Dabigatran etexilate for venous thromboembolism: a safety evaluation

Introduction: Recently, new oral anticoagulants (NOACs) have become available to treat thromboembolic disorders. The efficacy and safety of these agents have been thoroughly tested in various clinical trials. In this article, we discuss the evidence for the safety and efficacy of dabigatran in the prevention and treatment of venous thromboembolism (VTE).

Areas covered: We discuss the pharmacology of dabigatran and compare it to that of warfarin and two of the other popular NOACs, rivaroxaban and apixaban. The indications for and evidence behind dabigatran in the prevention of VTE are presented, as well as the trials examining its potential use for the treatment and extended treatment of VTE. We conclude by considering the safety aspects of the drug.

Expert opinion: For most patients the overall net clinical benefit would seem to be in favour of dabigatran. Both efficacy and safety have been proven in the setting of robust randomised controlled trials. ‘Real world’ registry data as well as long-term trial follow-up will add further critical information. Long-term experience might be one of the few advantages warfarin still has over dabigatran in patients who are eligible for both.     

Tolterodine for the treatment of urge urinary incontinence

Introduction: Overactive bladder (OAB) and its resultant urge urinary incontinence (UUI) are significant problems that medically, psychologically and financially affect people. The constellation of symptoms comprising OAB affects ～ 16% of the adult population and its prevalence increases with aging. The typical class of medications used to treat OAB is antimuscarinics.

Areas covered: OAB medications, with a focus on tolterodine for the treatment of UUI are reviewed. A thorough review of English language literature using EMBASE/Medline and PubMed has been performed.

Expert opinion: Tolterodine provides a reasonable starting point when treating patients with OAB and UUI. Efficacy and tolerability are generally comparable between tolterodine and other newer antimuscarinics. Tolterodine is a good option as part of the algorithm in the treatment of OAB and UUI.     

Safety and tolerability of extended-release niacin with laropiprant

Introduction: Niacin is one of the oldest drugs used in the treatment of dyslipidemia. Previously its use has been limited because of excessive flushing. Now an agent laropiprant (LRP) has been developed, which blocks the flushing pathway. Therefore, it is time to collate available information to assess the safety and tolerability of combining niacin with LRP.

Areas covered: The authors searched PubMed and MEDLINE for literature published between January 2006 and July 2011, for safety and tolerability reports of extended-release niacin (ERN) with LRP.

Expert opinion: The addition of LRP to ERN, by reducing the side effect ‘flushing’, may enable lipidologists and physicians to use niacin more widely as part of lipid modification therapy, especially since the combination can be safely added to statins. However, it has to be accepted that the addition of LRP does not completely abolish flushing. The favorable safety profile supports the use of LRP to achieve higher therapeutic dosing of niacin.     

Quetiapine for the treatment of acute bipolar mania,mixed episodes and maintenance therapy

Introduction: Bipolar disorder is characterized by mood instability, which can be challenging to manage. First-line pharmacological approaches usually involve lithium, anticonvulsants and antipsychotics. Over the past fifteen years, several second-generation antipsychotics have demonstrated benefits for various phases of this disorder.

Areas covered: This article examines the pharmacodynamics and pharmacokinetics of quetiapine; its evidence base as an acute and maintenance monotherapy or adjunctive therapy for bipolar manic or mixed episodes is also discussed, along with the related issues of its safety and tolerability.

Expert opinion: In the context of bipolar disorder, quetiapine is the only agent approved as a monotherapy or adjunct therapy for acute manic/mixed episodes in adults and adolescents; as a monotherapy for acute depressive episodes in adults; and as an adjunctive maintenance therapy for bipolar I and II disorder in adults. In addition to its antipsychotic properties, this broad mood-stabilizing potential may simplify the management of select patients.     

Dimethyl fumarate: a Janus-faced substance?

Introduction: Dimethyl fumarate (DMF) has been used as fungicide, but oral DMF activates anti-inflammatory and anti-oxidative pathways that are beneficial in the treatment of psoriasis. BG-12, a specific formulation of DMF, has been approved very recently for the treatment of relapsing-remitting multiple sclerosis (RRMS), which is characterized by both autoimmune lymphocytes leading to inflammation and mitochondrial alterations associated with oxidative stress.

Areas covered: This review describes the pharmacokinetics and the mode of action of DMF, with a focus on molecular and cellular pathways, and discusses clinical results of DMF in RRMS treatment. To identify relevant publications, the author searched the PubMed database by using appropriate keywords and by searching for references cited within the obtained articles.

Expert opinion: DMF demonstrated efficacy in several RRMS outcome measures related to disease activity and severity, but results on disability progression have been inconsistent. The overall safety profile might qualify DMF for long-term use, the frequency of side effects such as gastrointestinal complaints and flushing might hamper treatment adherence of MS patients. Since DMF covalently binds to intracellular proteins, the fate of this molecule in the body might need thorough long-term observation during clinical use.     

Peginesatide for the treatment of renal disease-induced anemia

Introduction: Erythropoiesis-stimulating agents (ESAs) are the mainstay of treatment in anemic chronic kidney disease (CKD) patients. A tailored ESA therapy should combine maximal efficacy and safety with greatest convenience in dosing. Peginesatide, recently approved in the US for once-monthly dosing in adult patients on dialysis, is a promising novel PEGylated erythropoietin-mimetic peptide for the treatment of renal disease-induced anemia.

Areas covered: Published animal and human studies that evaluated the pharmacodynamics, pharmacokinetics, clinical efficacy and safety of peginesatide were critically analyzed.

Expert opinion: Peginesatide has a well-studied pharmacological and immunological profile, and latest published data favor the use of peginesatide in place of epoetin in dialysis patients. A more detailed evaluation of its safety profile particularly in trials with CKD patients not requiring dialysis is urgently needed, as peginesatide could be a perfect treatment solution for these patients. In addition, clinical long-term data and results from supplemental studies, e.g., with the PEGylated continuous erythropoietin receptor activator as comparator, should briefly follow. The fate of peginesatide on the highly competitive ESA market is currently not predictable and depends on safety and efficacy results of upcoming trials as well as finally on market and price policy.     

A drug safety evaluation of everolimus in kidney transplantation

Introduction: Calcineurin inhibitors (CNI) have greatly reduced the rate of acute rejection and improved short-term graft survival after organ transplantation, however, long-term survival has hardly changed since their introduction. CNIs are believed to contribute to graft fibrosis, have side effects that adversely affect cardiovascular risk, and are associated with an increased rate of post-transplant malignancies. Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, is not associated with graft fibrosis, has a superior cardiovascular risk profile to CNI therapy and has shown potential for the prevention and treatment of diverse forms of cancer.

Areas covered: This review summarizes key aspects of everolimus, including its mechanism of action, pharmacokinetics, pharmacodynamics, drug–drug interactions and pivotal clinical studies with a focus on safety and efficacy.

Expert opinion: Everolimus is effective in improving graft function in selected kidney transplant patients. Most adverse events are present for a short time after the introduction of everolimus, and are manageable. Everolimus has the potential to become an important agent in de novo and maintenance immunotherapy in kidney transplant recipients.     

Asenapine review,part II: clinical efficacy,safety and tolerability

Introduction: Asenapine is a second-generation (atypical) antipsychotic currently marketed for the treatment of schizophrenia and bipolar mania/mixed episodes.

Areas covered: The purpose of this review is to describe the clinical profile of asenapine.

Expert opinion: Asenapine's efficacy in the treatment of schizophrenia and in the acute management of bipolar manic or mixed episodes, within the recommended therapeutic dose range of 5 – 10 mg twice a day, is evidenced by a broad clinical development program. Asenapine's overall tolerability profile is notable for the potential for sedation (time-limited) and, to a lesser extent, extrapyramidal symptoms/akathisia, dizziness, and oral hypoesthesia. Asenapine's effects on weight and metabolic variables appear modest, as are its effects on the ECG QTc interval and on prolactin.     

Lenalidomide as a novel treatment of acute myeloid leukemia

Introduction: Lenalidomide is an oral immunomodulatory drug derived from thalidomide. This drug has been approved by the Food and Drug Administration for transfusion-dependent anemia due to low-risk myelodysplastic syndromes (MDS) associated with deletion 5q abnormality with or without additional cytogenetic abnormalities and multiple myeloma in combination with dexamethasone. Trials have been conducted for its use in higher-risk MDS and acute myeloid leukemia (AML).

Areas covered: The pharmacokinetic and mechanism of action are discussed and clinical studies of lenalidomide in AML are reported herein in detail. An overview of safety and tolerability is also presented.

Expert opinion: Lenalidomide has clinical activity in AML with manageable toxicity. The population that would benefit from lenalidomide and optimal dose needs to be better defined. Recent trials have focused on combining lenalidomide with other agents active in MDS and AML and promising data are emerging.     

Overview and safety of fingolimod hydrochloride use in patients with multiple sclerosis

Introduction: Fingolimod (Gilenya®, FTY720) is an oral sphingosine-1-phosphate analogue that was approved by the FDA in 2010 for the treatment of relapsing forms of multiple sclerosis (MS). Fingolimod’s mechanism of action is primarily related to lymphocyte sequestration in primary and secondary lymphoid tissues. Phase III trials demonstrated a reduction in annualized relapse rate and MRI progression in fingolimod-treated subjects compared with both placebo and IFN-β-treated subjects. Frequent adverse effects include fatigue, gastrointestinal disturbance, headache and upper respiratory tract infection. More serious, but rare, adverse events associated with fingolimod include atrioventricular block, symptomatic bradycardia, herpetic viral infections and macular edema.

Areas covered: We discuss the mechanism of action, pharmacokinetics, clinical efficacy and safety profile of fingolimod in patients with relapsing MS.

Expert opinion: Fingolimod is an effective treatment for relapsing MS and its oral route of administration may be preferred by some. Fingolimod is generally well tolerated but requires diligence in patient selection and monitoring. Additional information is needed regarding risk of infection, malignancy and rebound disease with long-term use of fingolimod.     

Pregabalin for the treatment of social anxiety disorder

Introduction: Social anxiety disorder (SAD) is one of the most common psychiatric disorders, causing a reduction of in the quality of life by impairing functioning in social situations. The lifetime prevalence of SAD is estimated to be 12%. Selective serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitors (SNRIs) are considered first-line drugs for SAD. However, new effective therapeutic options are still needed. Pregabalin is a novel anxiolytic, which seems to be a promising therapy for SAD.

Areas covered: This review presents the results of three randomized controlled trials (RCTs) comparing the efficacy and safety of pregabalin with placebo in patients with generalized SAD. The authors also discuss the long-term safety and tolerability data from an extension study.

Expert opinion: The results of the RCTs have demonstrated efficacy and safety with pregabalin at doses of 600 mg or 450 mg/d for treating generalized SAD. Thus, pregabalin may be an effective therapeutic option, especially for patients who cannot tolerate the adverse effects or who demonstrate a lack of efficacy with SSRIs or SNRIs. In addition to being an alternative therapy to SSRIs or SNRIs, it may also have value as an add-on therapy, either to augment pharmacotherapy or in addition to cognitive-behavioral therapy.     

Everolimus for the treatment of pancreatic neuroendocrine tumors

Introduction: Pancreatic neuroendocrine tumors (PNET) represent the second most common primary malignancy of the pancreas. Until recently, therapeutic options for advanced PNET have been limited.

Areas covered: A recently published Phase III clinical trial demonstrated striking therapeutic activity of the mTOR inhibitor everolimus in advanced PNET and led to its approval for this indication by the FDA. This review discusses this landmark discovery in the context of currently available therapeutic options, pathophysiology and molecular genetics of PNET.

Expert opinion: The approval of everolimus for the treatment of PNET marks a major step forward in the clinical management of this disease and represents a notable example of the successful translation of a targeted therapy that was initially developed based on findings at the lab bench, into everyday clinical practice. These results encourage hopes that the overall therapeutic efficacy of such approaches can be further enhanced by the introduction of combinatorial regimens, simultaneously targeting more than one oncogenic signaling pathway, as well as by stratification of patients based on the individual genetic setup of their tumors.     

Desvenlafaxine for the treatment of major depressive disorder

Introduction: Major depressive disorder (MDD) is a chronic and debilitating condition often characterized by inadequate treatment. Notwithstanding the availability of more than a dozen first-line agents across disparate classes (e.g., selective serotonin reuptake inhibitors), the majority of individuals with MDD do not achieve and sustain a recovered state. A substantial percentage of MDD patients require a treatment change due to poor efficacy or tolerability.

Areas covered: This review focuses on recent (≤ 5 years) literature describing the pharmacokinetics, efficacy, and tolerability of desvenlafaxine, one of the more recently approved antidepressant drugs. Published papers identified via PubMed search and congress presentations were included. Results from short-term, placebo-controlled, MDD trials and randomized withdrawal trials, as well as post hoc analyses in patient subgroups, are reviewed.

Expert opinion: Desvenlafaxine has been shown to be an effective antidepressant with a favorable safety and tolerability profile in the general MDD population and in important patient subgroups. It has several notable differences from other serotonin-norepinephrine reuptake inhibitors, and those differences suggest populations in which it may have the most clinical benefit.     

Macitentan for the treatment of pulmonary arterial hypertension

Introduction: Pulmonary arterial hypertension (PAH) is a serious disease characterized by elevation of pulmonary artery pressures and right ventricular failure. It is a progressive disease with a poor 5-year survival despite recent advances in treatment. Endothelin plays an important role in the development and progression of the disease. Endothelin receptor blockers have been used to treat PAH since 2001. More recently, macitentan was approved for treatment of PAH.

Area covered: This review covers the preclinical and clinical data on macitentan.

Expert opinion: Macitentan is a more potent ERA and has been shown to delay progression of the disease. It does not appear to have any significant hepatotoxicity and has a convenient once-a-day dosing. In the large event driven trial, macitentan significantly reduced morbidity in patients with PAH. It was safe and well tolerated and the benefit was seen in treatment-naïve patients and those already receiving PAH therapy.     

Long-term safety of ustekinumab for psoriasis

Introduction: The biologic, Ustekinumab (Stelara®, Centocor, Inc., Malvern, PA, USA), is a fully human monoclonal antibody with a high affinity for the shared p40 subunit of interleukins 12 and 23 (IL-12 and IL-23). Approved for use in treating moderate-to-severe psoriasis in 2009, there has been considerable interest in the long-term safety of ustekinumab.

Areas covered: This review discusses the use of ustekinumab in the treatment of psoriasis and its potential to be an effective and well-tolerated therapy. A literature search was performed for articles published through April 2013 to identify any safety concerns.

Expert opinion: Our results indicate that ustekinumab has demonstrated higher efficacy rates as compared to traditional therapies; and with a favorable dosing schedule and stable safety profile, patients with recalcitrant disease will now have another option for treatment.     

Safety and tolerability of pazopanib in the treatment of renal cell carcinoma

Introduction: Renal cell carcinoma (RCC) is still a challenging disease. Over the last 6 years, the use of novel targeted therapies interfering with vascularization and inhibition of other downstream pathways has revolutionized the therapy of this disease, leading to an improvement of patient outcomes. In particular, dysregulation of the vascular endothelial growth factor (VEGF) pathway and VEGF protein overexpression have proved important, as they result in increased tumor angiogenesis and RCC growth and development.

Areas covered: This review briefly discusses the mechanisms of action and clinical applications of pazopanib. It mainly outlines the safety and tolerability of pazopanib for locally advanced/metastatic RCC. Phase III pazopanib safety data are also indirectly compared with other standard, antiangiogenic receptor tyrosine kinase inhibitors currently used in the management of RCC.

Expert opinion: Pazopanib is a new drug available in the oncology portfolio to treat patients with predominantly clear-cell RCC. The toxicity profile of pazopanib is comparable, but in some ways distinct, from other antiangiogenic drugs used in the treatment of RCC. Long-term data about late side effects of this treatment are awaited.     

Lacosamide in patients with pharmacoresistant epilepsy

Introduction: Lacosamide is a novel antiepileptic drug licensed in the US and Europe as adjunctive therapy for partial-onset seizures in adults. The efficacy, safety, tolerability and favorable pharmacokinetic profile in the adult population suggest that lacosamide could be of benefit for patients with partial-onset seizures.

Areas covered: This paper reviews the available evidence and most recent data concerning the efficacy, safety, tolerability and pharmacokinetics of lacosamide in adults, as well as in the pediatric population.

Expert opinion: Lacosamide is one of the newest drugs of the antiepileptic armamentarium, and it is expected to compete directly with compounds that are currently used for adjunctive therapy in adults with refractory partial epilepsy. The intravenous formulation may be used for replacement therapy in patients temporarily unable to take oral medication. An apparent lack of sedative or cognitive effects might render this drug preferable in patients with mental insufficiency and/or epileptic encephalopathy.