of acute manic and mixed episodes have resulted in US FDA approval of CBZ-ERC, and have reinvigorated the importance of understanding the role of CBZ in bipolar disorder (BD) pharmacotherapy. Additional data suggest that CBZ may have a use in BD maintenance treatment and possibly in acute BD depression. Optimal use of CBZ requires sound knowledge of adverse effects and pharmacokinetic interactions with this agent. Adverse effects commonly involve benign side effects but can rarely include serious haematological, dermatological and hepatic manifestations. On the other hand, metabolic adverse effects (thyroid, glucose, lipid disturbances and significant weight gain) can be less problematic with CBZ, compared with lithium, valproate and atypical antipsychotics. Pharmacokinetic considerations (cytochrome P450 3A3/4 metabolism, active epoxide metabolite and catabolic enzyme induction) can influence the clinical use of CBZ. Managing adverse effects and pharmacokinetic complexities is important for optimising pharmacotherapy with CBZ in patients with BD. This paper reviews the chemistry, pharmacodynamics and pharmacokinetics of CBZ, as well as reviews of the controlled trials of CBZ in acute bipolar mania, acute bipolar depression and bipolar maintenance treatment.

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.

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.

Carbamazepine extended-release capsules vs. oxcarbazepine: computer simulations of the effect of missed doses on drug plasma concentrations

ABSTRACTObjective: Plasma concentrations of antiepileptic drugs (AEDs) can vary and are not always an indication of clinical utility. However, adverse event occurrence can be correlated to fluctuations in plasma drug levels that occur with varying dosing regimens of the many AEDs. In this study, we present the results of computer simulations of plasma concentrations of the AEDs carbamazepine (CBZ) extended-release capsules (CBZ‐ERC) (Carbatrol) and oxcarbazepine (OXC).* Carbatrol is a registered trade name of Shire, Wayne, Pa, USAResearch design and methods: A one-compartment open model with first-order absorption and elimination was generated from the results of a previous study measuring plasma concentrations following one 400 mg fasting dose of CBZ‐ERC. This model was used to simulate plasma concentrations of CBZ following multiple 400 mg doses of CBZ‐ERC at 12-hour intervals, and then when a missed dose is taken 3, 6, or 9 hours late; when two doses are taken at one time; and when a single dose is taken at the time of the next dosing. In comparison, similar modeling was done for monohydroxy derivative (MHD) of OXC at doses of 600 or 1200 mg.Results: Plasma drug concentrations after 24 hours without medication were 4.1 mg/L for CBZ‐ERC, 8 mg/L for 600 mg OXC, and 16 mg/L for 1200 mg OXC. If a patient was to take only a single dose 24 hours late, it would take 24 hours to reach steady-state trough values for CBZ‐ERC, 36 hours for 600 mg OXC, and 2 days for 1200 mg OXC. The trough plasma concentration following a missed dose and the peak plasma concentration following a double dose (administered 12 hours after the missing of a dose) differed by a factor of two in the CBZ‐ERC simulation, compared with a factor of three in both OXC simulations.Conclusions: The ultimate goal of antiepileptic therapy is a seizure-free state without side effects. The current computer simulation study indicates that AEDs such as CBZ‐ERC and OXC, which produce relatively stable plasma concentrations, should be useful in attaining this goal. Nonetheless, simulated plasma concentrations resulting from CBZ‐ERC treatment tended to oscillate less dramatically compared with simulated plasma concentrations resulting from treatment with 600 or 1200 mg OXC.

Carbamazepine extended-release capsules for the treatment of bipolar I disorder

An extended-release capsule formulation of carbamazepine (Equetro™; Shire, PA, USA) was approved by the US Food and Drug Administration in December 2004 for the treatment of acute manic and mixed episodes associated with bipolar I disorder. Extended-release capsule formulation of carbamazepine offers several advantages to immediate-release carbamazepine formulations such as decreased dosing frequency and lowered plasma carbamazepine fluctuations. These important considerations combine to enhance patient compliance and tolerability, which is essential for the success of any therapeutic treatment regimen. The efficacy, safety, and tolerability of the extended-release capsule formulation of carbamazepine was demonstrated in two randomized, double-blind, placebo-controlled trials and an open-label extension study in patients with bipolar I disorder experiencing either manic or mixed episodes. Although further study is required, the data garnered in these studies, along with the agent’s recent approval by the ...

Carbamazepine extended-release capsules for the treatment of bipolar I disorder

Carbamazepine extended-release capsules for the treatment of bipolar I disorder

Studies of Carbamazepine Extended-Release Capsules in Bipolar Disorder

This discussion reviews data from two 3-week, double-blind, placebo-controlled pivotal trials of carbamazepine extended release capsules (CBZ ERC; SPD417.301 and SPD417.304); pooled results from these trials; data from a 3-week, double-blind, placebo-controlled trial in lithium non-responders or non-tolerators (SPD417.302); and additional supportive data from a 6-month, open-label, extension trial (SPD417.303). In addition, information on a retrospective chart review of 600 adolescent and adult bipolar patients on CBZ ERC is presented.In the first large double-blind, placebo-controlled study assessing CBZ ERC in acute mania, manic and mixed bipolar patients from multiple centers were hospitalized and all medications were discontinued. After reaching a stable baseline 2–5 days later, the patients were randomized to CBZ ERC (n=101; 59% with mixed states) or placebo (n=103; 47% with mixed states) for 3 weeks. An aggressive initial titration schedule was implemented, beginning with 200 mg BID and increased by 200 mg/day until good clinical response was achieved or the patient could not tolerate the dosage. Many patients were taking 1,200–1,600 mg/day by the end of week 1. Efficacy was assessed using the Young Mania Rating Scale (YMRS). The Clinical Global Impressions (CGI) scale and the Hamilton Rating Scale for Depression (HAM-D) were also followed.

Reassessing Carbamazepine in the Treatment of Bipolar Disorder Clinical Implications of New Data

This monograph summarizes the proceedings of a roundtable meeting convened to discuss the role of carbamazepine in the treatment of bipolar disorder, in light of new data and the recent indication of carbamazepine extended-release capsules (CBZ ERC) for use in the treatment of acute manic and mixed episodes. Two lectures were presented, followed by a panel discussion among all 6 participants. A summary of the two pivotal trials of CBZ ERC and their pooled data along with other relevant data is presented first. Next, historical trends of carbamazepine and the agent's use in acute mania, bipolar depression, and maintenance are reviewed, emphasizing clinical implications of efficacy, safety, tolerability, and drug interactions. Finally, the panel discussion provides recommendations for the use of carbamazepine in different phases of the illness, taking into account adverse effects and drug-drug interactions. Panel discussants agree that current data confirm the utility of CBZ ERC as an effective treatment for acute manic and mixed episodes in bipolar disorder. Carbamazepine may also prove to be an option for maintenance treatment. Tolerability of the drug is related to dose and titration, and overall safety limitations regarding carbamazepine usage are comparable to other medications. For some patients, the main challenges to use of carbamazepine may be common drug-drug interactions and increased side effects related to aggressive introduction during treatment of acute manic and mixed episodes. Thus, carbamazepine may be a lower priority option for patients who are taking multiple medications, such as elderly individuals with medical comorbidity, due to the potential for drug interactions. Important benefits of carbamazepine include the low propensity toward weight gain and evidence of good tolerability with long-term treatment. (At present there are no available data from long-term, placebo-controlled studies evaluating the effects of carbamazepine or CBZ ERC on weight.) Thus, carbamazepine may be a good option for patients who are concerned about weight gain or who are intolerant of or respond poorly to other medications. Further efforts are needed to update physicians on the use of carbamazepine relative to other medications in the treatment of bipolar disorder.

Carbamazepine extended-release capsules [Equetro; Shire Pharmaceuticals Group] are now available in the US

Carbamazepine extended-release capsules [Equetro; Shire Pharmaceuticals Group] are now available in the US

Study of In‐Vitro Release Characteristics of Carbamazepine Extended Release Semisolid Matrix Filled Capsules Based on Gelucires

Various extended release carbamazepine (CBZ) formulations have been developed previously, in order to reduce the frequency of dosing in chronic therapy and to decrease the variability in drug plasma concentration. In the present study, the suitability of different grades of Gelucires (G, glyceride based excipients) to formulate CBZ extended release capsules by the application of semisolid matrix (SSM) filling capsule technology was investigated. The possible modification of CBZ release kinetics by using Gelucire blends or inclusion of hydrophilic additives in the SSM was studied. The effect of ageing on some selected formulations was also evaluated, using scanning electron microscopy and differential thermal analysis. Twenty‐one capsule formulations were prepared and assessed for their release characteristics. The mechanism of drug release from the test formulations was studied. The following results were obtained: a) Release data could not be correlated to the melting point (mp) of Gelucires used, pointing to relative lipophilicity of the base as a more important determinant of drug release. Among Gelucire grades having melting points higher than 37°C, the release rate proved to be highly dependent on the HLB value and matrix composition. b) CBZ release occurred by different mechanisms, including matrix disintegration, diffusion and or erosion depending on the vehicle employed. c) Zero order release profiles of CBZ were obtained from SSM‐based on G50/13, G53/10 and their blends in ratios higher than 1:1 and G53/10 containing croscarmellose sodium. d) The ageing study revealed that these latter formulations, except those based on G50/13, also showed high dissolution stability during one year of shelf ageing. e) PVP, as a polymorphic transformation inhibitor, can be used to reduce the storage‐induced changes of some grades of Gelucires. From the above data, it can be concluded that different grades of Gelucires and their blends as well as hydrophilic additives could be successfully used to formulate CBZ extended release SSM filled capsules with various release kinetics.The paper has been presented as a poster at the FIP‐World‐Congress, held at Nice, France, September, 2002.