New therapeutic agents marketed in 2017: Part 3

Transcription

1 New therapeutic agents marketed in 2017: Part 3 Introduction Part 1 (Pharmacy Today, September 2017) of this three-part series on new FDAapproved therapeutic agents marketed in 2017 reviewed seven new therapeutic agents: ocrelizumab (Ocrevus Genentech), safinamide mesylate (Xadago Newron), edaravone (Radicava Mitsubishi Tanabe), valbenazine (Ingrezza Neurocrine), deutetrabenazine (Austedo Teva), crisaborole (Eucrisa Pfizer), and dupilumab (Dupixent Regeneron; Sanofi). Part 2 (Pharmacy Today, December 2017) reviewed nine new agents: sofosbuvir/velpatasvir/voxilaprevir (Vosevi Gilead), glecaprevir/pibrentasvir (Mavyret AbbVie; representing two new agents), bezlotoxumab (Zinplava Merck), betrixaban (Bevyxxa Portola), plecanatide (Trulance Synergy), brodalumab (Siliq Valeant), guselkumab (Tremfya Janssen), and sarilumab (Kevzara Sanofi). This third and concluding part of the series covers nine additional agents (see Table 1, page 65) marketed in 2017: delafloxacin meglumine (Baxdela Melinta), meropenem trihydrate/vaborbactam (Vabomere The Medicines Co.), secnidazole (Solosec Symbiomix), benznidazole (distributed by Exeltis), letermovir (Prevymis Merck), naldemedine tosylate (Symproic Purdue; Shionogi), abaloparatide (Tymlos Radius), etecalcetide hydrochloride (Parsabiv Amgen), and latanoprostene bunod (Vyzulta Valeant). In addition, summary information is provided for 14 drugs for cancers and four drugs for rare disorders that were FDA approved by in Following our review of each new therapeutic agent, we compare the new drug to the older medication(s) with which it is most similar in properties and uses, and we identify the most important advantages and disadvantages. Advantages and disadvantages are identified when a drug is first marketed and do not reflect approval of additional new drugs and/or other changes that occur after a drug is initially marketed. Daniel A. Hussar, PhD, Remington professor of pharmacy, Philadelphia College of Pharmacy at the University of the Sciences, Philadelphia Eric F. Hussar, MD, primary care physician, Susquehanna Family Medicine, Marietta, PA Accreditation information Activity type: Knowledge-based Learning level: 1 Provider: American Pharmacists Association Target audience: Pharmacists and pharmacy technicians Release date: March 1, 2018 Expiration date: March 1, 2021 A Universal Activity Number: H01-P / H01-T credit: 2 hours (0.2 CEUs) Fee: There is no fee associated with this activity for members of APhA. APhA is accredited by the Accreditation Council for Pharmacy Education (A) as a provider of continuing pharmacy education (). Advisory board: Daniel A. Hussar, PhD, Remington professor of pharmacy, Philadelphia College of Pharmacy at the University of the Sciences, Philadelphia; Eric F. Hussar, MD, primary care physician, Susquehanna Family Medicine, Marietta, PA; and Mark Johnson, PharmD, BCPS, professor and vice chair of pharmacy practice and director of postgraduate education, Shenandoah University Bernard J. Dunn School of Pharmacy, Winchester, VA. Disclosures: Daniel A. Hussar, PhD; Eric F. Hussar, MD; Mark Johnson, PharmD, BCPS; and APhA s editorial staff declare no conflicts of interest or financial interests in any product or service mentioned in this activity, including grants, employment, gifts, stock holdings, and honoraria. For complete staff disclosures, please see Development: This home-study activity was developed by APhA. Learning objectives At the conclusion of this knowledgebased activity, pharmacists and pharmacy technicians will be able to: Identify the new therapeutic agents and explain their appropriate use. Identify the indications and mechanisms of action of the new agents. Identify the most important adverse events and other risks of the new agents. State the route of administration for each new drug and the most important considerations for dosage and administration. Compare the new agents with older medications to which they are most similar in properties and/or use, and identify the most important advantages and disadvantages of the new drugs. MARCH 2018 PharmacyToday 63

2 Preassessment questions Before participating in this activity, test your knowledge by answering the following questions. These questions will also be part of the assessment. 1. Which of the following drug : use pairings is correct? a. Benznidazole : bacterial vaginosis b. Meropenem/vaborbactam : pneumonia c. Delafloxacin : skin infections d. Letermovir : hepatitis C infection 2. With use of which of the following agents is there an important risk of hypocalcemia? a. Abaloparatide b. Etecalcetide c. Letermovir d. Secnidazole 3. Which of the following statements is correct regarding latanoprostene? a. It acts by reducing the formation of aqueous humor. b. Its properties are most similar to those of brimonidine. c. Increased pigmentation of the iris is reversible in most patients. d. Its formulation includes benzalkonium chloride. Antibacterial agents Approximately 3 million patients are hospitalized each year with acute bacterial skin and skin structure infections (ABSSSI) such as cellulitis, wound infection, major cutaneous abscess, and burn infection. Empiric treatment is often initiated before the results of cultures are available and commonly includes an antibiotic such as vancomycin, which has a high level of activity against gram-positive bacteria, and an antibiotic such as aztreonam, which has a high level of activity against gram-negative bacteria. Delafloxacin meglumine (Baxdela Melinta) is a fluoroquinolone antibacterial agent with properties that are most similar to other members of this class, including levofloxacin, moxifloxacin, and ciprofloxacin. It is supplied in formulations for oral and I.V. administration and is indicated for the treatment of adults with ABSSSI caused by susceptible isolates of the gram-positive bacteria Staphylococcus aureus (including methicillin-resistant [MRSA] and methicillin-susceptible [MSSA] isolates), Staphylococcus haemolyticus, Staphylococcus lugdunensis, Streptococcus agalactiae, Streptococcus anginosus group (including Streptococcus anginosus, Streptococcus intermedius, and Streptococcus constellatus), Streptococcus pyogenes, and Enterococcus faecalis, and the gram-negative bacteria Escherichia coli, Enterobacter cloacae, Klebsiella pneumoniae, and Pseudomonas aeruginosa. It is the first fluoroquinolone demonstrated to be effective in the treatment of infections caused by MRSA, and its spectrum of antibacterial action, which also includes problem pathogens such as Pseudomonas aeruginosa, is broader than that of other antimicrobial agents indicated for treatment of ABSSSI. Effectiveness of delafloxacin was demonstrated in two noninferiority studies in approximately 1,500 patients, in which it was compared with I.V. use of vancomycin and az- 64 PharmacyToday MARCH 2018 treonam. Aztreonam was discontinued if no gram-negative bacteria were identified in the baseline cultures. An objective clinical response at 48 to 72 hours after initiation of treatment was defined as a 20% or greater decrease in lesion size. This response was achieved in approximately 80% of the patients with both of the treatment regimens in both studies. The success of treatment, defined as cured plus improved in clinically evaluable patients as assessed by the investigators on follow-up at about 14 days, exceeded 95% for both treatment regimens. In addition to approval for treatment of ABSSSI, levofloxacin, moxifloxacin, and ciprofloxacin have been approved for the treatment of numerous other types of infections (e.g., urinary tract, respiratory tract). However, these are not labeled indications for delafloxacin at present. Delafloxacin was well tolerated in the clinical studies, with the most commonly experienced adverse events being nausea (8%), diarrhea (8%), headache (3%), transaminase elevations (3%), and vomiting (2%). Treatment was discontinued because of adverse events in fewer than 1% of patients, compared with discontinuation in approximately 3% of patients treated with vancomycin and aztreonam. Because Clostridium difficile associated diarrhea has been reported with use of almost all systemic antibacterial agents, this possibility should be considered in any patient who experiences diarrhea while being treated with delafloxacin. Phototoxicity and QT interval prolongation have been reported with use of other fluoroquinolones but were not experienced in the clinical studies with delafloxacin. As with the other fluoroquinolones, the labeling for delafloxacin includes boxed warnings on the risks of tendinitis, tendon rupture, peripheral neuropathy, central nervous system effects (e.g., dizziness, confusion, tremors), and exacerbation of myasthenia gravis. These risks are associated with serious and potentially irreversible complications, and fluoroquinolones should be avoided in patients with a history of tendon disorders, peripheral neuropathy, or myasthenia gravis. Treatment with a fluoroquinolone should be immediately discontinued in patients in whom such adverse events occur. Patients should be advised to not drive or engage in other activities that require mental alertness and coordination until they know how the drug affects them. Data on use of delafloxacin during pregnancy and in nursing mothers are very limited, but studies in animals have not suggested a risk of significant problems. Because fluoroquinolones have been reported to cause arthropathies in juvenile animals, use of delafloxacin in children is not recommended. Use of any of the systemic fluoroquinolones in children is limited to treatment of serious infections (e.g., inhalational anthrax, plague) for which there are very few antimicrobial treatment options. Following oral administration of delafloxacin, the absolute bioavailability is approximately 60%. Glucuronidation is the primary pathway of metabolism, and approximately 65% of a dose of the drug is excreted in the urine as unchanged drug and glucuronide metabolites, with most of the remaining part of the dose excreted in the feces as unchanged drug. Adjustment of dosage is not necessary in patients with he-

3 patic impairment or in patients with mild or moderate renal impairment. In patients with severe renal impairment (estimated glomerular filtration rate [egfr] ml/min/1.73 m 2 ) in whom delafloxacin is to be administered intravenously, the dosage should be reduced because of potential accumulation of the I.V. vehicle, sulfobutylether-beta-cyclodextrin. Serum creatinine concentrations should be closely monitored in patients with severe renal impairment receiving delafloxacin intravenously. If serum creatinine concentrations increase, changing to oral administration of the drug should be considered. If egfr decreases to less than 15 ml/min/1.73 m 2, delafloxacin should be discontinued. Use of the drug is not recommended in patients with end-stage renal disease. Delafloxacin is less likely than ciprofloxacin and certain other fluoroquinolones to interact with other medications. However, all of the fluoroquinolones may form chelates with multivalent metal cations (e.g., in antacids and vitamin/mineral formulations) that may reduce absorption of the antibacterial agent following oral administration. Accordingly, delafloxacin should be administered at least 2 hours before or 6 hours after products containing metal cations. When administered intravenously, delafloxacin should not be coadministered with any solution containing multivalent cations (e.g., magnesium) through the same I.V. line. Bioavailability of a single oral dose of 450 mg of delafloxacin is comparable to that of a single I.V. dose of 300 mg. The tablets may be administered with or without food. The recommended dosage of delafloxacin is 300 mg every 12 hours over 60 minutes by I.V. infusion or 450 mg every 12 hours orally. Treatment may be initiated intravenously and then switched to oral administration as appropriate. Duration of treatment is 5 to 14 days. In patients with severe renal impairment, the dosage for I.V. administration should be reduced to 200 mg every 12 hours. Delafloxacin meglumine is supplied in tablets and as a lyophilized powder for injection in quantities equivalent to 450 mg delafloxacin (tablets) and 300 mg for injection. The contents of a vial for I.V. use must be reconstituted with 10.5 ml of 5% dextrose injection or 0.9% sodium chloride injection. The vial should be shaken vigorously until the contents are dissolved, and the reconstituted solution should then be diluted with the same vehicle to a total volume of 250 ml to achieve a concentration of 1.2 mg/ml. Comparison of delafloxacin with levofloxacin and moxifloxacin Advantages Has been demonstrated to be effective in the treatment of ABSSSI caused by MRSA Spectrum of antibacterial action includes a larger number of grampositive and gram-negative bacteria May be less likely to cause QT interval prolongation and phototoxicity May be less likely to interact with other medications Labeled indications are more limited (whereas comparable drugs are also indicated for respiratory and certain other infections) Is administered every 12 hours (whereas comparable drugs are administered every 24 h) Table 1. New therapeutic agents marketed in the United States in 2017: Part 3 Generic name Trade name Manufacturer Therapeutic classification Route of administration Abaloparatide Tymlos Radius Osteoporosis S.C. 1-S Benznidazole Exeltis Antiparasitic Oral 1-P Delafloxacin meglumine Baxdela Melinta Antibacterial Oral; I.V. 1-P Etecalcetide hydrochloride Latanoprostene bunod Parsabiv Amgen Hyperparathyroidism I.V. 1-S Vyzulta Valeant Glaucoma Ophthalmic 1-S Letermovir Prevymis Merck Antiviral Oral; I.V. 1-P Meropenem trihydrate/ vaborbactam Naldemedine tosylate Vabomere The Medicines Co. Antibacterial I.V. 1,4-P Symproic Purdue; Shionogi Constipation Oral 1-S Secnidazole Solosec Symbiomix Antibacterial Oral 1-P a FDA classification of new drugs: 1 = new molecular entity; 4 = combination product; S = standard review; P = priority review. FDA classification a MARCH 2018 PharmacyToday 65

4 Beta-lactam antibacterial agents (e.g., penicillins, cephalosporins, carbapenems) are highly effective in the treatment of many bacterial infections. However, an increasing number of bacteria are able to produce beta-lactamase enzymes (penicillinases, cephalosporinases, carbapenemases) that break the beta-lactam ring and inactivate the antibacterial agent. To address this common mechanism of resistance, pharmaceutical companies have developed betalactamase inhibitors that preserve and extend the activity of the beta-lactam antibacterial agents with which they are used in combination. Early examples of these combination formulations include amoxicillin with clavulanate potassium (e.g., Augmentin) and piperacillin with tazobactam (e.g., Zosyn). More recently, combinations of a beta-lactamase inhibitor with a cephalosporin have been developed and include ceftolozane with tazobactam (Zerbaxa) and ceftazidime with avibactam (Avycaz). The latter combination was the first to have activity against some carbapenem-resistant enterobacteriaceae, including those that produce Klebsiella pneumoniae carbapenemase (KPC). It was approved in 2015 for the treatment of complicated urinary tract infections (including pyelonephritis) caused by susceptible gramnegative bacteria and, in combination with metronidazole, for the treatment of complicated intraabdominal infections caused by susceptible gram-negative bacteria. Carbapenem antibacterial agents marketed in the United States include imipenem (used in combination with cilastatin [e.g., Primaxin]), meropenem (e.g., Merrem IV), ertapenem (Invanz), and doripenem (Doribax). The indications for meropenem include complicated skin and skin structure infections, complicated intra-abdominal infections, and bacterial meningitis. Meropenem trihydrate/vaborbactam (Vabomere The Medicines Co.) represents a combination of meropenem with the new beta-lactamase inhibitor, vaborbactam, a cyclic boronic acid beta-lactamase inhibitor. Vaborbactam does not have antibacterial activity but protects meropenem from degradation by certain serine beta-lactamases such as KPC. Meropenem/vaborbactam, which is administered intravenously, is indicated for the treatment of adult patients with complicated urinary tract infections (cuti), including pyelonephritis caused by Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae species complex. Effectiveness of meropenem/vaborbactam was demonstrated in a multicenter trial in which the agent was compared with piperacillin/tazobactam. At the end of I.V. treatment with meropenem/vaborbactam, 98% of patients compared with 94% of patients treated with piperacillin/ tazobactam had cure or improvement of symptoms and a negative urine culture. Approximately 7 days after completing treatment, 77% of patients treated with meropenem/vaborbactam compared with 73% of patients treated with piperacillin/tazobactam had resolved symptoms and a negative urine culture. Hypersensitivity reactions were experienced by 2% of the patients who received meropenem/vaborbactam in the clinical studies, and the combination is contraindicated in 66 PharmacyToday MARCH 2018 patients with known hypersensitivity to any component of the product or to other drugs in the same class, as well as in patients who have had anaphylactic reactions to any beta-lactam antibacterial agent. The most frequently experienced adverse events with meropenem/vaborbactam include headache (9%), phlebitis/infusion site reactions (4%), and diarrhea (3%). Treatment was discontinued because of adverse events in 3% of the patients treated with meropenem/vaborbactam and in 5% of the patients treated with piperacillin/tazobactam. Almost all systemic antibacterial agents, including meropenem, have been reported to cause Clostridium difficile associated diarrhea, and this possibility should be considered in all patients who experience diarrhea following use of an antibacterial agent, including the period of time following completion of treatment. Use of meropenem has been infrequently associated with seizures and other adverse central nervous system (CNS) experiences (e.g., delirium, headache) that could interfere with mental alertness and/or cause motor impairment. Individuals who are being treated with meropenem/ vaborbactam on an outpatient basis should be advised to not operate machinery or motorized vehicles until it is known that the treatment is well tolerated. The risk of serious CNS adverse events is greater in patients with underlying CNS disorders (e.g., seizures). Use of meropenem and other carbapenems has been reported to reduce the concentration of valproic acid or divalproex sodium, thereby increasing the risk of breakthrough seizures. In patients whose seizures are well controlled with these antiepileptic agents, concurrent use of meropenem/vaborbactam is generally not recommended, and use of other antibacterial agents should be considered. Although meropenem is not likely to be associated with problems if used during pregnancy or by a woman who is breastfeeding, limited information is available on the use of vaborbactam in such situations. Effectiveness and safety of meropenem/vaborbactam in patients younger than 18 years have not been established. Meropenem is metabolized to a limited extent via hydrolysis, and vaborbactam does not undergo metabolism. Most of the dose of each agent is excreted unchanged in the urine, and the dosage should be reduced in patients with impaired renal function. Probenecid competes with meropenem for active tubular secretion, resulting in increased plasma concentrations of meropenem. Therefore, concurrent use of probenecid is not recommended. Meropenem/vaborbactam is supplied as a sterile powder for constitution in single-dose vials containing meropenem trihydrate in an amount equivalent to 1 g of meropenem and 1 g of vaborbactam. The sterile powder is constituted with 0.9% sodium chloride injection and subsequently diluted with the same vehicle, according to the instructions provided in the product labeling. The I.V. infusion of the diluted solution should be completed within 4 hours if stored at room temperature or 22 hours if stored in a refrigerator. In adult patients with an egfr of 50 ml/min/1.73 m 2

5 or greater, the recommended dosage is 2 g of meropenem with 2 g of vaborbactam every 8 hours by I.V. infusion over 3 hours for up to 14 days. This dosage is identified in the product labeling as 4 g of the product, which represents 2 g of meropenem plus 2 g of vaborbactam provided in two vials. The dosage should be reduced in patients with an egfr of less than 50 ml/min/1.73 m 2, and for patients with changing renal function, serum creatinine concentrations and egfr should be monitored at least daily and the dosage adjusted accordingly. In patients with an egfr of 30 to 49, the recommended dosage is 1 g of meropenem with 1 g of vaborbactam every 8 hours; in patients with an egfr of 15 to 29, the recommended dosage is 1 g of meropenem with 1 g of vaborbactam every 12 hours; and in patients with an egfr of less than 15, the recommended dosage is 0.5 g of meropenem with 0.5 g of vaborbactam every 12 hours. Comparison of meropenem/vaborbactam with ceftazidime/ tazobactam (Avycaz) Advantage May be effective in certain infections (e.g., those caused by certain carbapenem-resistant enterobacteriaceae) that do not respond to other antibacterial agents) Indication for urinary tract infections is more limited (does not include infections caused by Citrobacter freundii complex, Proteus mirabilis, or Pseudomonas aeruginosa) Labeled indications are more limited (ceftazidime/avibactam with metronidazole are also indicated for the treatment of complicated intra-abdominal infections) Is infused intravenously over 3 hours (whereas ceftazidime/avibactam is infused over 2 h) Bacterial vaginosis is the most common vaginal infection in women during their reproductive years. It is typically associated with vaginal itching, burning during urination, a thin vaginal discharge, and an abnormal fishy odor. It is thought to result from an overgrowth of certain bacteria (primarily anaerobic bacteria) that are normally present in the vagina, with the result that the normal flora/balance of bacteria is disrupted. Risk factors for experiencing bacterial vaginosis include douching and sexual activity. Although bacterial vaginosis is not a sexually transmitted infection (STI), some of the symptoms are similar, and the possibility of an STI (e.g., gonorrhea, chlamydial infection) should be considered. Treatment options for bacterial vaginosis include oral or intravaginal administration of metronidazole (e.g., Flagyl), oral use of tinidazole (Tindamax), and intravaginal or oral use of clindamycin. Secnidazole (Solosec Symbiomix) is a nitroimidazole antimicrobial agent with properties that are most similar to those of metronidazole and tinidazole. It is active in vitro against most isolates of the following organisms associated with bacterial vaginosis: Gardnerella vaginalis, Mobiluncus spp., Bacteroides spp., Prevotella spp., and Megasphaera-like type I/II. It is thought that nitroimidazole antimicrobial agents enter bacterial cells as an inactive prodrug and that the nitro group is reduced by bacterial enzymes to radical anions that interfere with bacterial DNA synthesis of susceptible isolates. Secnidazole is indicated for the treatment of bacterial vaginosis in adult women. Its effectiveness as a single-dose treatment was demonstrated in two placebo-controlled clinical trials. The percentage of patients experiencing a clinical response was significantly greater in those treated with the medication (68%; 53%) than in those receiving placebo (18%; 19%). In addition to bacterial vaginosis, metronidazole is approved for the treatment of numerous types of systemic anaerobic bacterial infections, as well as the protozoal parasitic infections amebiasis and trichomoniasis. Tinidazole is approved for the treatment of amebiasis, giardiasis, and trichomoniasis. However, these are not labeled indications for secnidazole at present. The most frequently experienced adverse event in the clinical studies of secnidazole is vulvovaginal candidiasis (10%), which may require treatment with an antifungal agent. Other commonly reported adverse events are headache (4%), nausea (4%), dysgeusia (4%), vomiting (3%), diarrhea (3%), abdominal pain (2%), and vulvovaginal pruritus (2%). Other nitroimidazole antimicrobial agents have been reported to be carcinogenic in studies in animals. However, it is not known if a single dose of secnidazole is associated with such a risk in patients. Use of secnidazole is contraindicated in patients with a history of hypersensitivity to any of the nitroimidazole derivatives. Metronidazole and tinidazole are contraindicated during the first trimester of pregnancy. Studies on the risk of using secnidazole during pregnancy are very limited and insufficient to inform a drug-associated risk of adverse developmental outcomes. Because nitroimidazole derivatives are present in human milk, breastfeeding is not recommended during treatment with secnidazole or for 96 hours following administration. Effectiveness and safety of the new drug in patients younger than 18 years of age have not been established. Disulfiram-like reactions following the consumption of alcoholic beverages have been reported with use of metronidazole and tinidazole, and warnings to avoid use of such beverages during and soon after treatment are included in the labeling for these agents. In vitro studies show that secnidazole has no effect on aldehyde dehydrogenase activity, and its labeling does not include a precaution for use of alcoholic beverages. Secnidazole is metabolized via hepatic CYP450 enzyme pathways, and approximately 15% of a drug is excreted as unchanged drug in the urine. Because it is used as a singledose treatment, drug interactions or risk in patients with hepatic or renal impairment are not likely. Secnidazole is supplied as oral granules in a unit-of-use foil packet, with each packet containing 2 g of the drug. The recommended dosage is a single dose of 2 g that may be administered without regard to food. The contents of a packet of the drug should be sprinkled onto applesauce, yogurt, or pudding, and the mixture should be consumed within 30 minutes without chewing or crushing the granules. A glass MARCH 2018 PharmacyToday 67

6 of water may be taken after administration of the drug to aid in swallowing. The granules of the medication will not dissolve and are not intended to be dissolved in any liquid. Comparison of secnidazole with metronidazole (e.g., Flagyl) and tinidazole (Tindamax) Advantages Is administered as a single-dose treatment (whereas tinidazole is used in two-dose or five-dose regimens and metronidazole in more-frequent treatment regimens) May be safer for use during pregnancy (studies on the risk of using secnidazole during pregnancy are very limited and insufficient to inform a drug-associated risk of adverse developmental outcomes) Is less likely to interact with other medications (e.g., disulfiramlike reactions have been experienced following the consumption of alcoholic beverages in patients treated with metronidazole and tinidazole) Has not been directly compared with other drugs in clinical studies Labeled indications are more limited (metronidazole is also indicated for numerous types of systemic anaerobic bacterial infections, amebiasis, and trichomoniasis, and tinidazole is also approved for amebiasis, giardiasis, and trichomoniasis) Route of administration/formulation options are more limited (compared with metronidazole, which is also administered intravaginally for the treatment of bacterial vaginosis) Administration requires sprinkling granules onto applesauce, yogurt, or pudding Antiparasitic agent Chagas disease, also known as American trypanosomiasis, is a parasitic infection caused by the protozoal organism Trypanosoma cruzi. Although Chagas disease primarily affects people in South and Central America, an estimated 300,000 people in the United States may have the infection. The parasite is transmitted via exposure in various ways to feces of a certain insect, including infestation of materials used in building shelters or homes. It may also be transmitted via blood transfusions or from a mother to her child during pregnancy. The infection is often initially experienced during childhood and may be characterized by fever, lymphadenopathy, and facial edema. After years of infection, patients may experience serious heart disease (e.g., cardiomyopathy), as well as gastrointestinal (GI) problems involving swallowing and digestion. Benznidazole and nifurtimox have been available as investigational agents from CDC for treatment of the infection. Benznidazole is a nitroimidazole antimicrobial agent with properties that are most similar to those of metronidazole and tinidazole. It is the first medication to be approved in the United States for the treatment of Chagas disease and is distributed by Exeltis. It is specifically indicated for pediatric patients aged 2 to 12 years for the treatment of Chagas disease caused by Trypanosoma cruzi. The drug was approved under the provisions of the accelerated approval program on the basis of patients who became immunoglobulin G antibody negative against the recombinant antigens of T. cruzi. Studies to determine the clinical benefit of treatment are continuing. Effectiveness of benznidazole was evaluated in two placebocontrolled clinical trials in children aged 6 to 12 years. The percentage of patients who seroconverted from positive to 68 PharmacyToday MARCH 2018 negative was significantly greater in the patients treated with benznidazole (60%; 55%) compared with the patients who received placebo (14%; 5%). An additional study of the safety and pharmacokinetics of the drug in patients aged 2 to 12 years provided information for dosage recommendations for children down to 2 years of age. The most commonly experienced adverse events with use of benznidazole (and their incidence in Trial 1) included abdominal pain (25%), rash (16%), weight loss (13%), and headache (7%). The drug was discontinued because of adverse events in 9% of the patients. Some patients have experienced hypersensitivity skin reactions, and benznidazole is contraindicated in patients with a history of hypersensitivity to any of the nitroimidazoles. If serious cutaneous reactions such as erythema multiforme occur, treatment should be discontinued immediately. If less serious skin reactions are experienced but additional symptoms or signs of systemic involvement occur (e.g., fever, purpura), treatment discontinuation is recommended. Benznidazole may cause paresthesia or symptoms of peripheral neuropathy that may take several months to resolve, and CNS effects (e.g., dizziness) have also been experienced. If neurological symptoms occur, immediate discontinuation of treatment is recommended. There have been reports of hematological manifestations of bone marrow depression, such as neutropenia, thrombocytopenia, anemia, and leukopenia. Complete blood counts should be monitored, and total and differential leukocyte counts are recommended before, during, and after therapy. Benznidazole has been associated with fetal malformations in animal studies, and pregnancy testing is recommended when it is considered for use in females of reproductive potential. Patients of reproductive potential should be advised to use effective contraception during treatment and for 5 days following the last dose. Breastfeeding is not recommended during treatment. Effectiveness and safety of the agent have not been established in patients younger than 2 years and older than 12 years. A study in pediatric patients evaluating the cytogenetic effect of benznidazole has demonstrated a twofold increase in chromosomal aberrations. It is not known whether the new drug is associated with carcinogenicity in humans. However, carcinogenicity has been reported in studies in animals that were treated chronically with other nitroimidazoles. Use of benznidazole is contraindicated in patients who have taken disulfiram within the previous 2 weeks because of the potential for psychotic reactions. Consumption of alcoholic beverages is also contraindicated, and these beverages, as well as products containing propylene glycol, should be avoided during treatment and for at least 3 days following treatment. The recommended total daily dosage of benznidazole in patients aged 2 to 12 years is 5 mg/kg to 8 mg/kg, administered in two divided doses separated by approximately 12 hours for 60 days. The drug may be administered with or without food. Tablets are supplied in 12.5-mg and 100-mg potencies. The tablets containing 100 mg of the drug are functionally scored twice and can be administered whole or be broken at the scored lines to provide doses in the amounts of 25 mg, 50 mg, and 75 mg. The product labeling should be consulted for

7 information on preparing a slurry of the tablets in water as an alternative method of administering the drug in children who cannot swallow tablets. Benznidazole No comparable drugs for Chagas disease; however, it is a nitroimidazole antimicrobial agent with some properties that are similar to those of metronidazole and tinidazole Advantage Is the first drug approved for treatment of Chagas disease A clinical benefit has not yet been demonstrated Clinical trials have not been conducted in patients older than 12 years Antiviral agent Cytomegalovirus (CMV) is a common herpes virus to which exposure results in the virus remaining in the body for life, usually in an inactive or latent form. Many adults have CMV antibodies in their blood and are CMV seropositive, indicating a previous exposure to or primary infection with CMV. Individuals with normal immune function rarely develop CMV symptoms after an initial infection that is typically mild in severity. However, in patients with compromised immune function, there is a greater likelihood of the virus being reactivated and causing symptomatic infection or a secondary infection due to other pathogens. In these patients, CMV infection may result in serious complications, such as retinitis and possible resultant blindness, pneumonia, and GI diseases. Recipients of stem cell and organ transplants are particularly vulnerable to CMV infection and complications, including transplant failure and death. Antiviral agents that have been used to treat and/or prevent CMV infection include ganciclovir (e.g., Cytovene), valganciclovir (e.g., Valcyte), foscarnet (e.g., Foscavir), and cidofovir (Vistide). However, these medications are also associated with a risk of serious adverse events. Hematopoietic stem cell transplantation (HSCT) is a procedure performed in some patients with certain blood or bone marrow cancers (e.g., leukemias, lymphomas). Although HSCT offers the best hope for a continuing remission for many of these patients, the procedure and immunosuppression are associated with important risks, including the increased possibility of CMV infection. Letermovir (Prevymis Merck) is an antiviral agent with activity against CMV that inhibits the CMV DNA terminase complex, which is required for viral DNA processing and packaging. Administered orally or as an I.V. infusion, it is indicated for prophylaxis of CMV infection and disease in adult CMV-seropositive recipients (R+) of an allogeneic HSCT. Effectiveness of letermovir was evaluated in a placebo-controlled clinical trial in patients with conditions such as acute myeloid leukemia, myelodysplastic syndrome, and lymphoma who received an HSCT. The primary efficacy endpoint was the incidence of clinically significant CMV infection through week 24 posttransplant (prophylaxis failure). Significantly fewer patients in the letermovir group (38%) experienced failure with prophylaxis, compared with 61% of those in the placebo group. All-cause mortality at week 24 posttransplant was also lower in those treated with letermovir (12%) than in those receiving placebo (17%). The most commonly reported adverse events in the clinical study of letermovir included nausea (27%), diarrhea (26%), vomiting (19%), peripheral edema (14%), cough (14%), headache (14%), fatigue (13%), and abdominal pain (12%), although the incidence of most of these events was only slightly lower in the patients receiving placebo. The new drug appears less likely to cause serious adverse events than ganciclovir or valganciclovir, the labeling for which includes boxed warnings on the risks of hematologic toxicity, impairment of fertility, teratogenicity, and carcinogenicity. Letermovir interacts with many other medications. It inhibits the CYP3A metabolic pathway and increases the action of medications that are substrates for this pathway (e.g., pimozide and ergot alkaloids, with which concurrent use of the new drug is contraindicated). Concurrent use of letermovir and cyclosporine may result in increased activity of both drugs; therefore, letermovir should be used in a reduced dosage of 240 mg once a day, and cyclosporine concentrations should be monitored frequently. When letermovir and cyclosporine are coadministered, concurrent use of pitavastatin or simvastatin is contraindicated, and concurrent use of atorvastatin or lovastatin is not recommended. In patients in whom cyclosporine is not coadministered, concurrent use of letermovir with pitavastatin or simvastatin is not recommended, the dosage of atorvastatin should not exceed 20 mg daily, and the dosage of fluvastatin, lovastatin, pravastatin, and rosuvastatin may have to be reduced. Concomitant use of letermovir may also increase the action of sirolimus, tacrolimus, alfentanil, fentanyl, midazolam, quinidine, amiodarone, glyburide, rosiglitazone, and repaglinide. In patients treated with letermovir and cyclosporine, use of repaglinide is not recommended. Letermovir may decrease the action of warfarin, phenytoin, voriconazole, omeprazole, and pantoprazole, and patients should be monitored closely for reduced effectiveness of these agents. The action of letermovir may be reduced by rifampin, and concurrent use is not recommended. There are insufficient data to determine whether letermovir presents a risk to pregnancy outcomes or to breastfed children. Effectiveness and safety of the new drug in patients younger than 18 years have not been established. Letermovir is metabolized to only a limited extent. More than 90% of a dose is excreted in the feces, primarily as unchanged drug. It is not necessary to adjust the dosage of letermovir in patients with mild or moderate hepatic impairment, but the bioavailability of the drug is approximately fourfold higher in patients with severe hepatic impairment, and use in these patients is not recommended. Dosage adjustment is not necessary in patients with creatinine clearance greater than 10 ml/min, but there are insufficient data to make dosing recommendations in patients with creatinine clearance of 10 ml/min or less or in patients on dialysis. The vehicle for the parenteral formulation of letermovir includes hydroxypropyl betadex, which may accumulate in patients with creatinine clearance less than 50 ml/min, and serum creatinine concentrations should be closely monitored in these patients. MARCH 2018 PharmacyToday 69

8 Letermovir tablets may be administered with or without food, and the recommended dosage is 480 mg once a day. Treatment should be initiated between day 0 and day 28 posttransplantation and continued through day 100 posttransplantation. In patients who are also being treated with cyclosporine, the dosage of letermovir should be reduced to 240 mg once a day. Letermovir injection for I.V. administration should be used only in patients who are unable to take oral therapy, and the recommended dosage, without or with cyclosporine, is the same as for oral administration. Patients should be switched to the tablet formulation as soon as they are able to take oral medications, and dosage adjustment is not necessary when switching formulations. The injection formulation is diluted and administered by I.V. infusion via a peripheral catheter or central venous line at a constant rate over 1 hour. When letermovir prophylaxis is complete, monitoring for CMV reactivation is recommended. Letermovir tablets are supplied in 240-mg and 480-mg potencies, and the injection is supplied in single-dose vials containing 240 mg/12 ml (20 mg/ml) and 480 mg/24 ml (20 mg/ml). The contents of a vial should be added to a 250-mL prefilled I.V. bag containing either 0.9% sodium chloride injection or 5% dextrose injection. The product labeling should be consulted for information on compatible I.V. infusion bags and infusion set materials. Comparison of letermovir with valganciclovir (Valcyte) Advantages Is the first drug with a labeled indication for preventing CMV infection in recipients of an HSCT (although ganciclovir has a labeled indication for prevention of CMV disease in adult transplant recipients at risk) Use has not been associated with renal adverse events Is not likely to cause hematologic toxicity, impairment of fertility, teratogenicity, or carcinogenesis (whereas these risks are the subjects of boxed warnings in the labeling for valganciclovir and ganciclovir) Is available in formulations for oral and I.V. use Labeled indications are more limited (valganciclovir is also indicated for prevention of CMV disease in kidney, heart, and kidney pancreas transplant recipients and prevention of CMV retinitis in patients with AIDS) Has not been evaluated in pediatric patients (whereas valganciclovir is indicated for children as young as 1 month) Interacts with more medications Agent for constipation Use of opioid analgesics for management of chronic pain often results in patients experiencing constipation (i.e., opioidinduced constipation [OIC]). Laxatives and stool softeners may be of benefit in preventing or treating OIC in many patients treated with an opioid analgesic, but these products do not provide an adequate response in others. In 2008, the opioid antagonist methylnaltrexone (Relistor) was approved for S.C. use to treat OIC in patients with advanced illness who are receiving palliative care when their response to laxative therapy has not been sufficient. It was subsequently approved for treatment of OIC in adult patients 70 PharmacyToday MARCH 2018 with chronic noncancer pain and, in 2016, was also approved in an orally administered formulation for this indication. In 2014, the opioid antagonist naloxegol (Movantik), a derivative of naloxone, was also approved for treatment of OIC in adults with chronic noncancer pain. Lubiprostone (Amitiza), another option for treatment of OIC, acts as a chloride channel activator in the GI tract (GIT). Initially approved in 2006 for the treatment of patients with chronic idiopathic constipation, it has been subsequently approved to treat irritable bowel syndrome with constipation in women aged 18 years and older, as well as to treat OIC in adults with chronic noncancer pain. Naldemedine, a derivative of naltrexone, is a peripherally acting mu-opioid receptor antagonist in tissues such as the GIT. It is supplied as naldemedine tosylate (Symproic Purdue; Shionogi) and is indicated for the treatment of OIC in adults with chronic noncancer pain. Naldemedine differs structurally from naltrexone by the addition of a side chain that reduces the ability of the new drug to cross the blood brain barrier. It is also a substrate of the P-glycoprotein (P-gp) transporter and, based on these properties, the central nervous system penetration of naldemedine is expected to be negligible when it is used in the recommended dosage, which limits the potential for interference with centrally mediated opioid analgesia. Effectiveness of naldemedine was demonstrated in two placebo-controlled studies in patients with OIC and non cancer-related pain (e.g., back pain) who had been treated with an opioid for at least 4 weeks. A responder was defined as a patient who had at least three spontaneous bowel movements (SBMs) per week and a change from baseline of at least one SBM per week for at least 9 out of the 12 study weeks and 3 out of the last 4 weeks. In the two studies, 48% and 53% of the patients treated with naldemedine experienced an increase in the number of SBMs per week, compared with 35% and 34% of those receiving placebo. Naldemedine is contraindicated in patients with known or suspected GI obstruction and patients at increased risk of recurrent obstruction because of the potential for GI perforation. It must be used with caution in patients in whom there is or may be impaired integrity of the GIT wall (e.g., peptic ulcer disease, Crohn disease), and patients should be monitored for the development of severe, persistent, or worsening abdominal pain. Adverse events experienced most often in the clinical trials included abdominal pain (8%), diarrhea (7%), nausea (4%), and gastroenteritis (2%). Although naldemedine is not likely to cross the blood brain barrier, patients with disruptions of this barrier may be at increased risk of opioid withdrawal or reduced analgesia. Symptoms related to opioid withdrawal (e.g., hyperhidrosis, chills, flushing) have been experienced by approximately 1% of the patients treated with the new drug, a rate that was similar to placebo. Although naldemedine is not considered to have a risk of abuse or dependency, it was initially classified as a Schedule II controlled substance because it is structurally related to agents that do have such a risk. However, it has subsequently been descheduled as a controlled substance by DEA.

9 Naldemedine should be used during pregnancy only if the anticipated benefit justifies risk to the fetus. Because the blood brain barrier has not fully matured in the fetus, naldemedine could precipitate opioid withdrawal. It is not known whether naldemedine is excreted in human milk, and a decision should be made to discontinue nursing or not use the drug. If the drug is discontinued to reduce the exposure of a breastfed infant, breastfeeding may be resumed 3 days after the final dose of naldemedine. Effectiveness and safety of the new drug have not been established in pediatric patients. Consumption of a high-fat meal reduces the rate but not the extent of absorption of naldemedine, and the drug may be administered with or without food. The drug is metabolized primarily via the CYP3A pathway to metabolites that have weaker opioid antagonist activity than the parent compound. Approximately 57% of a dose is excreted in the urine and 35% in the feces. The activity of the drug is not likely to be significantly changed in patients with impaired renal function or in patients with mild or moderate hepatic impairment. Naldemedine has not been studied in patients with severe hepatic impairment, and use of the drug should be avoided in these patients. Naldemedine is a substrate of P-gp as well as CYP3A, and concurrent use of a moderate CYP3A inhibitor (e.g., diltiazem, fluconazole), a strong CYP3A inhibitor (e.g., clarithromycin itraconazole), or a P-gp inhibitor (e.g., amiodarone, cyclosporine) may increase the concentration and risk of adverse events of the new drug and should be monitored. Conversely, a strong CYP3A inducer (e.g., carbamazepine, rifampin, St. John s wort) may significantly reduce the concentration and effectiveness of naldemedine, and concurrent use should be avoided. Concurrent use of another opioid antagonist also should be avoided because of the increased risk of opioid withdrawal. The recommended dosage of naldemedine is 0.2 mg once a day. If treatment with the opioid analgesic is discontinued, naldemedine also should be discontinued. Naldemedine tosylate is supplied in tablets in an amount equivalent to 0.2 mg of naldemedine. Comparison of naldemedine with methylnaltrexone (Relistor) and naloxegol (Movantik) Advantages May be administered without regard to food (compared with naloxegol, which should be taken on an empty stomach) Dosage does not have to be reduced in patients with renal impairment (compared with naloxegol) Concurrent use with a strong CYP3A4 inhibitor is not contraindicated (compared with naloxegol, with which concurrent use is contraindicated) May interact with P-glycoprotein (P-gp) inhibitors (e.g., cyclosporine) Is more likely to interact with CYP3A inhibitors and inducers (compared with methylnaltrexone) Route of administration options are more limited (compared with methylnaltrexone, which may also be administered subcutaneously) Use should be avoided in patients with severe hepatic impairment (compared with methylnaltrexone) Agent for osteoporosis Osteoporosis, characterized by a reduction in bone mineral density and bone strength, is often asymptomatic until a fracture occurs. It is most commonly experienced in women following menopause when a reduction in estrogen concentrations results in a bone remodeling imbalance in which bone loss (resorption) exceeds bone formation. Approximately 8 million women in the United States have osteoporosis, and about 2 million osteoporotic fractures occur each year. Prevention and treatment of postmenopausal osteoporosis have included the use of calcium and vitamin D supplements, bisphosphonates (alendronate, ibandronate, and risedronate for oral use; ibandronate and zoledronic acid for I.V. administration), selective estrogen receptor modulators (raloxifene; bazedoxifene in combination with conjugated estrogens [Duavee]), calcitonin (administered subcutaneously, intramuscularly, or as a nasal spray), the monoclonal antibody denosumab (Prolia), and the parathyroid hormone receptor agonist teriparatide (Forteo). Abaloparatide (Tymlos Radius) is a synthetic 34-amino acid peptide that is an analog of human parathyroid hormone-related peptide. Like teriparatide, it is a parathyroid hormone receptor agonist that stimulates bone formation, whereas other prescription medications used for postmenopausal osteoporosis inhibit bone resorption. Both drugs are administered subcutaneously, and abaloparatide is specifically indicated for the treatment of postmenopausal women with osteoporosis who are at high risk for fracture. This is defined as a history of osteoporotic fracture, multiple risk factors for fracture, or failure of or intolerance to other available osteoporosis therapy. Effectiveness of abaloparatide was demonstrated in a placebo-controlled clinical study in which most of the patients had experienced at least one prior fracture. The primary endpoint was the incidence of new vertebral fractures, and over an 18-month treatment period, a significant reduction occurred in the incidence of these fractures in patients treated with the new drug (0.6%) compared with the patients receiving placebo (4.2%). A significant reduction also occurred in the incidence of nonvertebral fractures. Although some patients in the study were treated with teriparatide, there are insufficient data to permit a comparison of the two drugs for incidence of fractures. In addition to its use as treatment for postmenopausal women with osteoporosis, teriparatide is also indicated for treatment of men and women with osteoporosis associated with sustained systemic glucocorticoid therapy who are at high risk for fracture, and for increase of bone mass in men with primary or hypogonadal osteoporosis who are at high risk for fracture. However, these are not labeled indications for abaloparatide at present. The most commonly experienced adverse events in the clinical trial of abaloparatide included hypercalciuria (11%), dizziness (10%), nausea (8%), headache (8%), and palpitations (5%). Ten percent of the patients discontinued treatment with the new drug because of adverse events, compared with 6% of those receiving placebo. Because abaloparatide may cause hypercalciuria, MARCH 2018 PharmacyToday 71