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.     

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.     

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.     

Entecavir for the treatment of patients with hepatitis B virus-related decompensated cirrhosis

Introduction: Chronic hepatitis B (CHB) infection is common and carries a significant risk for the development of cirrhosis, hepatic decompensation, and hepatocellular carcinoma. The goal of treatment in patients with CHB-related decompensated cirrhosis is to improve hepatic dysfunction and reduce mortality through the inhibition of viral replication. Several studies have now shown nucleot(s)ide analogs to be safe and effective in decompensated cirrhosis due to CHB.

Areas covered: A review of the evidence for the use of entecavir in the treatment of decompensated hepatitis B cirrhosis is discussed.

Expert opinion: Entecavir is an effective treatment option for most patients with CHB. In treatment naïve patients, it is a potent antiviral agent with a very low resistance rate, making it an excellent option for the treatment of decompensated hepatitis B cirrhosis. The use of entecavir monotherapy in patients with a known rtM204V lamivudine-resistant mutation should be avoided due to increased risk of developing entecavir resistance and failing treatment.     

Umeclidinium for treating COPD: an evaluation of pharmacologic properties,safety and clinical use

Introduction: Umeclidinium (UMEC) is a long-acting inhaled antagonist of muscarinic cholinergic receptors. The FDA approved UMEC for maintenance treatment of chronic obstructive pulmonary disease (COPD) in 2013 and it became available for commercial use as a single agent in 2014. After tiotropium, this is the only other once daily LAMA available for COPD patients.

Areas covered: In this article, we have comprehensively reviewed the pharmacokinetic properties and analyzed the currently available randomized controlled trials on the efficacy and safety profile of UMEC. We have discussed the current clinical application of UMEC and its future implication.

Expert opinion: UMEC is the newer long-acting antimuscarinic agent (LAMA) that has demonstrated significant improvement in lung function and improved the quality of life in moderate-to-severe COPD patients. It is suitable for once daily dosing, has low anticholinergic side effects and is well tolerated. Overall, it is a safe, effective and convenient LAMA for maintenance therapy in COPD patients.     

A review of iniparib in ovarian cancer

Introduction: Patients with metastatic ovarian cancer continue to experience high recurrence rates and significant morbidity from standard treatments. There is a great need for efficacious tumor-specific agents in ovarian cancer. Iniparib (BSI-201) is a targeted drug currently under investigation.

Areas covered: The authors identified the mechanistic and clinical data available on the role of iniparib in ovarian cancer. Iniparib was initially thought to act via the poly-ADP ribose polymerase 1 (PARP-1) pathway, but recent studies have shown only nonspecific interactions between the drug and PARP proteins. Although iniparib is only active in cancer cells, the exact mechanism of action remains unclear. Iniparib was well tolerated at all dose levels in Phase I studies of solid organ malignancies. Preliminary data from Phase II studies of iniparib for the treatment of platinum-sensitive and platinum-resistant recurrent ovarian cancer show improvement in survival compared to historic controls. There are currently no Phase III studies.

Expert opinion: Iniparib shows promise in early clinical trials; however, understanding the pathways of cytotoxicity will be crucial as cancer therapy becomes increasingly individualized.     

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.     

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.     

Drug safety evaluation of pregabalin

Introduction: Pregabalin is an anticonvulsant with one known mechanism of action which is used most specifically in the management of neuropathic pain.

Areas covered: The adverse effect profile of this medication from controlled, randomized studies as well as open and long-term studies is described with consideration of the evidence-based results for pregabalin's clinical use.

Expert opinion: Pregabalin is a mostly well tolerated medication for the management of neuropathic pain and other conditions. Pregabalin use is associated with benign central nervous system and systemic adverse effects with very limited metabolic, idiosyncratic, or teratogenic adverse effects. Understanding of these adverse effects is essential for the clinician treating the patient and for the patient receiving treatment. Sedation, dizziness, peripheral edema, and dry mouth are the most prevalent adverse events experienced in all clinical populations. Other adverse effects are rare, but are discussed.     

Drug safety evaluation of naltrexone/bupropion for the treatment of obesity

Introduction: Obesity is a known health risk for the development of several preventable diseases. Obesity-related metabolic alterations negatively impact different physiological mechanisms, which supports the rationale for the use of combined drug therapy. Naltrexone is an opioid antagonist for the treatment of opioid and alcohol dependency, whereas bupropion is a norepinephrine/dopamine reuptake inhibitor used to treat depression and smoking cessation. Although not effective as individual monotherapies for obesity, naltrexone and bupropion in combination produce weight loss and a metabolic profile beneficial for the potential treatment of obesity.

Areas covered: This review examines the safety and antiobesity effects of naltrexone and bupropion alone and in combination. It reviews the results of four Phase III clinical trials of a novel fixed dose of sustained-released naltrexone/bupropion.

Expert opinion: Naltrexone/bupropion has a greater weight loss efficacy than two FDA-approved medications, orlistat and lorcaserin. Although the weight loss produced by phentermine/topiramate is superior to naltrexone/bupropion, the safety profile of naltrexone/bupropion has less severe adverse effects. In addition, naltrexone/bupropion is well tolerated, with nausea being the most reported adverse event. Unlike other centrally acting medications, lorcaserin and phentermine/topiramate, naltrexone/bupropion has no abuse potential.     

Bazedoxifene + conjugated estrogens in HT for the prevention of osteoporosis and treatment of vasomotor symptoms associated with the menopause

Introduction: The recent concept that estrogen agonist–antagonists, often referred to as selective estrogen receptor modulators, can be combined with an estrogen has led to the development of a novel form of menopausal therapy called Tissue-Selective Estrogen Complex (TSEC). This paper reviews the TSEC bazedoxifene and conjugated equine estrogens (BZA/CE).

Areas covered: This review is based on clinical trials and a PubMed search. The pharmacokinetics and pharmacodynamics of BZA in BZA plus CE are reviewed. This review outlines the effects of this particular TSEC, which maintains or increases bone mineral density in women at high risk for osteoporosis, and has clinical qualities of a promising new menopausal therapy. The potential adverse effects of BZA/CE combinations are summarized.

Expert opinion: A TSEC that contains CE and BZA that has both estrogen agonist and antagonist effects has reached clinical development. Phase III clinical trials show this TSEC relieves hot flashes, improves vulvo-vaginal atrophy and its symptoms, does not stimulate the endometrium, and prevents bone loss. In the trials so far it appears to have a good safety and tolerability profile. The optimum combination of BZA/CE combination is 20 mg BZA with CE 0.45 and 0.625 mg daily.     

Treatment of postmenopausal osteoporosis with odanacatib

Introduction: The market of antiosteoporosis drugs has been declining in recent years, possibly in part due to the publicity around adverse events observed with bisphosphonates. Also, the proportion of patients with clinical fracture who receive adequate treatment remains low. So there are still unmet needs in this field. Odanacatib is a cathepsin K inhibitor currently being developed for the treatment of postmenopausal osteoporosis that could be an advance in this context.

Areas covered: Odanacatib is a bone resorption inhibitor, but it preserves some degree of bone formation, which differentiates this new family of drugs from existing therapies. Odanacatib increases bone mineral density at the spine and hip, improves estimated bone strength using finite element analysis at the spine and hip as well as at the distal tibia and radius. The safety profile has been satisfactory so far. A robust antifracture efficacy has been announced when the Phase III pivotal trial was terminated after interim analysis, but we do not yet have access to the complete results.

Expert opinion: Odanacatib may have an important role in future guidelines if it provides a substantial advantage compared to the effective and inexpensive current generic drugs, in terms of antifracture efficacy or safety.     

Clozapine for the treatment of schizophrenia

Introduction: Despite considerable progress in the pharmacological treatment of schizophrenia, about 30% of patients are minimally responsive to antipsychotics and there is still an excessively high rate of mortality in schizophrenia patients. Clozapine, a D₂-5HT₂ antagonist, was the first antipsychotic to demonstrate efficacy in treatment-resistant patients, and to be associated with the lowest risk of death.

Areas covered: The pharmacodynamics, pharmacokinetics, clinical efficacy, safety and cost-effectiveness of clozapine are covered in this article, based on a literature review (PubMed) from 1975 to 2012. Pivotal, as well as supporting, randomized controlled trials are reviewed, along with observational and/or naturalistic safety studies. This review of clozapine will allow the reader to determine the place for clozapine in the schizophrenia treatment landscape. Expert opinion: Studies conducted so far suggest that clozapine is the treatment of choice for schizophrenic patients who are refractory to treatment, display violent behaviors, or who are at high risk of suicide. However, it is also the antipsychotic with the worst side effect profile, the highest risk of complications, and the most difficult to prescribe. Experience with clozapine should therefore be included in the education of future physicians.     

Bendamustine for treatment of chronic lymphocytic leukemia

Introduction: Chronic lymphocytic leukemia (CLL) often has an extended disease course. With a median age at diagnosis of 72 years, newer treatment options with less toxicity than standard nucleoside analogue-based regimens are needed. Historically, few therapy options are available once CLL has become refractory to nucleoside analogues. Bendamustine has emerged as a feasible therapy for older and less fit CLL patients, with clinical efficacy in previously untreated and refractory CLL.

Areas covered: This paper reviews several of the pivotal clinical trials that established the clinical activity of bendamustine in previously untreated and relapsed/refractory CLL. The toxicity profile of bendamustine, primarily myelosuppression and infections, is reviewed and compared across different CLL populations. A review of the clinical data focuses on potential explanations for differences in response rates and duration of remission reported across studies and how this may impact the development of therapies for CLL.

Expert opinion: Bendamustine is a valuable new agent for the management of CLL. Ongoing clinical trials are comparing bendamustine with standard CLL regimens in untreated disease, and investigating bendamustine combinations with novel targeted therapies and monoclonal antibodies. These studies will help to define the optimal role for bendamustine in CLL management.     

Clinical management of rivaroxaban-treated patients

Introduction: Until recently, only vitamin K antagonists (VKAs) were used for long-term anticoagulation. New oral anticoagulants, with pharmacokinetic and pharmacodynamic characteristics different to VKAs, are now available for some indications. Rivaroxaban (Xarelto®) is an oral Factor Xa inhibitor approved in many countries for long-term treatment of patients with atrial fibrillation or venous thromboembolism. This article is addressed to all professionals involved in the management of treated patients to highlight the characteristics of rivaroxaban and provide practical guidance on management of treated patients.

Areas covered: This article is based on a consensus of specialists involved in the management of anticoagulant treatment, including thrombosis experts, cardiologists, neurologists, emergency medicine specialists, and general practitioners. The authors performed a nonsystematic review of the literature, and expressed guidance statements based on the results of the review as well as personal experience.

Expert opinion: Availability of new anticoagulant drugs, including rivaroxaban, is an important step forward to allow easier, more effective, and safer long-term anticoagulation in patients in whom adequate anticoagulation is currently denied due to the limitations of VKAs. However, given their totally new properties, associated risks, and expected broad clinical use, expert professionals and manufacturers must urgently tackle a series of issues.     

The potential role of sunitinib targeting melanomas

Introduction: Metastatic melanoma – independently of its cutaneous, uveal or mucosal origin – represents an exceptionally aggressive tumor with poor prognosis. Molecular and genetics investigations permitted to identify several important driver mutations: BRAF, NRAS, c-Kit, GNA11 and GNAQ. Additionally, hypervascular and immunlogenic characteristics of metastatic melanoma make in this tumor a unique therapeutic target. In this regard, the antiangiogenic, antiproliferative and immunomodulator properties of sunitinib make it an attractive drug to explore in melanoma.

Areas covered: In this article, the currently available data on sunitinib in terms of its pharmacokinetics and mechanisms of action is summarized. The reader will also be updated on current clinical experience using this drug in the treatment of cutaneous, mucosal and uveal melanomas. Special attention is placed on the scientific rationales behind its development in melanoma including the potentiality to broadly attack receptor-tyrosine kinases as well as its remarkable but certainly still unexplored immunomodulatory qualities.

Expert opinion: Given its wide spectrum of actions and the encouraging results obtained from the limited clinical experience, sunitinib remains as a promising drug, especially for mucosal and uveal melanoma, that deserves further exploration in properly designed clinical trials.     

Riociguat for the treatment of pulmonary hypertension

Introduction: Pulmonary arterial hypertension (PAH) is still an incurable disease with high mortality despite recent treatment advances. Chronic thromboembolic pulmonary hypertension (CTEPH) is a specific form of pulmonary hypertension due to thromboembolic occlusion of pulmonary arteries. Although 50 – 60% of the CTEPH patients can be cured via pulmonary endarterectomy (PEA), a significant portion is inoperable. For both diseases, therefore, new treatments are urgently needed.

Areas covered: The review will explain the mechanism of action of the soluble guanylate cyclase stimulator riociguat (BAY 63-2521) and will give an overview regarding the current scientific and clinical data of riociguat in both indications PAH and CTEPH. The most relevant publications up to date were used as sources for this review.

Expert opinion: Riociguat is a novel treatment option in PAH class 1, which, in contrast to phosphodiesterase-5 inhibitors, acts independently of endogenous nitric oxide and has shown efficacy in combination therapy with endothelin-1 receptor antagonists. Riociguat is the first approved drug for non-operable CTEPH and sustained CTEPH after PEA, thus introducing a proven pharmacologic treatment option for this group of patients. Long-term results in the real-life setting are still lacking and are needed to provide evidence for the true amount of progress riociguat adds to the field.     

Nintedanib for the treatment of non-small-cell lung cancer

Introduction: In NSCLC, increased microvessel count, often used as a measure of angiogenesis, has been correlated with poor prognosis and associated with advanced disease and inferior outcomes. In the clinical development of antiangiogenic therapies, two approaches have been used; the first has been to inhibit ligand binding and receptor activation using targeted antibodies, whereas the second has been to inhibit receptor activation using tyrosine kinase inhibitors that target VEGF receptor (VEGFR), platelet-derived growth factor receptor (PDGFR) and/or fibroblast growth factor receptor (FGFR). Nintedanib is a triple angiokinase inhibitor that simultaneously acts on VEGFR, PDGFR and FGFR. It has shown significant antiangiogenic and antineoplastic activities in vitro, in preventing tumor growth and overcoming drug resistance.

Areas covered: Medline search was used with the following keywords: non-small-cell lung cancer and nintedanib or BIBF 1120, ASCO abstracts 2013 with nintedanib, and Phase I and Phase II abstracts lung cancer and nintedanib.

Expert opinion: Recent Phase III trials have shown promising efficacy results of nintedanib in NSCLC; however, many questions still need to be answered before it is put into routine use.     

Efficacy of desvenlafaxine succinate for menopausal hot flashes

Introduction: The concern for the development of breast cancer, stroke, cardiovascular disease and deep venous thrombosis with the use of hormonal therapy has led to the development of alternative nonhormonal forms of therapy like desvenlafaxine for the management of hot flashes.

Areas covered: This review is based upon a PubMed search and clinical trials. The pharmacokinetics and pharmacodynamics of desvenlafaxine are reviewed. This review outlines the effects of desvenlafaxine in management of severity and frequency of vasomotor symptoms, sleep quality and quality of life in postmenopausal women. The potential adverse effects of desvenlafaxine are summarized.

Expert opinion: Based on the evidence from randomized clinical trials, desvenlafaxine is an alternate viable option for reducing the frequency and severity of hot flashes when other treatments fail. In clinical trials, it has been shown that desvenlafaxine reduced the frequency of hot flashes by 55 – 69%. In the trials so far it appears to have good safety and tolerability profile when the drug is initiated in titrating doses. The optimum dose is 100 mg/day and is to be started at 50 mg/day for 3 days and titrated to 100 mg/day. The most common adverse events reported were nausea, dry mouth, fatigue, constipation, diarrhea and somnolence.