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.     

Nalfurafine hydrochloride for the treatment of pruritus

Introduction: Severe pruritus associated with end-stage renal disease is a particularly troublesome complication, because no effective treatment has been established. However, based on the findings of a recent randomized controlled trial, nalfurafine hydrochloride was officially approved in Japan for the treatment of resistant pruritus in hemodialysis patients.

Areas covered: This review is based upon a PubMed search and personal experience with nalfurafine hydrochloride. The pharmacokinetics and pharmacodynamics of nalfurafine hydrochloride are reviewed and its efficiency and potential adverse effects are discussed, mainly based on the findings of randomized controlled trials.

Expert opinion: A recent long-term open trial showed that the effect of nalfurafine hydrochloride was enhanced by continuous, long-term administration. It will be of future interest to investigate its effect on excoriations, lichen simplex, prurigo nodularis and acquired perforating dermatosis (all caused by uremic pruritus), because it targets both the skin and the central nervous system. In clinical practice, it should be kept in mind that basic skin care with emollients and other topical drugs is essential for stopping the itch–scratch cycle, and the resultant skin barrier dysfunction.     

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.     

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.     

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.     

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.     

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.     

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.     

Resiquimod,a topical drug for viral skin lesions and skin cancer

Introduction: Resiquimod is an immune response modifier which stimulates cells through a toll-like receptors (TLR) 7 and 8 dependent pathway resulting in activation of immune responses that are effective against viral and tumor lesions.

Areas covered: Studies on genital herpes, hepatitis C and actinic keratosis (AK) as well as papers of molecular activities of resiquimod were identified by a PubMed search. Although effective against genital HSV-2 in animal models, development of topical resiquimod for the treatment of recurrent genital herpes in humans was stopped due to inconsistent results in clinical trials. Reduction of HCV viral load was achieved by oral application but was associated with unacceptable side effects. Topical treatment of AK was well tolerated and effective with clearance rates higher compared to imiquimod. The molecular mode of action underlying the clinical efficacy primarily depends on cytokine induction in TLR7/8 expressing dendritic cells in the skin.

Expert opinion: Topical resiquimod was shown to be a safe and effective treatment option for AK and appears to have potential as a treatment modality for patients with extended skin areas affected with AK (field cancerization). Resiquimod may also have potential for the therapy or prevention of epithelial viral infections.     

Vandetanib for the treatment of lung cancer

Introduction: VEGF and EGFR are validated pathways for targeted therapy in non-small cell lung cancer (NSCLC). Once considered to be separate targets, VEGF and EGFR are now shown to have interconnected downstream pathways, potentiating the effectiveness of their dual signaling inhibition in cancer therapy. Molecules such as vandetanib that inhibit VEGFR and EGFR have also been reported to inhibit other receptors, including RET and additional kinases, and may be beneficial in treating patients with solid tumors.

Areas covered: This review covers the significance of targeting VEGF and EGFR in the treatment of NSCLC and the rationale behind their dual inhibition. Clinical trials that evaluate the use of vandetanib in the setting of refractory NSCLC are also explored.

Expert opinion: Vandetanib is currently not approved in the setting of NSCLC. However, its approval for medullary thyroid cancer makes it promising for identifying markers and potentially a NSCLC patient population who will benefit from the treatment.     

Cladribine tablets for the treatment of relapsing–remitting multiple sclerosis

Introduction: Multiple sclerosis (MS) is a chronic immune-mediated disorder of the central nervous system leading to progressive neurodegeneration and disability. Until 2010, all approved disease-modifying drugs for MS required parenteral administration, which is associated with suboptimal adherence. It was anticipated that new approaches to treatment, including oral agents such as cladribine tablets, may improve adherence. In 2011, the development of cladribine tablets was stopped following negative feedback from the EMA and FDA.

Areas covered: This article provides an overview of the chemistry, mechanism of action and pharmacological properties of cladribine tablets therapy, and highlights the rationale for its development as an oral treatment for MS. Key efficacy and safety data from the pivotal Phase III CLARITY study are presented, providing context for the opinion received from the regulatory agencies.

Expert opinion: Despite the promising efficacy data observed in the cladribine tablets clinical trial program, regulatory agencies identified a potential risk of increased malignancies, and raised concerns about the implications of sustained lymphocyte depletion. Following the feedback received from the regulatory agencies, Merck Serono made the decision to withdraw the agent from the regulatory approval process. The experience gained will benefit other research efforts to address the outstanding unmet treatment needs of patients with relapsing MS.     

Should ranolazine be used for all patients with ischemic heart disease or only for symptomatic patients with stable angina or for those with refractory angina pectoris? A critical appraisal

Introduction: Ranolazine is a novel antianginal and anti-ischemic agent, that, unlike other available antianginal drugs in the United States (beta-blockers, organic nitrates, and calcium channel blockers), has no significant effect on either heart rate or blood pressure. Its exact mechanism of action is unknown. Ranolazine does increase electrocardiographic QTc interval in a dose-related manner, but at therapeutic doses it has no proarrhythmic effects. Ranolazine (ER) at doses of 500 and 1,000 mg twice daily is currently approved for the treatment of angina pectoris either as monotherapy or added to beta-blockers, nitrates, and calcium channel blockers. Ranolazine (ER) is currently not approved for the treatment of unstable angina, silent ischemia, or cardiac arrhythmias. The most common adverse effects reported in clinical trials during ranolazine (ER) treatment are dizziness, headaches, constipation, and nausea.

Areas covered: Recent changes in ranolazine (ER) labeling have led to its increased use for treating patients with ischemic heart disease. This review addresses its appropriate use. All publications were reviewed and those relevant were included.

Expert opinion: Ranolazine (ER) is an effective antianginal and anti-ischemic agent, but I restrict its use to treat patients with stable angina pectoris.     

Dapagliflozin: a review on efficacy,clinical effectiveness and safety

Introduction: The prevalence of type 2 diabetes mellitus has reached epidemic proportions. Progressive deterioration in glycaemic control and the current limitations of existing therapies such as weight gain and hypoglycaemia led us to welcome the first of a new class of drugs. Sodium-glucose co-transporter 2 (SGLT2) inhibitors represent a novel mode of therapy independent of insulin secretion or action. By blocking glucose reabsorption in the kidney they lead to an increase in urinary glucose excretion with reduction in plasma glucose levels.

Areas covered: In this article, we will review inhibition of SGLT2 as a novel strategy for the treatment of type 2 diabetes mellitus with dapagliflozin. PubMed and MEDLINE were searched for literature published up to July 2012, for efficacy, clinical effectiveness and safety reports of dapagliflozin.

Expert opinion: Improvement in glycaemic control with a low risk of hypoglycaemia, concomitant weight loss and the potential of lowering of blood pressure make SGLT2 inhibition an attractive approach using dapagliflozin therapy. Many SGLT2 inhibitors are undergoing Phase III clinical trials and more are in Phase I and II clinical trials.     

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.     

Bepotastine besilate for the treatment of pruritus

Introduction: Bepotastine besilate 1.5% is a newly approved second-generation topical antihistamine indicated for the pruritus associated with allergic conjunctivitis. In Japan, the oral formulation is approved to manage pruritus associated with allergic rhinitis and urticaria.

Areas covered: Bepotastine is a piperidine derivative that antagonizes H1 receptors with high selectivity. It has been labeled a dual-acting or multiple-acting antiallergic medication, because it inhibits histamine at H₁ receptors and stabilizes mast cells to prevent histamine release. Bepotastine may also have other immunoactive properties, such as inhibition of eosinophil migration, interleukin-5 (IL-5), leukotrienes (e.g., LTB₄) and platelet-activating factor (PAF). Human clinical trials demonstrate the efficacy and safety of systemic and ophthalmic bepotastine for pruritus relief, limited penetration across the blood–brain-barrier and kinetics suitable for twice-daily administration.

Expert opinion: Bepotastine besilate 1.5% ophthalmic solution is a safe and effective treatment option for allergic conjunctivitis associated pruritus. Side-effect profile is similar to other ocular antihistamine agents. Additional comparative-effectiveness studies would further advance its clinical use. Oral bepotastine is a safe and effective treatment option approved in Japan for allergic rhinitis, urticaria and pruritus associated with skin diseases.     

Fidaxomicin for treatment of clostridium difficile-associated diarrhea and its potential role for prophylaxis

Introduction: Clostridium difficile has become the most important healthcare-associated infection worldwide within the past decade. This is in part due to the emergence of a highly virulent epidemic strain of C. difficile as well as the relative ineffectiveness of current therapies at producing a sustained response. Fidaxomicin is a novel antibiotic that demonstrates a greater sustained response for C. difficile-associated diarrhea (CDAD) compared to existing drugs and its potential role as a prophylactic agent against C. difficile infection (CDI) is being intensely studied.

Areas covered: In this article, we address the emergence of CDI and the current treatment options and identify the unmet needs of the marketplace. We also summarize the pharmacodynamic and pharmacokinetic properties of fidaxomicin, and review the current literature related to the use of fidaxomicin for both treatment and prophylaxis of CDI.

Expert opinion: Fidaxomicin is clearly as effective in the treatment of CDAD as oral vancomycin. It has also been shown to reduce recurrent CDAD, and we hypothesize that the same properties that confer reduced recurrence make it a promising agent for prophylaxis, particularly in high-risk patients.     

A safety evaluation of ranibizumab in the treatment of age-related macular degeneration

Introduction: The use of intravitreal ranibizumab has transformed the outcomes for thousands of patients with wet age related macular degeneration (AMD), which is the leading cause of blindness in developed countries. Prior to its introduction, most patients with wet AMD would rapidly lose central vision. The use of intravitreal ranibizumab has been shown to reduce certifiable visual loss by about a half. Current treatment regimens with ranibizumab in wet AMD require multiple injections over several years and so it is highly relevant to review the safety record of this important drug.

Areas covered: This review considers the important ocular and systemic adverse events (AE) that have been reported in the literature, particularly in the context of the pivotal clinical trials that have been performed. It also reviews the safety of other anti-VEGF drugs that are used in wet AMD, namely bevacizumab and aflibercept, and compares these drugs with ranibizumab.

Expert opinion: Overall, intravitreal ranibizumab can be considered a safe and highly effective drug for patients with wet AMD. However recent concerns about retinal thinning following ranibizumab therapy, possible systemic AE associated with all anti-VEGF drugs and the occurrence of complications relating to drug preparation and delivery must be considered.     

Empagliflozin for the treatment of type 2 diabetes

Introduction: Despite the availability of numerous anti-diabetes drugs and treatment guidelines, many patients with type 2 diabetes mellitus (T2DM) do not reach recommended targets for glycemic control. There remains an unmet need for effective and well-tolerated anti-diabetes agents that can be used as monotherapy or in combination with other therapies to improve glycemic control in patients with T2DM. Sodium glucose cotransporter 2 (SGLT2) inhibitors are a new class of treatment for T2DM that reduce hyperglycemia by reducing renal glucose reabsorption and thereby increasing urinary glucose excretion.

Areas covered: This paper reviews the pharmacokinetic and pharmacodynamic properties of the SGLT2 inhibitor empagliflozin, the results of clinical trials investigating the efficacy of empagliflozin given as monotherapy or as add-on therapy on glycemic control, body weight, and blood pressure in patients with T2DM, and the safety and tolerability profile of empagliflozin.

Expert opinion: Empagliflozin offers good glycemic efficacy, weight loss, blood pressure reduction, and a low risk of hypoglycemia. These attributes, coupled with the ability to be used in virtually any combination with other anti-diabetes agents and at any stage in the disease process, provide a welcome new agent to our armamentarium of drugs to help manage T2DM.