Safety of 25- and 50-mg capsules in the initiation of zonisamide therapy in patients with epilepsy: an uncontrolled, open-label study

OBJECTIVE: This study was designed to assess the safety of 25- and 50-mg dosage strengths of zonisamide for initial titration in patients with epilepsy. Research design and methods: This phase 3, multicenter, open-label, uncontrolled study conducted at 26 study sites in the United States included male and female patients with epilepsy >or= 12 years of age. After a screening visit, subjects began zonisamide therapy at a dosage depending on their body weight. Zonisamide was titrated to 100 mg/day. MAIN OUTCOME MEASURES: At the study's conclusion, information regarding adverse events (AEs) and body weight was recorded. RESULTS: One hundred forty-three subjects enrolled and received at least one zonisamide dose. Of these subjects, 125 reached at least the 100-mg dosage before terminating the study. Eighty-two subjects (57.3%) experienced at least one AE. Most commonly reported AEs included headache, somnolence, asthenia, rhinitis, nausea, and rash. No significant change in patient body weight was noted during the study (95% confidence interval: -0.1, 0.6). CONCLUSIONS: Study limitations include the open-label design and the lack of direct comparison between lower (25- and 50-mg) and higher (100-mg) starting dosages. Despite these limitations, the 25- and 50-mg zonisamide dosage formulations were well tolerated in this study.     

Utilization of zonisamide inpatients with chronic pain orepilepsy refractory to othertreatments: a retrospective,open label,uncontrolled studyin a VA hospital

SUMMARY

Objectives: Zonisamide (1,2-benzisoxazole-3-methanesulfonamide) is a novel antiseizure medication approved for use in the United States as adjunct therapy in the treatment of partial seizures in adults with epilepsy. It has also been used to treat other conditions including intractable pain. The aim of this study was to determine the usefulness of zonisamide in patients whose seizures were not controlled after having been treated with at least three other currently available anticonvulsant medications or in patients whose pain control was suboptimal despite the use of commonly used drug regimens.

Methods: This was a retrospective study documenting the efficacy of zonisamide in 48 consecutive patients who presented at an outpatient neurology clinic at a Veterans Administration hospital. The patients were diagnosed with refractory partial seizures (n?=?21) or a variety of intractable neuropathic pain syndromes (n?=?27).

Results: Sixteen out of 21 seizure patients (76%) experienced a 50% or greater reduction in seizure frequency when zonisamide (100–200?mg daily) was added to their existing anticonvulsant medication regimen. Of 27 patients with neuropathic pain, 17 (59%) responded to zonisamide, reporting subjective reduction in pain by at least 50%. The most common adverse events were gastrointestinal upset, somnolence, and one case of skin rash.

Conclusions: In this study, zonisamide appeared to be an effective adjunct therapy in the treatment of partial seizures in adults who continued to experience frequent episodes while taking other anticonvulsant medications, and in adults whose neuropathic pain was not well controlled with analgesics. These promising results must be tempered by the fact that this investigation included a small patient population in an uncontrolled study design. Further research into the efficacy and tolerability of zonisamide in these areas is warranted.     

Safety and efficacy of rotigotine transdermal patch in patients with restless legs syndrome: a post-hoc analysis of patients taking 1 – 3 mg/24 h for up to 5 years

Objective: This post-hoc analysis of a prospective open-label study investigated patients with restless legs syndrome (RLS) taking approved dosages (1, 2 or 3 mg/24 h) of rotigotine transdermal patch for up to 5 years.

Research design and methods: Following 6 weeks' double-blind treatment, patients with moderate-to-severe RLS received open-label rotigotine titrated to optimal dosage.

Main outcome measures: Safety was assessed by adverse events (AEs) and efficacy was assessed by the International Restless Legs Syndrome Study Group Rating Scale (IRLS).

Results: Of 295 patients who entered the open-label study, 198 (67%) began the maintenance period taking rotigotine dosages of 1 – 3 mg/24 h, or increased their dosage from 0.5 mg in the first 3 months of the maintenance period. Of the 198 patients, 45 patients (23%) completed 5 years of follow-up within this dosage range, 79 patients (40%) had their dosage adjusted outside this range during follow-up and 74 patients (37%) withdrew (including 49 [25%] due to AEs and 6 [3%)] for lack of efficacy). Application site reactions were the most common AEs (102 of 198 patients [52%]), with an incidence of 35% (69 of 198) in year 1, 19% (19 of 102) in year 2, and 4 – 6% during each of years 3 – 5. Mean IRLS total score decreased from 27.1 ± 6.0 at double-blind baseline to 6.5 ± 6.5 at the beginning of maintenance, and to 7.4 ± 8.4 after 5 years' treatment on 1 – 3 mg/24 h (n = 45); 21 patients (47%) were classified as symptom-free (IRLS = 0).

Conclusions: Consistent with the results for the overall population, rotigotine transdermal patch at approved dosages of 1 – 3 mg/24 h was generally well tolerated after the first year, with sustained efficacy in patients who completed 5 years of treatment at dosages of 1 – 3 mg/24 h.     

Zonisamide and renal calculi in patients with epilepsy: how big an issue?

ABSTRACT

Objectives: To determine the prevalence of renal calculi in patients treated with zonisamide during randomized, controlled and open-label clinical trials, and from post-marketing surveillance data.

Methods: Reports of renal calculi from four placebo-controlled double-blind trials of zonisamide, their long-term open-label treatment extension phases, and the US/European zonisamide clinical trial programme were reviewed. One double-blind study and its extension included routine ultrasound screening to identify asymptomatic calculi. Post-marketing surveillance data were also investigated, as was concomitant treatment with topiramate.

Results: No symptomatic renal calculi were reported during four randomized double-blind, placebo-controlled trials involving 848 subjects (including 498 zonisamide recipients) treated for up to 3 months. In long-term extension studies with treatment for up to 24 months, symptomatic renal calculi were reported in 9/626 (1.4%) patients. Pooled safety data from all US/European clinical trials identified 15/1296 (1.2%) patients with symptomatic renal calculi during treatment for up to 8.7 years. Post-marketing surveillance revealed nine cases from 59?667 patient-years of exposure in the USA, and 14 from 709?294 patient-years of exposure in Japan; only one case occurred during concomitant topiramate and zonisamide treatment. No imbalance in electrolyte levels was found from 35 patients receiving such co-treatment in clinical trials.

Conclusions: The available data suggest that the risk of developing renal calculi during zonisamide treatment is low. Data are insufficient to determine whether concomitant treatment with topiramate increases the risk of renal stones.     

Once-daily sitagliptin,a dipeptidyl peptidase-4 inhibitor,for the treatment of patients with type 2 diabetes

ABSTRACT

Objective: Sitagliptin, an oral, potent, and selective dipeptidyl peptidase-4 (DPP?4) inhibitor was evaluated as once-daily monotherapy in a 12-week randomized, double-blind, placebo-controlled, parallel group, dose-ranging study. Additionally, the glycemic response to sitagliptin 100?mg daily was evaluated as a once-daily (100?mg once-daily) or twice-daily (50?mg twice-daily) dosing regimen.

Research design and methods: In a multinational, double-blind, randomized, placebo-controlled, parallel-group, dose-range finding study, 555 patients, 23–74 years of age, with HbA_1c of 6.5–10.0% were randomized to one of five treatment groups: placebo, sitagliptin 25, 50 or 100?mg once-daily, or sitagliptin 50?mg twice-daily for 12 weeks. The efficacy analysis was based on the all-patients-treated population using an ANCOVA model.

Results: Mean baseline HbA_1c ranged from 7.6 to 7.8% across treatment groups, with 29% of all patients with values ≤?7%. After 12 weeks, treatment with all doses of sitagliptin significantly (?p < 0.05) reduced HbA_1c by –0.39 to –0.56% and fasting plasma glucose by –11.0 to –17.2?mg/dLrelative to placebo, with the greatest reduction observed in the 100-mg once-daily group. Mean daily glucose was significantly (?p < 0.05) reduced by –14.0 to –22.6?mg/dL with all doses of sitagliptin relative to placebo. HOMA?β was significantly (?p < 0.05) increased by 11.3–15.2 with all sitagliptin doses relative to placebo. QUICKI and HOMA?IR were not significantly changed with sitagliptin treatment. There were no significant differences observed between the sitagliptin 100?mg once-daily and 50?mg twice-daily groups for any parameter. For sitagliptin, the incidence of adverse events of hypoglycemia was low, with one event in each of the 25- and 50-mg once-daily and 50-mg twice-daily treatment groups and two events in the 100?mg once-daily treatment group. There was no mean change in body weight with sitagliptin relative to placebo. Study duration may be a limitation because the extent of the glycemic response and the safety and tolerability may not have been fully elucidated in this 12-week study.

Conclusion: Sitagliptin monotherapy improved indices of glycemic control compared to placebo and was generally well-tolerated in patients with type 2 diabetes. The glycemic response to treatment with sitagliptin 100?mg/day was similar between the sitagliptin 100-mg once-daily and 50-mg twice-daily dose regimens.     

Long-term safety and tolerability of entecavir in patients with chronic hepatitis B in the rollover study ETV-901

Objective: To review long-term safety data from the rollover study ETV-901, focusing on adverse events (AEs) with a potential nucleos(t)ide association.

Methods: The open-label study ETV-901 (AI463901) assessed the safety of entecavir in chronic hepatitis B patients who received entecavir, lamivudine or adefovir monotherapy in previous entecavir Phase II/III studies. Long-term cumulative safety results are based on reported AEs, regardless of causal relationship.

Results: Median exposure to entecavir in study ETV-901 was 184 weeks. Commonly reported AEs (≥ 10%) were upper respiratory tract infection, headache and nasopharyngitis. Most AEs were mild to moderate; 203 (19%) patients reported grade 3 – 4 AEs, with 45 (4%) considered related to entecavir. There were 14 (1%) discontinuations due to AEs. On-treatment alanine aminotransferase (ALT) flares were reported in 32 (3%) patients and were associated with a reduction in hepatitis B virus DNA of more than 2 log₁₀ copies/ml in 25/32 patients. AEs potentially associated with nucleos(t)ide analogs were infrequent, the most common being myalgia (n = 54; 5%) and neuropathy-related AEs (hypoparesthesia and hyperparesthesia, polyneuropathy; n = 42; 4%).

Conclusions: Long-term administration of entecavir was associated with low rates of serious AEs, discontinuations due to AEs and ALT flares. AEs potentially associated with nucleos(t)ide use occurred at low rates.     

Pharmacokinetic comparison of an oral diclofenac potassium liquid-filled soft gelatin capsule with a diclofenac potassium tablet

Objective: To compare the pharmacokinetic profiles of diclofenac potassium liquid-filled soft gelatin capsules (DPSGC) using patented ProSorb^® dispersion technology with an immediate-release, diclofenac potassium 50-mg comparator tablet in two open-label, single-dose, randomized, crossover relative bioavailability studies in healthy volunteers. Methods: In Study 1, volunteers (n = 21) received DPSGC 50 mg or a diclofenac potassium 50-mg comparator tablet in two inpatient study periods. In Study 2 (n = 54), volunteers received DPSGC 25 mg, DPSGC 50 mg, or a diclofenac potassium 50-mg comparator immediate-release tablet in three inpatient study periods. Results: In both studies, DPSGC 50 mg displayed a significantly shorter T_max and higher C_max than the 50-mg diclofenac potassium comparator tablet. DPSGC 25 mg (Study 2) produced a shorter T_max (0.45 h) and an equivalent C_max (1125 ng/ml) to the 50-mg comparator drug. Plasma diclofenac concentration–time courses for the diclofenac potassium 50-mg comparator tablet showed many low, delayed, or multiple peaks compared with DPSGC treatments. Conclusions: DPSGC 25 mg and 50 mg were more rapidly and consistently absorbed than diclofenac potassium 50-mg comparator tablets. The C_max of DPSGC 25 mg was equivalent to the 50-mg diclofenac potassium comparator tablet. These characteristics may be beneficial when fast, consistent drug absorption is needed.     

Dose-Proportional Absorption of Etretinate After Doses of 25, 50, 75, and 100 mg

Twelve healthy male subjects received single oral doses of etretinate, ranging from 25 to 100 mg (1 to 4 × 25-mg capsules) in an open-label, four-way randomized crossover design. Plasma concentrations of etretinate and two active metabolites were determined by a specific high-performance liquid chromatographic (HPLC) method. Analysis of variance and orthogonal contrasts were used to assess dose proportionality. Mean (± %CV) maximum concentrations after 25- to 100-mg doses were 133 (50), 195 (33), 261 (53), and 446 (65) ng/ml, whereas AUC_0–12 values were 581 (46), 1090 (39), 1500 (52), and 2440 (63) ng · hr/ml, respectively. The test for proportionality indicated that C _max and AUC_0–12 increased proportionally with an increase in dose (P > 0.05).     

Saponin and non-saponin fractions of red ginseng ameliorate cisplatin-induced pica in rats

Abstract

Context: Nausea and vomiting are considered as the foremost unpleasant side effects of chemotherapy experienced by 20–90% of cancer patients.

Objective: In the present study, the effects of Korean Panax ginseng C.A. Meyer (Araliaceae) (RG), ginseng saponin (GS) and non-saponin (GNS) on cisplatin (CP)-induced pica and gastric damage in rats were investigated.

Material and methods: Rats were treated with RG (25, 50, 100?mg/kg b.wt.), GS (5 and 10?mg/kg 100?mg/kg b.wt.) and GNS (50 and 100?mg/kg b.wt.) before or after a single intraperitoneal injection of CP (6?mg/kg b.wt.). Kaolin together with normal food intake, normal food alone, body weight, histological examination of stomach and small intestine were used as indices of CP-induced pica in rats.

Results: Pre-treatment with RG (50 and 100?mg/kg b.wt.) attenuated CP-induced kaolin intake at 24?h. CP-induced kaolin intake decreased upon post-treatment of rats with RG (50 and 100?mg/kg b.wt.) at 48?h. The incidence of body weight reduction at 48 and 72?h diminished in rats post-treated with RG (50?mg/kg b.wt.). Pre-treatment with GS (5 and 10?mg/kg b.wt.) and GNS (50 and 100?mg/kg b.wt.) attenuated CP-induced kaolin intake while normal food intake was not improved in 24 and 48?h.

Discussion and conclusion: The gastro-protective effects of RG, GS and GNS were further confirmed by histopathological (damage in glandular portion and villi with dilated appearance) findings. The study indicates that both the red GS and GNS improve feeding behavior against CP-induced pica in rats.     

Zonisamide in the treatment of epilepsy

Introduction: Epilepsy affects approximately 3 million people in the USA and up to 2% of the worldwide population. The yearly direct medical cost of epilepsy in the USA alone is estimated to be $9.5 billion. Epilepsy affects both children and adults and can significantly impair quality of life. Zonisamide is a second-generation antiepileptic drug (AED) that has broad-spectrum efficacy, a favorable side-effect profile and simpler dosing than earlier drugs.

Areas covered: The history of the development of zonisamide is reviewed in this paper. The data available demonstrating zonisamide's mechanism of action as a voltage-gated sodium channel inhibitor, a T-type calcium channel inhibitor, an enhancer of GABA release and an inhibitor of glutamate release are also reviewed. Four key Phase III clinical trials are reviewed in detail, as are subsequent postmarketing trials that have expanded the therapeutic indication for zonisamide.

Expert opinion: From the available clinical data, zonisamide is a viable first-line and adjunctive therapeutic for partial-onset epilepsy and should be considered as an adjunctive therapeutic for a wide-range of generalized epilepsies.     

An open-label study of a second course of hylan G-F 20 for the treatment of pain associated with knee osteoarthritis

SUMMARY

Objective: To evaluate the efficacy and tolerability of a second course of hylan G-F 20 for the treatment of osteoarthritic knee pain in patients who experienced a clinical benefit with an initial course of therapy.

Research design and methods: In this prospective, open-label study, men or women (≥40 years of age) with knee osteoarthritis (OA) received three weekly injections of hylan G-F 20. Consecutive patients who requested a second course of hylan G-F 20 therapy due to OA knee pain subsequent to pain relief with a first course of therapy were enrolled between October 26, 2000 and January 18, 2001.

Main outcome measures: Pain while walking on a flat surface (Western Ontario and McMaster's Universities Osteoarthritis Index, WOMAC, question A1), WOMAC domain C (physical functioning), full WOMAC, and patient and investigator overall visual analog scales (VAS). Efficacy variables were measured at baseline and at weeks 1,2,4,8,12 and 26. An analgesic washout was required before all efficacy evaluations.

Results: Patients receiving at least one injection of hylan G-F 20 (n?=?71) were predominantly Caucasian (84.5%) and female (64.8%), with a mean age of 65.5 years and mean weight of 200.1 pounds. The mean time between the first and second courses of hylan G-F 20 was 19.6 months (median 17.6 months). With hylan G-F 20, pain while walking on a flat surface was significantly lower (p?<?0.001) than baseline at all time points up to week 26 (mean?±?SEM: ?1.40?±?0.10 at week 26). Actual scores decreased from 2.4?±?0.10 at baseline to 0.97?±?0.11 at week 26. Scores for the WOMAC domain C, full WOMAC and patient and investigator overall VAS also significantly improved (p?<?0.001) at all time points. A second course of hylan G-F 20 was generally well-tolerated, based on the low incidence of local adverse events (AEs) -only one patient (1.4%) experienced a severe event, the types of AEs, and the fact that no patients discontinued the study due to these AEs. The types of related AEs observed were not qualitatively different from those listed in the current product information and published literature.

Conclusion: A second course of hylan G-F 20 therapy is an appropriate therapy for the treatment of OA knee pain in patients who had a previous favorable clinical response. For continued relief of osteoarthritis knee pain, this study supports repeat use of hylan G-F 20 in these patients.     

Repetitive dihydroergotamine nasal spray for treatment of refractory headaches:an open-label pilot study

ABSTRACT

Objective: To evaluate the safety and efficacy of a repetitive intranasal (IN) dihydroergotamine (DHE) burst protocol for treatment of refractory headaches.

Research design and methods: Patients with refractory headaches were enrolled in a prospective, open-label, pilot study. Patients were instructed to self-administer IN DHE every 8 hours for 3 days; each IN DHE dose consisted of one 0.5-mg spray in each nostril that was repeated 15 minutes later, for a total of 2.0?mg DHE per dose. Follow-up visits were scheduled approximately 3 weeks later.

Main outcome measures: Efficacy and safety measurements were collected during patient interviews. Primary efficacy measures were the change in headache frequency, duration, and severity (rated from 0 [none] to 5 [extremely severe]) between the initial and follow-up visits. Safety was assessed at the follow-up visits through the occurrence of adverse events (AEs).

Results: Twenty-six patients were enrolled in the study. Follow-up visits were completed by 24 patients whose mean headache frequency at study entry was 6.6 d/wk. The IN DHE burst protocol was associated with significant mean decreases in headache frequency (2.6 d/wk, p < 0.001), duration (5.8 hours, p = 0.03), and severity (1.2 units, p < 0.001) between study entry and the follow-up visit. One patient discontinued IN DHE use early because of an AE (nasal stuffiness); two additional patients each reported one AE (fatigue and increased headache) that was attributed to IN DHE.

Conclusions: The results of this pilot study suggest that the IN DHE burst protocol may be an effective and safe treatment for refractory headaches; interpretation of these results is limited by the open-label, uncontrolled design and the small number of patients. The development of a doubleblind, placebo-controlled study to further evaluate this treatment regimen is warranted.     

New levothyroxine formulation meeting 95–105% specification over the whole shelf-life: results from two pharmacokinetic trials

Objective: Small levothyroxine (L-T4) dose changes can lead to significant clinical effects. To ensure thyroid hormone levels are safely maintained, authorities are increasingly adopting stricter potency specifications for L-T4, the most stringent of these being 95–105% of the labeled dose over the whole shelf-life. Levothyroxine sodium (Euthyrox, Eutirox, Lévothyrox) has been reformulated, and two studies performed, to ensure bioequivalence to the currently marketed formulation and dosage form proportionality of the new formulation.

Methods: The bioequivalence study was an open-label, randomized, single-dose, two-period, two-sequence crossover comparing the highest dosage strengths of the currently marketed and the new L-T4 formulation at a total dose of 600?μg. The dosage form proportionality study was an open-label, randomized, three-period, six-sequence crossover, comparing 50?μg, 100?μg, and 200?μg L-T4 tablets, at a total dose of 600?μg. Blood samples were taken at predefined time intervals. Primary outcomes were area under the curve (AUC) and maximum concentration (C_max) of thyroxine (T4) in plasma.

Results: In the bioequivalence study, comparing the T4 profiles for the new and current formulation of L-T4, the geometric least square mean ratio of the baseline-adjusted AUC_0–72,adj was 99.3% (90% confidence interval [CI]: 95.6–103.2) and the C_max,adj was 101.7% (90% CI: 98.8–104.6). Bioequivalence was established if the 90% CI lay within the predefined 0.9–1.11 limits. In the dosage form proportionality study, pairwise comparisons ranged from 99.3% to 104.8%, and all 95% CIs were within the predefined CI range (0.8–1.25): the three dose strengths were dosage form proportional.

Conclusions: The new formulation of L-T4 meets the most stringent potency specification guidelines, and has been demonstrated to be bioequivalent to the current formulation and to show dosage form proportionality. The new formulation will enable patients to receive a dose fine tuned to their medical needs, contributing to improved safety in the use of L-T4.     

Sedative and anticonvulsant activities of styrax after oral and intranasal administration in mice

Context: Styrax, resin of Liquidambar orientalis Mill. (N.O. Hamamelaceae), belongs to resuscitation-inducing aromatic herbs in traditional Chinese medicine and functions in inducing resuscitation and restoring conscientiousness.

Objective: The possible sedative and anticonvulsant activities of styrax on CNS were investigated. The onsets of action of two different routes (oral and intranasal administration) were compared.

Materials and methods: Styrax was tested for sedative, hypnotic, and anticonvulsant effects using locomotor activity evaluation, pentobarbital-induced sleeping time, and pentylenetetrazol (PTZ)-induced convulsion, respectively.

Results: After oral administration (25, 50, 100?mg/kg), styrax prolonged the sodium pentobarbital-induced sleeping time. In comparison with oral administration, intranasal administration (12.5, 25, 50?mg/kg) prolonged the sleeping time at lower dosage. Moreover, styrax (100 and 200?mg/kg) promoted a significant protection against PTZ-induced seizures and mortality 30?min after oral administration. In contrast, 5?min after intranasal administration, styrax promoted significant protection at lower dosages (25 and 50?mg/kg). These data show that styrax had faster onset of action (5 vs. 30?min) and better anticonvulsant efficacy (25, 50 vs. 100, 200?mg/kg) by intranasal route in comparison with that by intragastric route. Styrax decreased the spontaneous locomotor movements at 100?mg/kg during 5–60?min interval after oral administration.

Discussion and conclusion: Styrax has sedative and anticonvulsant activities. Furthermore, styrax has faster onset of action as well as more potent efficacy after intranasal administration at lower dosage than by intragastric route. This result illustrates that intranasal administration may act as a promising alternative to conventional routes of administration.     

Assessing treatment satisfaction in patients treated with pramlintide as an adjunct to insulin therapy

ABSTRACT

Objective: This study was designed to assess treatment satisfaction in patients using pramlintide who had not previously achieved glycemic targets with insulin therapy alone. Assessment included the association between treatment satisfaction and clinical outcomes (changes in post-prandial glucose [PPG], glycosylated hemoglobin [HbA_1c], weight, and insulin requirements).

Research design and methods: In this open-label study 240 participants with type 1 diabetes and 160 participants with type 2 diabetes added pramlintide to their established insulin regimen. Mealtime insulin doses were subsequently adjusted to optimize glycemic control.

Main outcome measures: Seven-point glucose profiles, weight, and insulin requirements were obtained at baseline and months 1, 3, and 6; HbA_1c levels were obtained at baseline and months 3 and 6. Participants completed a treatment satisfaction questionnaire (TSQ) at months 1, 3, and 6.

Results: Participants rated the study treatment regimen including pramlintide significantly (?p < 0.001) superior to their pre-study regimens in terms of ‘glucose control’, ‘eating-weight control’, and ‘general benefits’ at all three TSQ administrations. Regression analysis of treatment satisfaction at 6 months revealed several independent predictors (?p < 0.05). Participants who were able to reach the maximum dosage of pramlintide per protocol, and those who experienced more reduction in PPG and insulin requirements during the study, reported higher satisfaction with glucose control and general benefits; those who lost more weight reported higher treatment satisfaction on all three TSQ measurements.

Conclusions: Greater satisfaction with the study regimen was reported on all treatment satisfaction factors at all three TSQ administrations, with all advantages representing large treatment effects. Treatment satisfaction was higher for patients who experienced better clinical outcomes (decreases in weight, insulin dose requirements, and PPG levels). Study limitations include the fact this was an open-label study.     

Clinical safety of tocilizumab in rheumatoid arthritis

Importance of the field: Tocilizumab is a new biologic disease-modifying antirheumatic drug directed against the activity of IL-6, a key pro-inflammatory cytokine in the pathogenesis of rheumatoid arthritis (RA). This drug has proved highly effective in RA patients, including those who had previously not responded to anti-TNFs. As side effects are a major cause for discontinuing biologic therapy, the present article focuses on the tolerability profile of tocilizumab.

Areas covered in this review: This review describes the adverse events (AEs) reported in RA patients treated with tocilizumab. Most data are derived from controlled clinical trials and their open-label extensions.

What the reader will gain: The reader will gain a comprehensive review of treatment-emergent AEs associated with tocilizumab therapy. These AEs include infections, including opportunistic infections, infusion and hyper-sensitivity reactions, gastrointestinal perforation, and laboratory test abnormalities, especially hepatic transaminase elevations, altered lipid profile and neutropenia.

Take home message: Based on current data, tocilizumab appears to have an acceptable safety profile inasmuch as most AEs were manageable or controllable. However, results from large scale pharmacoepidemiological investigations and appropriate post-marketing surveillance are awaited to identify the full spectrum of AEs and define the true benefit:risk ratio of tocilizumab.     

Lack of pharmacokinetic interactions between steady-state zonisamide and valproic acid in patients with epilepsy

OBJECTIVES: This study evaluated the effect of the addition of zonisamide on valproic acid (valproate sodium) pharmacokinetics under steady-state conditions in patients with epilepsy. A second aim was to characterise zonisamide pharmacokinetics in the presence of valproic acid. METHODS: Twenty-two patients (males and females, 18-55 years of age) with their seizure disorder stabilised on valproic acid monotherapy were included in a two-centre, open-label, one-way drug-interaction trial. The zonisamide dose was gradually increased from 100 mg/day to 400 mg/day. Three pharmacokinetic profiles were obtained: on days -7 and -1, to assess pharmacokinetic parameters of oral valproic acid administered alone, and on day 35, after 14 days of zonisamide treatment at the maximal tolerated dose, to evaluate the effect of zonisamide on valproic acid pharmacokinetics and to characterise zonisamide pharmacokinetics in the presence of valproic acid. RESULTS: Seventeen patients completed the study, with 16 patients contributing to the pharmacokinetic analyses. Coadministration of zonisamide and valproic acid appeared reasonably well tolerated. Steady-state dosing of zonisamide (200mg twice daily) had no statistically significant effect on the mean (+/- SD) maximum observed plasma concentration (C(max)) [70.8 +/- 20.5 vs 69.2 +/- 27.0 microg/mL], area under the plasma concentration-time curve from the time of dosing to 12 hours post-dose (AUC(12)) [689.3 +/- 250.4 vs 661.8 +/- 251.3 microg . h/mL] or other evaluated pharmacokinetic parameters for valproic acid measured before and after zonisamide administration. Furthermore, 90% confidence intervals for the ratio of the geometric means (day 35/day -1) of valproic acid pharmacokinetic exposure measures fell only slightly outside the 'no effect' range of 0.80-1.25. In the presence of valproic acid, mean zonisamide oral clearance (1.23 L/h) and elimination half-life (52.5 hours) are generally consistent with values reported for healthy volunteers receiving zonisamide monotherapy. CONCLUSION: There is no apparent clinically significant effect of steady-state dosing of zonisamide on valproic acid pharmacokinetics, and valproic acid did not appear to affect the pharmacokinetics of zonisamide, indicating that no dosage adjustment of either drug should be required when they are used in combination in patients with epilepsy.     

Albiglutide,a weekly GLP-1 receptor agonist,improves glycemic parameters in Japanese patients with type 2 diabetes over 1 year when added to single oral antidiabetic drugs

Objective: To evaluate the safety and efficacy of once weekly albiglutide added to a single oral antidiabetic drug (OAD) in Japanese patients with inadequately controlled type 2 diabetes mellitus (T2DM).

Research design and methods: In this phase 3, 1 year study (NCT01777282), patients (N?=?374) received albiglutide 30?mg plus a single OAD (sulfonylurea [n?=?120], biguanide [n?=?67)], glinide [n?=?65], thiazolidinedione [n?=?61], or α-glucosidase inhibitor [n?=?61]). Albiglutide could be increased to 50?mg after Week 4, based on glycemic criteria. Primary endpoints were the incidence of adverse events (AEs) and hypoglycemia; secondary endpoints were changes from baseline at Week 52 in HbA_1c and fasting plasma glucose (FPG), proportion of patients achieving HbA_1c ≤7.0%, and withdrawals due to hyperglycemia.

Results: On-therapy AEs occurred in 78.6% of patients and serious AEs in 2.1%. Common AEs were nasopharyngitis (32.6%), constipation (7.2%), and diabetic retinopathy (5.3%). No serious AEs occurred more than once or were reported in >1 patient. Hypoglycemia occurred in 6.4% of patients, mostly in the albiglutide?+?sulfonylurea (14.2%) and the albiglutide?+?glinide (6.2%) groups. Albiglutide was uptitrated in 53.2% of patients. Mean baseline HbA_1c was 8.1%. Mean decreases from baseline in HbA_1c were observed with the addition of albiglutide to thiazolidinediones (?1.42%), α-glucosidase inhibitors (?1.39%), sulfonylureas (?1.04%), glinides (?0.95%), and biguanides (?0.94%). HbA_1c of <7% in >50% of patients and mean reductions in FPG were achieved in all groups. Mean changes from baseline in body weight ranged from +0.52?kg (albiglutide?+?thiazolidinedione) to ?0.33?kg (albiglutide?+?biguanide). Limitations of the study included open label treatment that was not randomized.

Conclusions: When combined with a single OAD in Japanese patients with inadequately controlled T2DM, albiglutide led to favorable changes in all glycemic parameters, with minor changes in body weight depending on the background OAD. No new safety concerns were noted.     

Bioavailability of microsize and ultramicrosize griseofulvin products in man

The relative bioavailability of ten marketed dosage forms of griseofulvin was evaluated in two separate crossover studies. Each study utilized 12 healthy subjects, with eight of the subjects being common to both studies. Plasma griseofulvin concentrations were determined 1, 2, 3, 4, 6, 8, 10, 25, 34, 49, and 73 hr after dosing, using a high-pressure liquid chromatographic method. The high-dose study compared four microsize dosage forms administered as 500-mg doses and two ultramicrosize formulations given as 250-mg doses. The low-dose study employed four 250-mg microsize products and two 125-mg ultramicrosize products. The individual plasma level-time profiles for the majority of doses suggested prolonged absorption of microsize griseofulvin. The ultramicrosize dosage forms exhibited peak concentrations which were not significantly different (p>0.05) from those of the microsize products administered as twice the dose. In the high-dose study, the two 250-mg ultramicrosize dosage forms exhibited areas under the plasma level-time curve (AUC) which were significantly (p<0.05) less than the AUCs for all but one of the 500-mg microsize products. In the low-dose study the AUCs for the ultramicrosize products were significantly lower than the AUCs for all of the microsize dosage forms. Significant differences were also noted among the AUCs for the microsize products, although the maximum difference was less than 20% in both studies. A comparison of the AUCs observed in the high- and low-dose studies revealed that the AUCs for two of the 500-mg microsize dosage forms were only approximately 75% the AUC predicted from the 250-mg dose for the eight subjects common to both studies. All other formulations exhibited a dose proportionality for AUC.This work was supported in part by a contract from the Tennessee Department of Public Health and FDA Contract No. 223-77-3011.     

Tolerability and safety of topiramate in Chinese patients with epilepsy : an open-label, long-term, prospective study

OBJECTIVES: This study focused on (i) evaluating the long-term tolerability and safety of topiramate in Chinese patients with epilepsy, and (ii) comparing the tolerability and safety of topiramate monotherapy versus polytherapy in the same population. METHODS: This was a prospective, open-label, long-term (36 months) clinical trial. 320 patients (275 adults and 45 children) with epilepsy were recruited into the study; of these, 156 patients had generalised seizures, 151 patients had partial seizures and 13 patients had unclassifiable seizures. All patients received topiramate approximately 200 mg/day either as monotherapy or as adjunctive therapy. At each visit, a physical examination and routine laboratory analysis were performed, and the adverse event (AE) profile was obtained by face-to-face interview. RESULTS: 268 patients received topiramate 相似文献