Drugs New Practitioners Have You Considered a Drug Information Residency? 2015 Award Recipients

SEPTEMBER/OCTOBER 2015 CALIFORNIA JOURNAL OF HEALTH-SYSTEM PHARMACY VOL. 27 NO. 5

PEER REVIEW

Perspective

Continuing Pharmacy Education New Drugs New Practitioners Have You Considered a Drug Information Residency? 2015 Award Recipients

www.cshp.org partners in medication management John J. Carbone Memorial Scholarship

www.cshpfoundation.org CALIFORNIA JOURNAL OF HEALTH-SYSTEM PHARMACY

SEPTEMBER/OCTOBER 2015 VOL. 27 NO. 5

Perspective 137 Continuing Pharmacy Education 139 New Drugs New Practitioners 153 Have You Considered a Drug Information Residency? 2015 Award Recipients 157

CPE Self -Assesment Exam To complete the exams, go to http://cshp.wcea.education/ You will be asked to either create an account or log in. Once you complete the exam and evaluation, your credit will be automatically uploaded to CPE Monitor within 45 days. Free credit is only available to CSHP members. CSHP is not responsible for credit upload failure due to incomplete or inaccurate NABP information. VOL. 27 NO. 5

Peer Review Editor CSHP mission The California Journal of Health-System Pharmacy is a MaryAnne Bobrow, CAE, CMP, CMM, CHE To Represent and peer-reviewed publication! Managing Editor The CSHP Editorial Advisory Board is pleased to announce Cynthia Hespe, RPh, FCSHP Empower Pharmacists and that the California Journal of Health-System Pharmacy has completed the transition to peer review. Pharmacy Technicians Design Consultant Peer reviewed, or refereed, publications utilize an editorial HareLine Graphics Practicing in Health- process to ensure that the articles published are as scholarly as possible. From this point forward, when an Editorial Advisory Board Systems to Promote article is submitted to CJHP, the editors will send it out to other (peer) pharmacists and clinicians in the same field Ron Floyd, Chair Christopher Mapes Wellness, Patient Safety to obtain their opinion as to the appropriateness of the Marcus Ravnan, Chair-Elect Sarah McBane manuscript for publication, the relevance to the field of Gary Besinque Bailey Nguyen and Optimal Use of study, and the quality of the research. Tania Chopra Todd Okamoto Medications Angelic Ervin Anne Tran-Pugh Instructions for Authors California Society The California Journal of Health-System Pharmacy of Health-System Pharmacists welcomes article submissions in any field pertinent to CSHP vision Officers the practice of health-system pharmacy. All manuscripts Stacey Raff [email protected] submitted are subject to peer review. To submit a Pharmacists are Recog- President manuscript for publication, please visit http://cshpjournal. Kethen So [email protected] nized as Leaders in msubmit.net. Authors without access to the internet may President-Elect send a printed copy of their manuscript along with a CD, Wellness, Patient Safety Betty Jue [email protected] DVD or USB drive to: CJHP, attn: Managing Editor, 1314 H Chair, Board of Directors Street, Suite 200, Sacramento, CA 95814. and the Optimal Use of Brian Kawahara [email protected] For more information on article submission, Peer Review, or Chair, House of Delegates Medications CJHP, please contact Cindy Hespe, Managing Editor, CJHP at Jason Bandy [email protected] [email protected] or 916.447.1033. Treasurer MaryAnne Bobrow [email protected] Interim EVP/CEO

CJHP (ISSN 1097-6337) is published bimonthly by the California Society of Health-System Pharmacists, Directors 1314 H Street, Suite 200, Sacramento, CA 95814, under the guidance of the Editorial Advisory Board. Annet Arakelian [email protected] The CJHP is distributed as a regular membership service, paid through allocation of membership dues. Jeanette Carpenter [email protected] The subscription rate for non-members is $75 per year; single copies are $15. Periodicals postage paid at Elizabeth Chang [email protected] Sacramento, CA. Postmaster: Send address change to California Society of Health-System Pharmacists, Tania Chopra [email protected] 1314 H Street, Suite 200, Sacramento, CA 95814 (email: [email protected]). Martin Iyoya [email protected] The views expressed by authors of contributions in the California Journal of Health-System Pharmacy do Rich Levy [email protected] not necessarily reflect the policy of CSHP or the institution with which the author is affiliated, unless this is Jeanne Li [email protected] clearly specified. Policy statements and official positions of CSHP are clearly labeled as such. The editor and Lisa Lum [email protected] publisher assume no responsibility for material contained in articles and advertisements published, nor does Ken Schell [email protected] publication necessarily constitute endorsement by them. Letters to the editor are encouraged. Publisher Mariam Shafik [email protected] reserves the right to edit, reject or publish whole or part of manuscripts submitted. No portion of this Kali Sommer [email protected] magazine may be reproduced, in whole or in part, without written consent of CSHP. © 2014 by the California Anne Tran-Pugh [email protected] Society of Health-System Pharmacists. Payments to CSHP are not deductible as charitable contributions for federal income tax purposes; however, they may be deductible under other provisions of the Internal Revenue Code. For display and employment advertising, please contact CSHP Industry Relations at [email protected] or (916) 447-1033 Cover image: Triangle swirl

136 cjhp California Journal of Health-System Pharmacy September/October 2015 PERSPECTIVE CPE: Text

President’s From Where I Sit Perspective MaryAnne Bobrow, CAE, CMP, CMM Interim EVP/CEO Stacey Raff, PharmD, BCPS CSHP President

your outgoing president, I want to thank the California his time of the year is filled with thoughts and anticipation As Society of Health-System Pharmacists (CSHP) membership T for a great CSHP Seminar. All of the hard work of dedicated for the honor of allowing me to represent you this past year. 2015 volunteers, staff and the CSHP Board of Directors comes to brought many changes to CSHP, yet as a society, we have united fruition in San Diego in early October. Late summer and early and are forging forward. CSHP members’ passion and commit- fall brought new faces to CSHP and with those new faces came ment to the profession and our integrity as an organization have additional energy and new ideas to ensure CSHP’s signature never been more evident. event provided a positive and enriching experience for CSHP members. To say that the San Diego weather cooperated to provide During this time of transition, we have continued to make bright sunny days and warm nights was truly an understatement. an impact in the legislature and the California State Board of Breathing a sigh of relief that Seminar 2015 is done, CSHP staff, Pharmacy. CSHP has worked to continue to provide services committees and the Board of Directors went to work in earnest to to our membership and make changes to our infrastructure. continue to bring CSHP forward. Talented new support staff has been hired to complement skills of the existing team. Meanwhile, our Executive Vice President/ A new association management systems (AMS) was built in CEO Search Committee, chaired by Past President Alan Endo, the background as we continued to connect with members is working to find our new EVP/CEO. through older communication channels. Each day brought Coming out of Seminar, I’d like to thank the staff and committees who worked hard to plan and organize a great educational and networking event for our members. Seminar is the largest ASHP state-affiliate event, and San Diego provided a spectacular setting. The Seminar Planning Committee found a hilarious comedian-physician, Dr. Brad, as our opening keynote speaker. The CSHP Continuing Pharmacy Education Committee coordinated many great educational sessions. Most speakers were CSHP members who volunteered their time and shared their knowledge with the attendees. Our pharmacy technician, new practitioner and student groups tailored both educational and social events to make Seminar a great experience for their members as well. Volunteerism has always been at the core of CSHP’s culture, and this year was no exception. CSHP’s balance of volunteer commitment and staff expertise achieved a successful Seminar 2015. Thank you to each volunteer and staff member that contributed to making Seminar 2015 a great event for all! Our 2016 Committees, Councils, and Task Forces are being appointed by our incoming president, Kethen So. If you have ever considered volunteering for a committee, I highly recommend it. The experience is fulfilling and a great way to get involved in the pharmacy profession! o

September/October 2015 California Journal of Health-System Pharmacy cjhp 137 Perspective

minor triumphs and energy to tackle other tasks, forging ahead to bring all CSHP functions back on timeline. With time as our only enemy, CSHP is beginning to roll out new communication tools and additional information to help members excel in their professional lives. During this time, CSHP, through its CEO Search Committee, 2015 Corporate Members under the leadership of Alan Endo, conducted itself with due diligence in strategically assessing candidates to fill the vacant Diamond Bar CEO position. While the search continues, it will resume in early spring 2016. Meanwhile, other committees such as the Blue Ribbon Committee continued to work fearlessly to fulfill the charge given to them in July of 2015. Anyone not familiar with the governing documents of CSHP may have difficulties understanding why this work takes a long time, but when dealing with at least four sets of different documents, the review becomes problematics because of conflicts within the documents themselves. This committee, as well as the Board’s own Bylaws Committee have both been looking at CSHP governing documents closely to align all documents with CSHP’s purpose. The Blue Ribbon Committee and the Board’s Bylaws Committee are contemplating an early Spring meeting to see where joint recommendations for changes can be proposed to the membership. Progress is being made, but it is painstaking work. Sapphire As we move from early fall into the season of thanks, it is appropriate for me to thank not only staff but volunteers as well for the support and gratitude they have shown during my short time at CSHP. I wish all the blessings of the

Thanksgiving season. o

Emerald

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138 cjhp California Journal of Health-System Pharmacy September/October 2015 New Drugs

Gary Besinque, PharmD • Jennifer T. Chang, PharmD, MPH • Stephen C. Cheng, PharmD Joshua R. Chua, PharmD, BCPS • Nina M. Escasa, PharmD • Jonathan Goulding, PharmD Natalie Iwamiya, PharmD, BCPS • Anthony Lee, PharmD • Daniel C. Powers, PharmD, MBA, BCPS Cathlene Richmond, PharmD, BCPS • Jiwon Shin, PharmD • Monica A. Yoshinaga, PharmD

Introduction CONTINUING PHARMACY EDUCATION PHARMACY CONTINUING This article is the second of a series about new medications released from 2013 to 2016, and briefly reviews 15 new drug approvals of 2013. Part 1 was published in the March/April 2014 issue (vol. 26, no. 2) of the CJHP.1 The U.S. Food and Drug Administration (FDA) approved 35 novel drugs in 2013, in Learning Objectives: addition to many innovative new dosage forms.2,3 Among the new therapies approved through the FDA Center for Drug Evaluation and Research (CDER) After reading this article, the reader should be able to: were 25 new molecular entities (NMEs) and two therapeutic biologics.2 In 1. List the indications for select medications approved addition, eight novel products were approved by the FDA Center for Biologics by the U.S. FDA in 2013. Evaluation and Research (CBER). 2. Explain the appropriate dosing for new medications. Some of the most notable approvals in the second third of 2013 include 3. Discuss safety concerns for select medications five new oncologic products: radium Ra 223 (Xofigo) for prostate cancer, approved in 2013. trametinib (Mekinist) and dabrafenib mesylate (Tafinlar) for malignant 4. Identify criteria used for efficacy assessments for melanoma, afatinib dimaleate (Gilotrif) for non-small cell lung cancer, and new medications approved in 2013. mechlorethamine (Valchlor) for mycosis fungoides-type cutaneous T-cell 5. Identify potential drug-drug interactions of lymphoma. These middle months also saw the approval of several older medications approved in 2013. drugs in new dosage forms or for new indications: brimonidine (Mirvaso) for rosacea, paroxetine mesylate (Brisdelle) for vasomotor symptoms of menopause, nimodipine (Nymalize) for subarachnoid hemorrhage, and the Requests for Information: previously mentioned mechlorethamine (Valchlor). Daniel C. Powers, PharmD, In the first week of October 2014, a fortuitous situation occurred when the MBA, BCPS first study published on national trends in spending for oral oncology agents Drug Use Management was released the day after a 60 Minutes special aired on the high cost of cancer Southern California Region drugs. The study, published in Health Affairs, looked at nearly six years of cost Kaiser Permanente Medical Care Plan and usage data from 2006 through 2011 and concluded that although the use Downey, CA of oral agents had increased by 10% during the study period, the costs had [email protected] increased by 37%.4 This rate of increase was greater than that seen in any other therapeutic category during that time.4 Accreditation Information On the 60 Minutes report, Dr. Leonard Saltz, a gastrointestinal oncologist at 0126-0000-16-605-H01-P Memorial Sloan Kettering in New York, discussed the “financial toxicity” that Release Date: May 9, 2016 newer oncology agents exhibit.5 These new medications, costing over $100,000 Expiration Date: May 9, 2019 per year, typically offer modest improvements in median survival. Patients 1.5 Contact Hours dealing with fear and anxiety of their diagnosis must then deal with how to Target Audience: Pharmacists afford the treatment, often risking bankruptcy or depleting their children’s inheritance. Dr. Saltz stated that “The challenge is knowing where to draw the line between how long a drug extends life and how much it costs.”5 Dr. Hagop Kantarjian, head of the leukemia department at MD Anderson in Houston, noted that pricing of new oncology medications is unreasonable, unsustainable, and in his opinion, immoral. He stated, “The only drug that works is a drug that a patient can afford.”5

September/October 2015 California Journal of Health-System Pharmacy cjhp 139 CPE: New Drugs

Of note, there were nine new oncologics the number of days until adequate wound to oral iron, or have had unsatisfactory approved during 2013, five of these in healing is achieved (refer to prescribing response to oral iron.8 All of the the second four months of 2013: three information) are taken into account. For contemporary IV iron formulations are orals, one parenteral, and one topical. routine prophylaxis, the usual dose is colloids that consist of spheroidal iron- Wholesale costs on these five new 40 to 60 international units per kg body carbohydrate nanoparticles. The colloidal agents range from $5-$10 thousand per weight twice weekly.6 shell of carbohydrate stabilizes the month, $60-$120 thousand per year, and iron-oxyhydroxide core and slows down sadly continue the financial toxicity of Efficacy the release of bioactive iron to reduce oncologic therapies. Coagulation Factor IX (Recombinant) adverse effects.9 as Rixubis is a purified protein produced Provided below are the summaries of the by recombinant DNA technology with Dosage and Administration indication, dosing and administration, an identical amino acid sequence to the Ferric carboxymaltose (FCM) is efficacy, and safety of selected significant Ala-148 allelic form of plasma-derived available in 750 mg/15 ml single-use new drugs approved by the FDA from Factor IX. Approval of Rixubis was vials and is administered intravenously May through October 2013. Table 1 based on the results of a pivotal Phase as a 15-minute infusion or undiluted provides a more comprehensive listing I/III trial in 73 previously treated male as a slow push at 2 ml/min. For of New Drug Application (NDA) and patients treated for routine prophylaxis individuals weighing 50 kg or more, the Biologics License Application (BLA) or on-demand treatment.7 An ongoing FDA-approved dose is 750 mg given in approvals during this same period. study at the time of approval also two doses at least one week apart for a Efficacy and safety results based on evaluated previously treated patients total cumulative dose not to exceed 1.5 clinical data available at the time of FDA undergoing major or minor surgeries. gm of iron per course. For individuals approval, derived from the most current Rixubis increased plasma Factor IX weighing less than 50 kg, the dose is 15 prescribing information, are presented. levels to desired ranges and achieved mg/kg given as two doses at least seven hemostasis. A supplemental BLA for days apart, up to a maximum of 1.5 gm Blood Disorders approval to prevent and treat bleeding of iron per course.8 Coagulation Factor IX (Recombi- episodes in pediatric patients with Efficacy nant) (Rixubis) lyophilized powder hemophilia B was submitted to the FDA for injection in single-use vials in December 2013.7 FDA approval was based on two pivotal containing 250, 500, 1000, 2000, or Phase III randomized, open-label, 3000 international units Safety active-control trials: 1VIT09030 and Adverse reactions in clinical trials 1VIT09031. 1VIT09030 assessed the Indication included dysgeusia, pain in the extremity, efficacy and cardiovascular safety of Coagulation Factor IX (Recombinant) and positive furin antibody test. FCM compared to IV iron sucrose in (Rixubis) is indicated for adults Contraindications include hypersensitivity NDD-CKD patients with IDA. In terms and children with hemophilia B to hamster protein or components of of percentage of subjects achieving a for: (1) control and prevention of Rixubis, disseminated intravascular change-from-baseline hemoglobin (Hb) bleeding episodes; (2) perioperative coagulation (DIC), or signs of fibrinolysis. ≥ 1.0 gm/dl, FCM was non-inferior to management; and (3) routine Rixubis shares warnings and precautions iron sucrose at the end of the eight-week prophylaxis to prevent or reduce the with other Factor IX products, including trial. Superiority of FCM versus iron frequency of bleeding episodes.6 but not limited to, risk for thrombosis and sucrose was demonstrated, however, 6 Dosage and Administration nephrotic syndrome. in the primary endpoint of maximum change in Hb from baseline (1.13 ± 1.04 The specific activity of Rixubis is Ferric carboxymaltose (Injectafer) vs. 0.92 ± 0.92 g/dL, respectively; 95% CI greater than 200 international units per 50 mg iron/ml injection [0.13 to 0.28]).8 milligram of protein. For control and Indication prevention of bleeding episodes and 1VIT09031 was conducted to determine perioperative management, the initial Ferric carboxymaltose (Injectafer) is the safety and efficacy of FCM compared and maintenance intravenous dosing is a novel non-dextran intravenous (IV) to oral iron and IV standard-of-care calculated as a function of body weight iron treatment for adult patients with (IVSC) comprised of IV iron dextran, and the desired increase in Factor IX. iron-deficiency anemia (IDA) who have iron gluconate or iron sucrose for the Also, the type of bleed or surgery, the non-dialysis-dependent chronic kidney treatment of IDA. The study included intensity of the hemostatic challenge, and disease (NDD-CKD), have intolerance patients who were either intolerant to

140 cjhp California Journal of Health-System Pharmacy September/October 2015 CPE: New Drugs oral iron therapy or had an inadequate the incidence of cardiovascular events hours after application on day 29 (p < response (Hb increase < 1 gm/dl) after a and hypophosphatemia following 0.001).13 The secondary endpoint, a two-week lead-in period with oral iron. treatment with FCM.10,11 one-grade improvement of erythema 1VIT09031 demonstrated a statistically was also significant for the treatment significant number of patients with Hb ≥ Dermatology group versus the vehicle group at 3, 6, 12 gm/dl while receiving FCM (53.7%) 9 and 12 hours after application on day versus oral iron (29.1%) or IVSC (24.5%), Brimonidine (Mirvaso) 29. Tachyphylaxis or loss of effect was as well as superiority of FCM compared 0.33% topical gel not reported at 12 months of continued to oral iron for change in Hb from Indication use; however, only 62.1% of patients baseline to highest observed value (1.57 Brimonidine topical gel (Mirvaso) is completed 12 months treatment.13 ± 1.194 vs. 0.80 ± 0.80 g/dL, p < 0.001).8 the first pharmacologic agent to be FDA approved for the treatment of rosacea, Safety The benefit of IV over oral iron Brimonidine topical gel should be used supplementation has been explored in but it is only approved to treat subtype 1 (erythematotelangiectatic) rosacea. with caution in patients with depres- several meta-analyses demonstrating sion, cerebral or coronary insufficiency, both a superior increase in Hb and a It is an alpha-2 adrenergic agonist thought to reduce erythema through Raynaud’s phenomenon, orthostatic decreased need for erythropoietin- hypotension, thromboangiitis obliterans, stimulating agents. Three published direct vasoconstriction. It is indicated for persistent (non-transient) facial scleroderma, or Sjogren’s syndrome due head-to-head comparisons of IV iron to potentiation of vascular insufficiency. sucrose vs. low-molecular-weight iron erythema of rosacea in adults 18 years of age or older.12 Brimonidine may lower blood pressure dextran, FCM, and ferumoxytol have and caution should be used in patients shown no significant differences in Dosage and Administration with severe, uncontrolled or unstable efficacy or safety.9,10 Apply a pea-size amount of the gel once cardiovascular disease. Brimonidine use with monoamine oxidase inhibitors Safety daily to each of the five areas of the (MAOIs), cardiac glycosides, or antihy- The product information labeling for face: central forehead, chin, nose, and pertensives may theoretically increase the each of the IV iron products contain each cheek. The gel should be applied risk for hypotension. The most common warnings of the potential for rare, but smoothly and evenly as a thin layer adverse reactions are flushing (10%), serious, hypersensitivity reactions across the entire face avoiding the eyes erythema (8%), rosacea (5%), nasophar- (HSR) and caution that they should be and lips. The hands should be washed yngitis (5%), skin burning sensation administered only under close medical after application to the face. Brimonidine (4%), increased intraocular pressure supervision with trained personnel and topical gel is not for oral, ophthalmic, or 12 (4%), and headache (4%).12 therapies immediately available to treat intravaginal use. anaphylactic-type reactions. These HSRs Efficacy are attributed to the release into the Gynecology FDA approval was based on two four- bloodstream of significant amounts of week, randomized, double-blind, Paroxetine mesylate bioactive labile iron and have been largely vehicle-controlled trials evaluating the (Brisdelle) 7.5 mg capsules curtailed by more strict compliance with safety and efficacy of brimonidine 0.33% Indication recommendations for administration in as monotherapy versus vehicle in adults Paroxetine mesylate is a selective the labeling.11 Additionally, compared with moderate to severe erythema. A serotonin reuptake inhibitor (SSRI) to earlier IV iron products, FCM and two-grade improvement of erythema and Brisdelle is the first FDA-approved, the other newer IV iron formulations as measured by Clinician’s Erythema non-hormonal agent for the treatment of have more complex carbohydrate shells Assessment (CEA) and Patient’s Self- moderate to severe vasomotor symptoms that bind iron more avidly, limiting the Assessment (PSA) scale were considered (VMS) associated with menopause.14 release of labile iron and minimizing clinically relevant and was the primary the occurrence of HSR. These features endpoint of the pivotal trials. A Dosage and Administration allow for comparatively faster infusions two-grade improvement of erythema The recommended dose of Brisdelle is 7.5 of higher doses and even offer some was significant for the treatment group mg once daily, at bedtime.14 iron-deficient patients the potential for versus the vehicle group at 3 (28% complete iron repletion in a single dose. versus 10%), 6 (28% versus 9%), 9 (22% Compared to oral iron and IVSC, there versus 10%), and 12 (22% versus 9%) were statistically significant increases in

September/October 2015 California Journal of Health-System Pharmacy cjhp 141 CPE: New Drugs

Efficacy 14 days of stopping Brisdelle, is also patients, dolutegravir combined with The efficacy of paroxetine for the contraindicated. Paroxetine is a potent two nucleotide reverse transcriptase treatment of moderate to severe VMS at inhibitor of CYP2D6, and may reduce inhibitors (NRTIs) led to 48-week viral a dose of 7.5 mg once daily was evaluated the efficacy of tamoxifen.14 In December suppression rates of 88% in each trial. in two Phase III, randomized, double- 2014, the labeling for Brisdelle was This is compared to 86% with raltegravir blind, placebo-controlled studies (n = revised to note the risk for angle closure plus background regimen arm and 81% 1174).14,15 The primary endpoints were glaucoma in patients with untreated for the Atripla arm. For treatment- the reduction in daily VMS frequency anatomically narrow angles treated with experienced but integrase inhibitor-naïve and severity at weeks 4 and 12 from antidepressants.14 patients, 79% achieved viral suppression baseline. Postmenopausal women with at 24 weeks compared to 70% with a a minimum of 7-8 moderate to severe Infectious Diseasse raltegravir-based regimen. A single-arm vasomotor symptoms per day at baseline trial in treatment-experienced patients for 30 days before receiving study drug Dolutegravir sodium including integrase inhibitor-resistant were included. (Tivicay) 50 mg tablets patients demonstrated 63% rate of viral Indication suppression at 24 weeks. One open- The change in daily VMS frequency from label pediatric study demonstrated viral baseline (median at baseline for Study 1 Dolutegravir (Tivicay) is the third-in-class suppression of 70% at 24 weeks.17 = 10.4 for both arms; Study 2 = 9.9 for human immunodeficiency virus (HIV) antiretroviral to target the integrase Brisdelle, 9.6 for placebo) was statistically Safety significant for both Study 1 (-5.9 vs. -5.0 strand transfer enzyme, following The most common adverse events included with placebo; treatment difference = -0.9; raltegravir and elvitegravir. It is indicated insomnia and headache, with some p < 0.01) and Study 2 (-5.6 vs. -3.9 with in combination with other antiretrovirals hypersensitivity reactions being reported. placebo; treatment difference = -1.7; p < for HIV-1 infection in adults and children Increased transaminases can occur in 0.01) at week 12.14 aged 12 years and older. It is approved for adults who are both antiretroviral-naïve patients with underlying hepatic disease. The change in VMS severity (rated from and -experienced, including integrase Dolutegravir is metabolized by UGT1A 1 = mild to 3 = severe) from baseline inhibitor-experienced. It is also approved with some contribution by CYP3A. Higher (median at baseline = 2.5 for all arms in for children who are antiretroviral-naïve dolutegravir doses are necessary when both studies) was statistically significant or experienced, but integrase inhibitor- co-administered with potent inducers for Study 2 (-0.05 vs. 0.00 with placebo; naïve. For integrase inhibitor-experienced of these enzymes. Inhibitors of CYP3A treatment difference = -0.05; p <0.01), patients, the use of dolutegravir must had no clinically significant effect on 16 but not for Study 1 (-0.06 vs. -0.02 with be guided by the number and type dolutegravir pharmacokinetics. placebo; treatment difference = -0.04; p = of integrase strand transfer inhibitor 14 0.17) at week 12. baseline substitutions.16 Neurology The proportion of “responders” in Study Dosage and Administration Nimodipine (Nymalize) 2, defined as patients achieving a ≥50% 60 mg/20 ml oral solution The dose is 50 mg orally daily for both reduction in the frequency of moderate pediatric (age ≥ 12 and weight ≥ 40 kg) Indication to severe VMS at week 24 compared and adult patients. Dosing frequency Nimodipine (Nymalize) oral suspension to the baseline, was higher in patients is recommended to be increased to 50 is a calcium channel blocker indicated treated with Brisdelle (48% vs. 36% with mg twice daily with integrase inhibitor- for the improvement of neurological placebo; p=0.0066).14 associated resistance or due to drug-drug outcome in adult patients with Safety interactions. Co-administration with subarachnoid hemorrhage (SAH) from Brisdelle carries a boxed warning potent UGT1A or CYP3A inducers may ruptured intracranial berry aneurysms 16 regarding suicidal thoughts and behav- require use of the twice daily dose. by reducing the incidence and severity of 18 iors similar to other SSRIs.14 Similar ischemic deficits. Efficacy to other dosage forms of paroxetine, Approval of dolutegravir was based on Dosage and Administration the use of Brisdelle with an MAOI is three randomized, active-controlled Nymalize treatment should be initiated contraindicated because of an increased studies, and one open-label single within 96 hours of the onset of SAH.18 risk of serotonin syndrome. The use of arm study in HIV-infected patients. The recommended dose is 20 mL (60 mg) Brisdelle within 14 days of stopping an In two studies of treatment-naïve every 4 hours for 21 consecutive days. For MAOI, or the use of an MAOI within

142 cjhp California Journal of Health-System Pharmacy September/October 2015 CPE: New Drugs patients with cirrhosis, the dosage should Oncology be reduced to 10 mL (30 mg) every 4 Radium Ra 223 dichloride (Xofigo) hours, as the bioavailability of nimodipine 1,000 kBq/mL injection is significantly increased in this group of patients, which increases the risk for Indication serious hypotensive episodes.18 Radium Ra 223 dichloride (Xofigo) is an intravenous, alpha particle-emitting Efficacy radioactive therapeutic agent indicated The efficacy of Nymalize to improve for the treatment of patients with neurological outcome in adult patients castration-resistant prostate cancer with The only drug that with SAH is based on previously symptomatic bone metastases, and no available clinical studies with nimodipine known visceral metastatic disease.21 works is a drug the oral capsules. The bioavailability of patient can afford. nimodipine oral solution is comparable Dosage and Administration 18 The recommended dose of Xofigo is to nimodipine oral capsules. –Hagop Kantarjian, MD 50 kBq (1.35 microcurie) per kg body Safety weight, given at four-week intervals for Prior to the approval of Nymalize a total of six doses.21 Safety and efficacy oral suspension, nimodipine was only beyond six doses are unknown. The available as oral capsules. For patients volume to be administered must be who cannot swallow capsules whole, calculated using body weight, dosage the content of the liquid-filled gel level, radioactivity concentration of the capsules had to be extracted using product (1,000 kBq/mL = 27 microcurie/ syringes with needles. This practice mL) at the reference date, and a decay has resulted in serious and sometimes correction factor to account for the fatal consequences from accidently radioactive decay of radium 223. Xofigo administering the content of the syringe is administered intravenously slowly over as intravenous (IV) injection.19,20 one minute. The intravenous access line Parenteral administration of nimodipine should be flushed with isotonic saline intended for oral administration can before and after the dose is given.21 result in severe hypotension, cardiac arrest, or death. In January 2006, a boxed Efficacy warning was added to nimodipine oral Xofigo was studied in a double-blind, capsules prescribing information sheet to randomized, placebo-controlled Phase describe the risks of accidental parenteral III clinical trial of 921 patients with administration of nimodipine extracted castration-resistant prostate cancer and from oral capsules into syringes.19 In symptomatic bone metastases. The two August 2010, the FDA issued a warning treatment groups were radium Ra 223 to remind healthcare professionals about dichloride versus a matching placebo. the risks of accidental IV administration Additionally, both groups received best of oral nimodipine.19 standard of care therapy. The primary end point was overall survival. The Blood pressure should be closely interim analysis showed significantly monitored during nimodipine improved survival in the radium Ra 223 treatment. In clinical studies, dichloride group (p = 0.002).22 The study hypotension was reported more was terminated for efficacy during the frequently in patients treated with interim analysis. Nymalize (5% vs. 1% with placebo).18 Concomitant use of strong inhibitors of Safety CYP3A4 with nimodipine may increase Xofigo is contraindicated in pregnancy; 18 the risk of significant hypotension. however, it is not indicated for use in women. In the Phase III trial, 2% of

September/October 2015 California Journal of Health-System Pharmacy cjhp 143 CPE: New Drugs patients in the radium Ra 223 dichlo- trametinib and dabrafenib was based on at least one hour before or at least two ride group experienced bone marrow results from an open-label Phase I/II trial hours after a meal. The BRAF V600 failure or pancytopenia compared which showed that combination therapy mutation must be confirmed in tumor to 0% in the placebo group.21 Deaths improved the ORR when compared specimens before the initiation of treat- related to vascular hemorrhage in with dabrafenib alone (76% versus 54%, ment with dabrafenib.25 association with myelosuppression p=0.03).24 The median duration of were seen in 1% of the radium Ra response was 10.5 months with combina- Efficacy 223 dichloride group and 0.3% of the tion therapy compared with 5.6 months Dabrafenib prolonged the median PFS placebo group. The most common with dabrafenib alone. The combination by 2.4 months compared to dacarbazine adverse effects of radium Ra 223 of trametinib and dabrafenib, however, [(DTIC) 5.1 months vs. 2.7 months] dichloride were diarrhea, nausea, has not demonstrated an improvement in as a primary endpoint in the pivotal 26 vomiting, and peripheral edema.21 disease-related symptoms or OS.24 BREAK-3 study. The ORR was 50% for the dabrafenib arm compared to 6% for Trametinib (Mekinist) Safety the DTIC arm. The median OS was 18.2 0.5 mg, 1 mg, 2 mg tablets Common adverse events associated with months (95% CI: 16.6, not reached) for Indication trametinib monotherapy were rash, dabrafenib compared to 15.6 months for Trametinib (Mekinist) is indicated diarrhea, fatigue, peripheral edema, and DTIC [95% CI: 12.7, not reached; HR 23 as a single agent, and in combination acneiform dermatitis. Other safety issues 0.76 (0.48, 1.21)]. Forty-four percent with dabrafenib, for the treatment of identified as a possible class effect of MEK of patients crossed over from DTIC to patients with unresectable or metastatic inhibitors include hypertension, increased dabrafenib which may have confounded melanoma with BRAF V600E or aspartate aminotransferase (AST) and/ the OS results. Based on the 15-month V600K mutations as detected by an or alanine aminotransferase (ALT), and follow-up OS results, the number needed 26 FDA-approved test. Trametinib as a muscle weakness. The most common to treat (NNT) was eight. The approval single agent is not indicated for the adverse events associated with the combi- for the combination of dabrafenib and treatment of patients who have received nation of trametinib and dabrafenib trametinib was based on results from prior BRAF-inhibitor therapy.23 compared to dabrafenib monotherapy the Phase I/II trial previously discussed was pyrexia (71% vs. 26%).23 There is that showed that trametinib combined Dosage and Administration a decreased incidence of cutaneous with dabrafenib significantly improved The recommended dose is 2 mg once squamous-cell carcinoma in the combina- PFS and ORR when compared with 24 daily taken at least one hour before or tion therapy (7%) compared to dabrafenib dabrafenib alone. Although the combi- 23 at least two hours after a meal.23 monotherapy (19%, p=0.09). Monitor nation of trametinib and dabrafenib has patients throughout therapy for cardio- not demonstrated an improvement in Efficacy myopathy, ocular toxicities (e.g., retinal disease-related symptoms or OS, a Phase Trametinib prolonged-progression free vein occlusion), interstitial lung disease 3 study of this combination is currently survival (PFS) by 3.3 months compared (ILD), and serious skin toxicities.23 in progress. to chemotherapy [4.8 months vs. 1.5 months; HR 0.47 (95% CI: 0.34, 0.65); Dabrafenib (Tafinlar) 50 mg, Safety p < 0.0001] in the pivotal, Phase III 75 mg capsules The most commonly reported adverse METRIC study.23 Overall survival Indication events associated with dabrafenib were (OS) was the secondary endpoint, Dabrafenib in combination with hyperkeratosis, papillomas, palmer- but the data was not mature. Almost trametinib is indicated for the treatment plantar erythrodysesthesia syndrome, half of the patients were also allowed of patients with unresectable or pyrexia, fatigue, headache and 25 crossover to the trametinib arm. An metastatic melanoma with BRAF V600E arthralgia. Cutaneous squamous cell OS analysis of the intention-to-treat or V600K mutations as detected by an carcinomas (cuSCC) and keratoacan- population reported 16% mortality in FDA-approved test. Dabrafenib is not thoma occurred in 7% of patients treated the trametinib arm compared to 27% indicated for treatment of patients with with dabrafenib. Some unique adverse in the chemotherapy arm [HR 0.56 wild-type BRAF melanoma.25 events associated with dabrafenib were (95% CI 0.33, 0.95); p=0.0136]. The serious febrile drug reactions, hyper- 25 objective response rate (ORR) was 22% Dosage and Administration glycemia, uveitis, and iritis. In a Phase versus 2% in the chemotherapy arm.23 The recommended dose is 150 mg orally II study, the combination of dabrafenib The approval for the combination of twice daily. Dabrafenib should be taken and trametinib has led to decreased

144 cjhp California Journal of Health-System Pharmacy September/October 2015 CPE: New Drugs incidence of cuSCC, papilloma, and Mechlorethamine (Valchlor) Patients were randomized to receive hyperkeratosis which are commonly 0.016% topical gel either the Valchlor formulation or an 24 seen in dabrafenib monotherapy. There Indication Aquaphor-based mechlorethamine HCl was a higher incidence of severe pyrexia, 0.02% ointment (comparator). Sixty Valchlor is the first FDA-approved chills, and gastrointestinal effects, mainly percent of the patients in the Valchlor topical formulation of mechlorethamine Grade 1 and 2, while the incidence of arm and 48% of the patients in the HCl, a nitrogen mustard alkylating acneiform dermatitis was lower with comparator arm achieved a response agent. It is indicated for Stage IA and IB this combination.24 based on the Composite Assessment mycosis fungoides-type cutaneous T-cell of Index Lesion Severity (CAILS) lymphoma in patients who have received Afatinib (Gilotrif) score. Fourteen percent of patients prior skin-directed therapy.29 20 mg, 30 mg, 40 mg tablets achieved a complete response and 45% Indication Dosage and Administration of patients achieved a partial response Afatinib (Gilotrif) is a kinase inhibitor Valchlor must be stored in the in the Valchlor arm, compared to 11% indicated for the first-line treatment of refrigerator once dispensed.29 It is applied and 37% of patients in the comparator metastatic non-small cell lung cancer as a thin film once daily to the affected arm, respectively. Fifty percent of the (NSCLC) in patients whose tumors have areas of the skin. The skin should be patients on the Valchlor arm and 46% the EGFR exon 19 deletions or exon completely dry, and the application of the patients on the comparator 21 (L858R) substitution mutations as should be done more than four hours arm achieved a response based on the detected by an FDA-approved test.27 before or 30 minutes after showering Severity Weighted Assessment Tool or washing.29 The gel may be applied (SWAT) score. Seven percent of patients Dosage and Administration immediately or within 30 minutes after achieved a complete response and 43% The usual dose of afatinib is 40 mg orally, removal from the refrigerator. The of patients received a partial response once daily. Patients should be instructed treated areas should be allowed to dry in the Valchlor arm, compared to 3% to take afatinib at least one hour before for 5 to 10 minutes after application and 43% of patients in the comparator or two hours after a meal. The dose before covering with clothing. Emollients arm, respectively. Valchlor was found to 30 should be modified for drug-related may be applied two hours before or be non-inferior to the comparator. adverse reactions or concomitant therapy after application. Occlusive dressings 27 Safety with Pg-p inhibitors and inducers. should not be used with Valchlor.29 Mechlorethamine is an alkylating Because mechlorethamine is a cytotoxic Efficacy agent and safe handling is required. drug, thorough hand washing with In the pivotal LUX-Lung 3 study, The most common adverse effects with soap and water after handling and afatinib prolonged median PFS by incidence ≥5% are dermatitis, pruritus, application is required. Caregivers must 4.2 months compared to cisplatin bacterial skin infection, skin ulceration wear disposable nitrile gloves when plus pemetrexed (11.1. months vs. or blistering, skin hyperpigmentation, applying Valchlor to patients. If there 6.9 months, respectively).27,28 The OS reductions in hemoglobin, neutrophil is accidental skin exposure, caregivers data showed no significant difference count, or platelet count.29 The following must immediately wash exposed areas between afatinib and doublet may occur with mechlorethamine thoroughly with soap and water for chemotherapy treatment (median OS of treatment: mucosal eye injury, secondary at least 15 minutes and remove any 28.1 vs. 28.2 months, respectively).27,28 exposure, dermatitis, non-melanoma contaminated clothing.29 skin cancer, and embryo-fetal toxicity Safety 29 Efficacy (Pregnancy Category D). Of note, the Diarrhea is a common side effect (96% Valchlor was assessed in a randomized, mechlorethamine gel may be flammable; for all Grades and 15% for Grade 3 and multicenter, observer-blind, active- therefore open flame and smoking should above).27 The most frequently reported controlled, non-inferiority clinical trial be avoided during the application process serious adverse reactions include diarrhea of 260 patients with Stage IA, IB, and and until the gel has dried. (6.6%), vomiting (4.8%), dyspnea, fatigue, IIA mycosis fungoides-type cutaneous and hypokalemia (1.7% each). Reported T-cell lymphoma (CTCL) who had fatal adverse reactions include pulmo- received prior skin-directed therapy nary/interstitial lung disease (ILD)-like (including topical corticosteroids, adverse reactions (1.3%), sepsis (0.43%), phototherapy, bexarotine (Targretin) and pneumonia (0.43%).27 gel, and topical nitrogen mustard).30

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Neurology/Psychiatry At 40 mg per day, levomilnacipran Authors Levomilnacipran (Fetzima) resulted in a placebo-adjusted Gary Besinque, PharmD, FCSHP improvement of 3.2 and 3.3 points on the Pharmacist Evidence Analyst and Strategist 20 mg, 40 mg, 80 mg, 120 mg Drug Information Services – California Regions extended-release capsules Montgomery–Åsberg Depression Rating Kaiser Permanente Medical Care Plan Scale (MADRS) in patients with baseline [email protected] Indication scores of 36.0 and 30.8, respectively.31 Jennifer T. Chang, PharmD, MPH Levomilnacipran (Fetzima) is a serotonin At 80 mg, there was a placebo-adjusted Supervisor, Regional P&T Committee Coordinator Drug Information Services – California Regions and norepinephrine reuptake inhibitor improvement of 4.0 and 3.1 points on Kaiser Permanente Medical Care Plan (SNRI) indicated for the treatment of MADRS scores in patients with baseline [email protected] 31 major depressive disorder in adults. scores of 36.1 and 31.2, respectively.31 In Stephen C. Cheng, PharmD one fixed-dose study, the 120 mg daily Pharmacist Evidence Analyst and Strategist Dosage and Administration Drug Information Services – California Regions dose resulted in a 4.9-point placebo- The recommended dosing titration of Kaiser Permanente Medical Care Plan adjusted improvement over baseline [email protected] levomilnacipran is 20 mg daily for two of 36.0. The flexible-dose trial, which Joshua R. Chua, PharmD, BCPS days, followed by an increase to 40 mg Drug Education Coordinator studied doses ranging from 40 mg to daily. The daily dose may be increased by Pharmacy Services, East Bay Area 120 mg daily, found an overall 3.1-point Kaiser Permanente Medical Care Plan 20 mg at intervals of two or more days placebo-adjusted improvement in [email protected] up to a maximum recommended dose MADRS score over a baseline of 35.0.31 Nina Escasa, PharmD of 120 mg per day.31 The capsule must Pharmacist Evidence Analyst and Strategist Drug Information Services – California Regions be swallowed whole, and may be taken Safety Kaiser Permanente Medical Care Plan without regard to food. [email protected] Levomilnacipran carries the class boxed warning on suicidal thoughts and Jonathan Goulding, PharmD The maximum daily dose is reduced Pharmacist Evidence Analyst and Strategist to 80 mg per day in moderate renal behaviors in children, adolescents, and Drug Information Services – California Regions young adults taking antidepressants. Kaiser Permanente Medical Care Plan impairment (CrCl 30-59 mL/min) or [email protected] when used concomitantly with CYP 3A4 Levomilnacipran is not indicated for use in patients younger than 18 years of age.31 Natalie Iwamiya, PharmD, BCPS inhibitors, and is 40 mg per day with Pharmacist Evidence Analyst and Strategist severe renal impairment (CrCl 15-29 mL/ Drug Information Services – California Regions Pre-existing hypertension, tachycardia, Kaiser Permanente Medical Care Plan min). Patients with CrCl less than 15 mL/ or other cardiac disorders should 31 [email protected] min should not take levomilnacipran. be treated before consideration of Anthony Lee, PharmD* levomilnacipran therapy. Cardiovascular Clinical Scientist Associate When discontinuing treatment with Genetech levomilnacipran, the dose should be or cerebrovascular conditions may [email protected] tapered, and not abruptly stopped. be exacerbated by increases in heart Daniel C. Powers, PharmD, MBA, BCPS Abrupt discontinuation may cause rate and blood pressure caused by Manager, Drug Use Management levomilnacipran.31 Southern California Region adverse effects, including mood and Kaiser Permanente Medical Care Plan sensory disturbances, headache, pares- In clinical trials, levomilnacipran [email protected] 31 thesia, and seizures. Exact tapering increased heart rate by an average of Cathlene Richmond, PharmD, BCPS recommendations, however, were not Ambulatory Care Pharmacy Supervisor 7.4 beats per minute (bpm) versus 0.3 Kaiser Permanente San Rafael Medical Center provided by the manufacturer. bpm for placebo. At the 120 mg dose, Ambulatory Care Pharmacy Services the increase was 9.1 bpm. Systolic and [email protected] Efficacy diastolic blood pressure increased by an Jiwon Shin, PharmD There are no head-to-head Pharmacist Evidence Analyst and Strategist average of 3 mm Hg from baseline in trials comparing the efficacy of Drug Information Services – California Regions clinical trials, while blood pressure in Kaiser Permanente Medical Care Plan levomilnacipran against other patients taking placebo did not change. [email protected] antidepressants. The efficacy of Heart rate and blood pressure should be Monica Yoshinaga, PharmD levomilnacipran in adults was studied in Pharmacist Evidence Analyst and Strategist measured at baseline before initiating three eight-week randomized, double- Drug Information Services – California Regions treatment, and monitored periodically Kaiser Permanente Medical Care Plan blind, placebo-controlled studies.31 Two [email protected] thereafter. Discontinuation of levomil- studies used fixed-dose regimens, and the nacipran may be warranted in patients *At the time of writing this article, Dr. Lee was a third was a flexible-dose study. student at UCSF School of Pharmacy with a sustained increase in heart rate or blood pressure. Orthostatic hypotension may also occur.31

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Alcohol should be avoided in patients The dose should be reduced by one-half difference from placebo for the 5 taking levomilnacipran. Alcohol when taken concomitantly with strong mg and 10 mg dose, respectively. A disrupts the controlled-release CYP2D6 inhibitors, or in patients who study conducted in an elderly popula- mechanism of the capsule, causing are known to be poor metabolizers of tion found a 3.3-point difference in an influx of medication to enter the CYP2D6. When taken with strong HAMD-24 from placebo for the 5 mg system at an accelerated rate.31 As an CYP inducers for more than 14 days, dose (mean baseline 29.2).32 SNRI, the concomitant use of MAOIs an increase in vortioxetine dose should One maintenance study showed a is contraindicated due to the risk for be considered.32 13% relapse rate in patients taking serotonin syndrome. Likewise, the use of Abruptly stopping daily doses of 15 vortioxetine versus 26% of patients an MAOI within seven days of stopping to 20 mg may result in withdrawal taking placebo (p=0.0035).33 treatment with levomilnacipran, or symptoms including muscle tension, the use of levomilnacipran within 14 outbursts of anger, mood swings, Safety days of stopping an MAOI, is also dizziness, and headache. When Vortioxetine carries the class boxed contraindicated.31 discontinuing vortioxetine, it is warning on suicidal thoughts and Patients with seizures were excluded recommended to decrease the daily behaviors in children, adolescents, and from clinical trials of levomilnacipran; dose to 10 mg for at least one week to young adults taking antidepressants. therefore, it should be used with caution mitigate withdrawal symptoms.32 Vortioxetine is not indicated for use in in patients with seizure disorders. One patients younger than 18 years of age.32 case of seizure has been reported in a Efficacy The most common adverse effect is nausea, patient taking levomilnacipran.31 There are no head-to-head trials up to 32%. Nausea was the most common comparing the efficacy of vortioxetine reason for early study withdrawal. Other Common adverse effects with an against other antidepressants. The efficacy common adverse effects include diarrhea incidence ≥5% and at least twice the of vortioxetine in adults was studied in six (7-10%), dry mouth (6-8%), constipation rate of placebo-treated patients include: 6- to 8-week randomized, double-blind, (3-6%), vomiting (3-6%), flatulence nausea (17%), constipation (9%), placebo-controlled studies.32 Efficacy (1-3%), dizziness (6-9%), pruritus hyperhidrosis (9%), tachycardia (6%), results varied widely based on study site (1-3%), and abnormal dreams (< 1-3%).32 erectile dysfunction (6%), increased heart (U.S. and non-U.S.) and dose. Efficacy was Vortioxetine is a P450 substrate (primarily rate (6%), palpitations (5%), vomiting measured using the Montgomery–Åsberg CYP 2D6) and is, therefore, subject to (5%), and ejaculation disorder (5%). Depression Rating Scale (MADRS [4/6 significant drug-drug interactions that Dose-related adverse effects reported studies]) or the Hamilton Depression require dose adjustment.32 include urinary hesitancy (4%) and Scale (HAMD-24 [2/6 studies]). None of erectile dysfunction (5%).31 the studies conducted in the United States Rheumatology found the 5 mg, 10 mg, or 15 mg doses to Vortioxetine (Brintellix) 5 mg, 10 Golimumab (Simponi Aria) mg, 20 mg tablets be better than placebo. Only the 20 mg/day dose was found to be better than placebo 50 mg/4 mL (12.5 mg/mL) injection Indication across all studies in which it was used. Indication Vortioxetine (Brintellix) is indicated In U.S. studies, the 20 mg dose resulted Originally approved in 2009 as a for the treatment of major depressive subcutaneous injection, golimumab disorder (MDD) in adults.32 in placebo-adjusted improvements of 2.8 and 3.6 points in MADRS scores over (Simponi Aria) intravenous (IV) is a tumor necrosis factor (TNF) inhibitor Dosage and Administration mean baselines of 32.0 and 32.5 points, indicated for the treatment of adult The recommended starting dose is 10 mg respectively. The size effect was greater patients with moderately to severely daily, without regard to food. If tolerated, (7.1 points) in one non-U.S. study. The active rheumatoid arthritis (RA) in the daily dose should be increased to 20 5 mg, 10 mg, and 15 mg doses resulted combination with methotrexate.34 mg daily. Doses above 20 mg per day in placebo-adjusted improvements of Infliximab is the only other IV-infused have not been evaluated.32 If the initial 10 5.9, 5.7, and 5.5 points, respectively, in TNF inhibitor available, which was first mg dose is not tolerated, a decrease to 5 MADRS scores over baseline in non-U.S. approved in 1998.35 mg per day may be considered; however, studies only. These doses were not better two clinical studies found the 5 mg dose than placebo in U.S. studies.32 to be no better than placebo. A non-U.S. clinical trial using the HAMD-24 found a 4.1- and 4.9-point

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Dosage and Administration treatment of airflow obstruction in patients had higher rates of pneumonia and bone Dosing for golimumab is 2 mg/kg given as with chronic obstructive pulmonary disorders (including fractures) compared an IV infusion over 30 minutes at weeks 0 disease (COPD). It is also indicated for to those on vilanterol alone.34 and 4, then every 8 weeks thereafter.36 reducing exacerbations of COPD in patients with a history of exacerbations.34 Riociguat (Adempas) 0.5, 1, 1.5, 2, Efficacy 2.5 mg film-coated tablets There are no head-to-head trials Dosage and Administration Indication comparing golimumab IV to either Dosing for adults is one inhalation of Riociguat (Adempas) is indicated for subcutaneous golimumab or to inflix- Breo Ellipta 100 mcg/25 mcg once daily, the treatment of persistent/recurrent imab. The FDA approval was based on administered at the same time each chronic thromboembolic pulmonary the single Phase III GO-FURTHER day. After the administration of each hypertension (CTEPH) [World Health trial comprised of RA patients who had daily dose, patients should rinse their Organization (WHO) Group 4] after inadequate responses to methotrexate and mouths with water and spit. The device surgical treatment or inoperable CTEPH were also naïve to TNF inhibitor treat- should be discarded six weeks after it to improve exercise capacity and WHO ment. In combination with methotrexate, is removed from the foil tray or when functional class, and for the treatment of golimumab IV was shown to significantly the dose counter reads “0,” whichever pulmonary arterial hypertension (PAH) 34 improve RA signs and symptoms, disease comes first. Fluticasone exposure may (WHO Group 1) to improve exercise activity, physical function, and radio- be increased in patients with moderate capacity, improve WHO functional class graphic response versus methotrexate or severe hepatic impairment; therefore, and to delay clinical worsening.39 alone. The response rates generally appear monitoring for systemic corticosteroid consistent with those reported for other effects is recommended. Riociguat is a first-in-class small-mole- TNF inhibitors. Also, as typically seen cule agonist of soluble guanylate cyclase with other TNF inhibitors, the onset of Efficacy (sGC), which is the receptor for nitric response occurred as early as week 2. The The NDA for COPD was supported by oxide (NO). Stimulation of sGC results peak response appeared to plateau after 14 four pivotal studies which included two in the production of intracellular cGMP, weeks of therapy.36 24-week confirmatory lung function which influences cellular processes of trials and two 52-week exacerbation inflammation, proliferation, fibrosis, and Safety studies. In the two 24-week lung function vascular tone. Riociguat is thought to When prescribing golimumab IV, studies, patients on Breo Ellipta showed have a dual mode of action: it sensitizes the same standard warnings and significant improvements in lung sGC to endogenous NO by stabilizing precautions apply as for any of the other function versus placebo. In a pooled NO-sGC binding, and it directly stimu- TNF inhibitors (e.g., risk of serious analysis of two one-year exacerbation lates sGC via a different binding site, infections, malignancy, hepatitis B virus studies, Breo Ellipta was found to independently of NO. Pulmonary hyper- reactivation). In the pivotal trial, 3.5% significantly reduce the yearly rate of tension is associated with endothelial of patients treated with golimumab IV moderate/severe exacerbations compared dysfunction, impaired synthesis of nitric reported an infusion reaction (versus to vilanterol alone.35 oxide and insufficient stimulation of the 0.5% in the placebo group). The most NO-sGC-cGMP pathway.39 Other drug common symptom was rash, and no Safety therapies available for the treatment of serious infusion reactions were reported.34 A boxed warning on the product’s PAH include endothelin receptor antago- labeling states that LABAs increase nists (oral), PDE5-inhibitors (oral and 34 Pulmonology the risk of asthma-related death. IV), and prostacyclin analogs (oral, IV/ There is also an FDA-approved SC, and inhalation).39,42 Fluticasone furoate and medication guide for this drug. Breo vilanterol (Breo Ellipta) Ellipta is contraindicated in patients Riociguat is the first drug therapy 100/25 mcg inhalation powder with hypersensitivity to fluticasone, for the treatment of CETPH, prior to which surgery was the mainstay of Indication vilanterol, or any component of the medical treatment. However, riociguat Fluticasone furoate and vilanterol formulation, and also in patients with a is not curative and should not displace (Breo Ellipta) is a combination inhaled severe hypersensitivity to milk proteins. pulmonary endarterectomy as the corticosteroid (ICS)/long-acting beta- Common adverse effects include treatment of choice for either CTEPH agonist (LABA) indicated for the nasopharyngitis, upper respiratory tract or PAH.39 long-term once-daily maintenance infection, headache, and oral candidiasis. In clinical trials, patients on Breo Ellipta

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Dosing and Administration Enrollment and Agreement Form and (2) The 2014 CHEST guidelines endorse the Because dose-related hypotension and special certification of healthcare providers use of macitentan, “for treatment naïve syncope are by far the most commonly who prescribe riociguat, pharmacies, PAH patients with WHO functional class reported adverse effects, the initiation practitioners, and healthcare settings II or III symptoms...to delay the time and up-titration of riociguat treatment (dispensers) that dispense riociguat. to clinical worsening and to improve should be closely monitored. Treatment WHO FC in functional class III patients. Riociguat is rated pregnancy category should be initiated at 1 mg taken three (Both Grade CB recommendations)...In X. Females must not be pregnant or times a day; if hypotension results, the patients with PAH who remain symptom- become pregnant during treatment with dose should be reduced to 0.5 mg TID. atic on stable doses of a PDE5 inhibitor riociguat. Riociguat and the endothelin The dosage may be increased as tolerated or an inhaled prostanoid macitentan is antagonists share the same risk of tera- by 0.5 mg at no less than 2-week intervals suggested to improve 6MWD, improve togenicity, and the focus of the REMS is to a maximum of 2.5 mg TID.39 WHO FC or delay the time to clinical to prevent pregnancy; dual mechanical worsening. (All Grade CB).”46 Efficacy barrier contraceptive techniques are Two small pivotal registration trials, recommended in female patients of child- Dosing and Administration 39 CHEST-1 and PATENT-1, were bearing age taking these medications. The recommended dosage of placebo-controlled trials among PAH Overall, riociguat is well tolerated with macitentan is 10 mg once daily for and CTEPH patients, respectively. The adverse events that were frequently oral administration. Doses higher primary and secondary endpoints were characterized as mild and acceptable by than 10 mg once daily have not been the same for both trials. The change- patients; fewer than 5% discontinued studied in patients with PAH and are from-baseline in six-minute walk treatment because of adverse events. not recommended. Treatment with distance (6MWD) at the end of 12 Headache, dizziness, nausea, vomiting, macitentan in females of reproductive weeks was the primary endpoint. For diarrhea, and constipation were reported potential should be initiated only after PATENT-1, a 30-meter improvement in more than 3% of subjects; other more receipt of a negative pregnancy test and in 6MWD was demonstrated in the 2.5 rarely reported adverse events were right pregnancy tests should be obtained mg-maximum group, compared to a ventricular failure and hemoptysis. The monthly during treatment.43 6-meter decrease seen in the placebo incidence of hypotension is high (15%), group. Other significant improvements and syncope was reported often during the Efficacy compared to placebo were seen in up-titration phase at treatment initiation.39 Macitentan is an endothelin-1 (ET-1) pulmonary hemodynamic measures, receptor antagonist which prevents the The concomitant use of nitrates/nitric clinical worsening events, dyspnea binding of ET-1 to both ETA and ETB oxide donors or phosphodiesterase scores and WHO functional class.40 receptors on vascular endothelium inhibitors—both non-specific (e.g., In CHEST-1 compared to placebo, a and smooth muscle with an inhibitory theophylline, dipyridamole) and type-5 significant 46-meter increase in 6MWD potency ratio of 50:1. A study assessing (e.g., sildenafil, tadalafil, vardenafil)— was demonstrated in the riociguat arm hemodynamic parameters in patients are contraindicated.39 at the end of 16 weeks. Improvements in with PAH found that, compared to hemodynamic, dyspnea and biomarker Macitentan (Opsumit) placebo, after 6 months patients treated indices were also statistically significant.41 10 mg tablets with macitentan 10 mg achieved a The 2014 CHEST PAH guidelines give median reduction of 37% in pulmonary Indication a consensus-based recommendation to vascular resistance and an increase of 0.6 2 44 add riociguat treatment in PAH patients Macitentan (Opsumit) is the third oral L/min·m in cardiac index. endothelin receptor antagonist (ETRA) who remain symptomatic on stable In SERAPHIN, the pivotal registration trial approved by the FDA for the treatment of doses of bosentan, ambrisentan or an upon which the FDA based its approval, pulmonary arterial hypertension (PAH, inhaled prostanoid to improve 6MWD, macitentan demonstrated a significant WHO Group I) to delay disease progres- pulmonary hemodynamics and to delay reduction in hospitalization for worsening 42 sion (including death, initiation of IV/ the time to clinical worsening. PAH symptoms, mostly by delaying the SC prostacyclin analogues, or clinical need for additional PAH therapy and Safety worsening of PAH [signaled by decreased increasing 6MWD. SERAPHIN also was Risk Evaluation and Mitigation Strategy 6MWD, worsened PAH symptoms or distinguished because the median duration (REMS): This program requires (1) the the need for additional PAH treatment] use of an Adempas REMS Prescriber and to reduce hospitalization for PAH.43

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Table 1. New Molecular Entity and Biologic Approvals, May 2013 thru October 2013

Trade Name Active Ingredient(s) Manufacturer Approval Date FDA Category Therapeutic Category/ Pharmacologic Class Indication Application

Breo Ellipta Fluticasone furoate; Vilanterol GlaxoSmithKline 05/10/2013 1 S Inhaled corticosteroid (ICS), long-acting beta2-adrenergic agonist (LABA) Chronic obstructive pulmonary disease NDA # 204275

Nymalize Nimodipine Arbor Pharmaceuticals 05/10/2013 3 P Dihydropyridine calcium channel blocker Ischemic deficits in adult patients with subarachnoid hemorrhage NDA # 203340

Xofigo Radium RA-223 dichloride Bayer HealthCare 05/15/2013 1 P Alpha particle-emitting radioactive therapeutic agent Bone metastases in castration-resistant prostate cancer NDA # 203971

Mekinist Trametinib dimethyl sulfoxide GlaxoSmithKline 05/29/2013 1 S,O Mitogen-activated extracellular signal-regulated kinase 1 (MEK1) and MEK2 Unresectable or metastatic melanoma with BRAF V600E or V600K mutations NDA # 204114 inhibitor

Tafinlar Dabrafenib mesylate GlaxoSmithKline 05/29/2013 1 S,O BRAF kinase inhibitor Unresectable or metastatic melanoma with BRAF V600E mutation NDA # 202806

Rixubis Coagulation Factor IX Baxter Healthcare 06/26/2013 BLA Antihemophilic factor Control and prevention of bleeding episodes, perioperative management, and BLA # 125446 (recombinant) routine prophylaxis in hemophilia B

Brisdelle Paroxetine mesylate Noven Therapeutics 06/28/2013 3 S Selective serotonin reuptake inhibitor (SSRI) Moderate to severe vasomotor symptoms associated with menopause NDA # 204516

Gilotrif Afatinib dimaleate Boehringer Ingelheim 07/12/2013 1 P, O Tyrosine kinase inhibitor Metastatic non-small cell lung cancer (NSCLC) with growth factor receptor NDA # 201292 (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations

Simponi Aria Golimumab Janssen Biotech 07/18/2013 BLA Tumor necrosis factor (TNF) blocker Moderately to severe active rheumatoid arthritis in combination with BLA # 125433 methotrexate

Injectafer Ferric carboxymaltose Luitpold 07/25/2013 5 S Colloidal iron (III) hydroxide replacement Treatment of iron deficiency anemia NDA # 203565

Fetzima Levomilnacipran HCl Forest Laboratories 07/25/2013 2 S Serotonin and norepinephrine reuptake inhibitor (SNRI) Treatment of major depressive disorder NDA # 204168

Tivicay Dolutegravir sodium ViiV Healthcare 08/12/2013 1 P Human immunodeficiency virus type 1 (HIV-1) integrase strand transfer Treatment of HIV-1 infection NDA # 204790 inhibitor (INSTI)

Mirvaso Brimonidine tartrate Galderma Laboratories 08/23/2013 3 S Alpha adrenergic agonist Topical treatment of persistent (nontransient) facial erythema of rosacea NDA # 204708

Valchlor Mechlorethamine Ceptaris Therapeutics 08/23/2013 5 S Nitrogen mustard alkylating agent Topical treatment of Stage IA and IB mycosis fungoides-type cutaneous T-cell NDA # 202317 lymphoma

Brintellix Vortioxetine hydrobromide Takeda Pharmaceuticals USA 09/30/2013 1 S Serotonin (5-HT) reuptake inhibitor, 5-HT3 receptor antagonism, 5-HT1A Treatment of major depressive disorder NDA # 204447 receptor agonism

Adempas Riociguat Bayer Healthcare 10/8/2013 1 S Soluble guanylate cyclase agonist Treatment of pulmonary arterial hypertension and chronic thromboembolic NDA # 204819 pulmonary hypertension

Opsumit Macitentan Actelion Pharmaceuticals Ltd 10/18/2013 1 S Endothelin receptor antagonist Treatment of pulmonary arterial hypertension NDA # 204410

New Drug Application (NDA) Chemical Types Review Classification 1- New molecular entity (NME) P- Priority review: A drug that appears to represent an advance over available therapy. 2- New ester, new salt, or other noncovalent derivative 3- New formulation S- Standard review: A drug that appears to have therapeutic qualities similar to those of an already marketed drug. 4- New combination 5- New manufacturer O- Orphan drug: A drug developed under the Orphan Drug Act of January 1983 (“ODA”), a federal law concerning rare diseases 6- New indication (“orphan diseases”), defined as diseases affecting fewer than 200,000 people in the United States or low prevalence is taken as prevalence of less than 5 per 10,000 in the community. 7- Drug already marketed, but without an approved NDA 8- OTC (over-the-counter) switch BLA - Biologics License Application; sBLA – supplemental BLA

150 cjhp California Journal of Health-System Pharmacy September/October 2015 CPE: New Drugs