Maryam Iranikhah

Denosumab for the Prevention of Skeletal‐Related Events in Patients with Bone Metastasis from Solid Tumor

Most patients with advanced malignancy develop bone metastases during the course of their disease. For the remainder of the patients life, these bone metastases lead to skeletal‐related events such as pathologic fractures and spinal cord compression, as well as bone pain or lesions requiring palliative radiation therapy or surgery to prevent or treat fractures. Skeletal‐related events result in increased morbidity, mortality and health care costs. For the past decade, intravenous bisphosphonates (zoledronic acid, pamidronate) have been recognized as the primary pharmacologic options in the prevention or treatment of skeletal‐related events in patients with bone metastasis. Recently, the United States Food and Drug Administration approved denosumab, a fully human monoclonal antibody, for the prevention of skeletal‐related events in patients with bone metastases from solid tumors. Three prominent clinical trials were conducted to establish the efficacy of denosumab. In two of three trials, denosumab was found to delay the time to first skeletal‐related event significantly more than zoledronic acid in patients with breast or castration‐resistant prostate cancer with bone metastasis. The third trial found denosumab to be noninferior to zoledronic acid in patients with metastases from solid tumors, excluding breast and prostate solid tumors. Overall survival and progression‐free survival were similar between zoledronic acid and denosumab. Thus, evidence is insufficient to prove a greater efficacy of one agent over the other. According to the American Society of Clinical Oncology and the National Comprehensive Cancer Network, patients with bone metastasis should have zoledronic acid, pamidronate, or denosumab (with calcium and vitamin D supplementation) added to their chemotherapy regimen if they have an expected survival of 3 months or longer and have adequate renal function.

Effects of Denosumab on Bone Mineral Density and Bone Turnover in Postmenopausal Women

Osteoporosis is a degenerative bone disease affecting approximately 10 million American adults. Several options are available to prevent development of the disease or slow and even stop its progression. Nonpharmacologic measures include adequate intake of calcium and vitamin D, exercise, fall prevention, and avoidance of tobacco and excessive alcohol intake. Current drug therapy includes bisphosphonates, calcitonin, estrogen or hormone therapy, selective estrogen receptor modulators, and teriparatide. Denosumab, a receptor activator of nuclear factor‐K B ligand (RANKL) inhibitor, was recently approved by the United States Food and Drug Administration for treatment of postmenopausal osteoporosis. Patients treated with denosumab experienced significant gains in bone mineral density, rapid reductions in markers of bone turnover, and a reduced risk for new vertebral fracture. Compared with placebo, patients receiving denosumab 60 mg subcutaneously once every 6 months experienced gains in bone mineral density of 6.5–11% when treated for 24–48 months. One trial demonstrated the superiority of denosumab compared with alendronate, but the differences were small. The most common adverse reactions to denosumab include back pain, pain in extremities, musculoskeletal pain, and cystitis. Serious, but rare, adverse reactions include the development of serious infections, dermatologic changes, and hypocalcemia. The recommended dosing of denosumab is 60 mg every 6 months as a subcutaneous injection in the upper arm, upper thigh, or abdomen. Although beneficial effects on bone mineral density and fracture rate have been established in clinical trials, the risks associated with denosumab must be evaluated before therapy initiation. Of concern is the risk of infection, and denosumab should likely be avoided in patients taking immunosuppressive therapy or at high risk for infection. Therefore, bisphosphonates will likely remain as first‐line therapy. Denosumab should be considered in patients unable to tolerate or who have adherence issues or contraindications to other therapies.

Future of bisphosphonates and denosumab for men with advanced prostate cancer.

Prostate cancer is the most common cancer occurring in American men of all races. It is also the second leading cause of cancer death among men in the USA. Bone metastasis is a frequent occurrence in men with advanced prostate cancer, with skeletal-related events being a common complication and having negative consequences, leading to severe pain, increased health care costs, increased risk of death, and decreased quality of life for patients. Bone loss can also result from antiandrogen therapy, which can further contribute to skeletal-related events. Treatment with antiresorptive agents bisphosphonates, and the newly approved denosumab, a receptor activator of nuclear factor kappa-B ligand (RANK-L) inhibitor, has been shown to reduce the risk of skeletal-related complications and prevent treatment-induced bone loss in patients with advanced prostate cancer. This review discusses the role of antiresorptive agents bisphosphonates and RANK-L inhibitor in the current treatment of advanced prostate cancer by examining the primary literature and also focuses on the likely role of the bisphosphonates in the treatment of advanced prostate cancer in the future.

Tablet splitting: a review of weight and content uniformity.

OBJECTIVE To describe the product integrity and ethical/ legal issues associated with tablet splitting. DATA SOURCES PubMed (1966-June 2011), International Pharmaceutical Abstract (1975-June 2011), and bibliographic searches were conducted. STUDY SELECTION All studies that evaluated the weight/dose variations (N = 13) of split tablets were included. DATA EXTRACTION The American Pharmacists Association guidelines, recommendations from the Food and Drug Administration, and clinical studies evaluating product integrity of split tablets were used to provide an overview of issues related to this practice. Legal considerations from various sources were also included. DATA SYNTHESIS The practice of tablet splitting is increasing and is associated with variations in drug distributions related to the tablet-splitting technique and other causes. The first part of this two-part series will evaluate the product integrity and practice-related issues associated with tablet splitting. CONCLUSION The majority of the studies associated with tablet splitting reveal large fluctuations in weight/dosage, but few studies evaluate variability with narrow therapeutic index medications. Therefore, the clinical impact of these variations is not globally applicable across medication classes. Although tablet splitting has the potential to save patients and health care organizations a significant amount of money, appropriateness of tablet splitting should be determined for individual medications and individual patients. Assessments should include an evaluation of patient understanding and physical abilities for tablet splitting.

Tablet splitting: a review of the clinical and economic outcomes and patient acceptance. Second of a 2-part series. Part 1 was published in May 2012 (Consult Pharm 2012;27:239-53).

OBJECTIVE To describe the clinical outcomes, patient acceptance, and economic effect associated with tablet splitting. DATA SOURCES PubMed (1966-June 2011) and International Pharmaceutical Abstract (1975-June 2011) searches were conducted using tablet splitting as the search terms. STUDY SELECTION All studies that evaluated the clinical outcome (n = 4), patient acceptance (n = 5), and economic effects (n = 8) of tablet splitting were included. DATA EXTRACTION The American Pharmacists Association guidelines, recommendations from the Food and Drug Administration, and clinical trial data were evaluated. DATA SYNTHESIS The majority of trials conducted evaluating clinical outcomes associated with tablet splitting were evaluated in patients receiving statins and antihypertensives. Clinical outcomes associated with risperidone were assessed. No adverse clinical outcomes were observed with therapy. Most studies evaluating the economic effects of tablet splitting have revealed a cost savings associated with this process; however, many studies were subject to limitations. The first part of this two-part series reviewed the weight and content uniformity in tablet splitting. CONCLUSION Tablet splitting does not seem to significantly affect clinical outcomes related to management of hypertension, cholesterol, or psychiatric disorders, nor influence overall patient adherence.

Vilazodone for the Treatment of Major Depressive Disorder

Major depressive disorder (MDD) affects 121 million people globally and is one of the leading causes of functional disability worldwide. As a recurrent disorder, MDD is associated with significant morbidity and functional disability as well as high direct and indirect costs to the health care system. Although several drug therapies are available for treating MDD, many patients do not achieve a sustained remission. Vilazodone was approved by the United States Food and Drug Administration in 2011 and has a distinctive pharmacology profile, as the drug is a selective serotonin reuptake inhibitor and serotonin 5‐HT1A receptor partial agonist. In two 8‐week, double‐blind, placebo‐controlled trials, vilazodones overall rate of response was similar to other antidepressants for the treatment of MDD. Compared with placebo, remission rates were not significantly different in one trial and were not reported in the second trial. Vilazodone was generally well tolerated, with nausea and diarrhea being the most frequent adverse events reported. Postmarketing studies and further active comparative studies will provide additional insight to the potential benefits and safety of this novel drug.

Retained Skeletal Effects of Zoledronic Acid Following Discontinuation of Treatment: A Review of the Literature

OBJECTIVE To evaluate the effects on bone mineral density (BMD), bone turnover markers (BTMs), and fracture incidence following zoledronic acid (ZOL) discontinuation. DATA SOURCES A search of PubMed (1966-May 2016) and International Pharmaceutical Abstracts (1970-May 2016) was conducted using the MeSH terms zoledronic acid, osteoporosis, and withholding treatment. Free text searches included drug holiday and drug discontinuation. STUDY SELECTION AND DATA EXTRACTION An initial review yielded 87 articles. Six articles, which addressed the skeletal effects of ZOL after discontinuation of treatment, were included in the final review. DATA SYNTHESIS ZOL is a widely prescribed bisphosphonate agent. Studies have shown that discontinuation of ZOL may have lasting skeletal benefits. However, there is inconsistent evidence regarding the duration of the residual skeletal effects of ZOL after treatment discontinuation, or the continued length of therapy required for the prolonged protective benefits on BMD and BTMs. Sample sizes have been small, and studies were not adequately powered to evaluate fracture incidence. CONCLUSION A single ZOL infusion has been shown to decrease BTMs and improve BMD for at least 12 months after infusion. Patients may experience continued benefit beyond this period, but there is concern that this long-term effect may lead to severe bone-turnover suppression, increased bone fragility, and increased risk of fractures. Additional extension studies should be conducted to determine the long-term effects of discontinuing ZOL therapy on bone health as well as the length of preserved bone strength after last administration.

Antidepressant Pharmacology: Introduction for the Pharmacy Technician

Objective: To review the pharmacology of antidepressants and describe clinical applications of antidepressants in the treatment of depression. Data Sources: A MEDLINE/PubMed search (1995–July 2011) was conducted for English-language articles using the terms pharmacology, antidepressant, tricyclic antidepressants, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, venlafaxine, desvenlafaxine, duloxetine, bupropion, trazodone, nefazodone, mirtazapine, vilazodone, efficacy, adverse effects, and drug interactions. Book chapters related to the pharmacology of antidepressants were also searched. Study Selection and Data Extraction: Articles and book chapters relevant to the pharmacology of antidepressants were reviewed. Data Synthesis: Antidepressants exert pharmacologic actions via enzyme inhibition, reuptake inhibition, receptor antagonism, and receptor partial agonism. These actions can cause both therapeutic and adverse effects. Each antidepressant possesses a unique blend of pharmacologic actions, which helps to differentiate antidepressants and aids in the understanding of their particular efficacy profiles, adverse effect profiles, and pharmacodynamic drug interaction profiles. Conclusions: There are important clinical applications of the pharmacologic properties of antidepressants. Gaining familiarity with antidepressant pharmacology will enable the pharmacy technician to develop a more thorough understanding of the drug class.