CE LESSON. The two primary pathways of approval include new drug applications,

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1 By Clark Kebodeaux, Pharm.D., BCACP, assistant professor pharmacy practice and science, University of Kentucky College of Pharmacy Author Disclosures: Clark Kebodeaux and the DSN editorial and continuing education staff do not have any actual or potential conflicts of interest in relation to this lesson. Universal program number: H01-P CE Broker tracking number: Activity type: Knowledge-based Initial release date: Feb. 28, 2017 Planned expiration date: Feb. 28, 2020 This activity is worth two contact hours 0.2 CEUs Target Audience Pharmacists in community-based practice. Program Goal To provide pharmacists the foundational knowledge to improve patient care by implementation of new therapies from Learning Objectives: Upon completion of this program, the pharmacist should be able to: 1. Identify pertinent new molecular and biological entities to community and ambulatory practice that entered the U.S. drug market in the past year. 2. Describe each medication s mechanism, appropriate dosing parameters, contraindications and potential drug interactions. 3. Describe how new medications compare with previous agents used for the same indication. 4. List patient-specific characteristic and monitoring parameters for each of these medications. To obtain credit: To complete the program and receive CPE credit, view all lesson content and complete the learning assessment by submitting answers online. A minimum test score of 70% is needed to obtain credit. After successfully completing the learning assessment, participants must complete a program evaluation and claim the available CPE credit. Participants also must verify personal information required by CPE monitor and/or CE Broker (for Florida license holders) prior to submitting CPE credit claims. Official statements of credit are available only through CPE Monitor located at NABP.net. Questions: Contact the DSN customer service team at DRSNCE@LF1925.com. Drug Store News is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. New drugs of 2016 INTRODUCTION The pharmaceutical options available to patients continue to grow each year. The U.S. Food and Drug Administration, or FDA, approved 22 novel drugs in 2016, including approvals for new molecular entities known as NMEs or for new biologic therapeutics. 1 In 2016, the number of approvals saw a significant decrease from the two previous years. In 2015, the FDA approved 45 drugs and approved 41 drugs in The last year that had a smaller number of NME approvals than 2016 was 2010, when only 21 drugs were approved. 2 While the total number of new medication approvals was below the average approved over the last decade, a significant portion of the 2016 total is indicated for rare diseases diseases that affect fewer than 200,000 Americans and is classified as orphan drugs. Nine of the new biologic therapeutic approvals are orphan drugs that provide distinct options for patients who may not otherwise receive treatment. Of note, the FDA approved three biosimilar products that are not included in the novel drug total for While these new medications are classified as biosimilars, they are not considered interchangeable products and cannot be considered distinct approvals, depending upon how they are classified. FDA-APPROVAL PROCESS BACKGROUND The FDA is responsible for approving changes to combinations and new formulations of medications, in addition to the novel therapeutics. The two primary pathways of approval include new drug applications, or NDAs, and biologic license applications, or BLAs. NDAs are the most common route of drug approval with 10 distinct types of classifications, which range from new molecular entities, classified as type 1, to new dosage forms, new combinations, new formulations and Rx-to-OTC switches, among others. BLAs represent medications with distinct biologic considerations, including such common examples as certain blood products and vaccines. In total, 104 NDA and BLA district approvals were granted in Type 1 approvals of NMEs approved in 2016 are summarized in table 1. This review is intended for community pharmacists practicing in an outpatient setting. Since a significant portion of drugs approved in 2016 are either infused or are for rare diseases, this review will be limited to therapies or changes in formulation that are likely to impact community pharmacy practice. Summaries of new drugs approved in 2016 are organized by therapeutic category below. THERAPEUTIC CONSIDERATIONS Diabetes In 2016, one NME was approved for the treatment of diabetes. Specifically indicated for patients with Type 2 diabetes, lixisenatide (Adlyxin, Sanofi) is a glucagon-like peptide 1 receptor agonist, or GLP-1. 5 Joining multiple options already available to patients, lixisenatide is the sixth GLP-1 agonist to reach the U.S. market. Lixisenatide improves blood sugar levels in patients with Type 2 diabetes by reducing insulin secretions, decreasing glucagon release and slowing gastric emptying. Lixisenatide is available in two strengths as an injectable-dosage form. Both strengths are available in 3 ml-prefilled pens. The strengths of the pens are 50 mcg/ml for 14 preset doses at 10 mcg per dose and 100 mcg/ml for 14 pre-set doses at 20 mcg per dose. 5 To help reduce confusion, each pen has a distinct color. Pens that deliver the 10 mcg/dose are green and 20 mcg/dose pens are burgundy. Lixisenatide is dosed daily, beginning with a started titration schedule. The manufacturer recommends that patients begin with a once-daily 10 mcg, subcutaneous injection one hour prior to the first meal of the day for the first 14 days. If tolerated, patients should increase to the 20 mcg once-daily dose for the subsequent 14 days. 5 Pharmacists should be aware that lixisenatide is available as a starter pack that enables patients to complete the initial 28 days of therapy prior to the chronic dose and communicate it to the prescriber. Similar to other recommended titration schedules, such as the antidepressant vilazodone, pharmacists should expect that patients will receive two prescriptions one for the starter pack and the other for 1 FEBRUARY

2 Table FDA type 1 drug approvals 1* BRAND NAME GENERIC NAME FDA-APPROVAL DATE INDICATION Adlyxin lixisenatide 7/27/16 Type 2 diabetes Anthim obiltoxaximab 3/18/16 Anthrax Axumin fluciclovine F 18 5/27/16 Prostate cancer diagnostic agent Briviact brivaracetam 2/18/16 Partial-onset seizures Cinqair reslizumab 3/23/16 Severe asthma Defitelio defibrotide sodium 3/30/16 Hepatic veno-occlusive disease after transplant Epclusa sofosbuvir and velpatasvir 6/28/16 Hepatitis C virus Eucrisa crisaborole 12/14/16 Atopic dermatitis Exondys 51 eteplirsen 9/19/16 Duchenne muscular dystrophy Lartruvo olaratumab 10/19/16 Soft tissue sarcoma Netspot gallium Ga 68 dotatate 6/1/16 Diagnostic imaging agent Nuplazid pimavanserin 4/29/16 Parkinson s disease psychosis Ocaliva obeticholic acid 5/27/16 Chronic liver disease Rubraca rucaparib 12/19/16 Ovarian cancer Spinraza nusinersen 12/23/16 Spinal muscular atrophy (SMA) Taltz ixekizumab 3/22/16 Plaque psoriasis Tecentriq atezolizumab 5/18/16 Urothelial carcinoma Venclexta venetoclax 4/11/16 Chronic lymphocytic leukemia Xiidra lifitegrast ophthalmic solution 7/11/16 Dry eye disease Zepatier elbasvir and grazoprevir 1/28/16 Hepatitis C virus Zinbryta daclizumab 5/27/16 Multiple sclerosis Zinplava bezlotoxumab 10/21/16 Clostridium difficile * Adapted from FDA Novel Drug Approval 2016 Chart the higher strength, if tolerated to allow patients to achieve optimal therapy. Lixisenatide was approved based on multiple clinical trials, including monotherapy, as an additional agent with oral medications, and as adjunct therapy to basal insulin. When used as monotherapy, lixisenatide produced modest gains in A1c improvement, resulting in an absolute reduction of 0.65%. Lixisenatide also showed improvements in fasting plasma glucose, or FPG, and showed no significant difference in weight loss compared to placebo. 6,7 Results were similar when lixisenatide was used in combination with metformin and/ or a sulfonylurea. Lixisenatide also underwent clinical trials to determine the benefit of the drug on cardiovascular outcomes. The ELIXA study involved patients who had a recent acute coronary syndrome, or ACS, event. Researchers compared combined composite endpoints on future cardiovascular events in patients treated with lixisenatide as compared to placebo. Lixisenatide s hazard ratio, or HR, of 1.02 Confidence Interval 0.89 to 1.17 revealed no significant reduction in cardiovascular events. 8 Lixisenatide s adverse event profile is similar to currently approved GLP-1 agonists. It is contraindicated in patients with a history of hypersensitivity reactions and should not be used in patients with a history of pancreatitis or severe renal failure. Lixisenatide is not considered a substitute for insulin. Pharmacists need to counsel patients on lixisenatide s impact on gastric emptying, which can affect absorption of some oral medications such as antibiotics, acetaminophen, and oral contraceptives resulting in necessary changes in the dosing schedule. 5 Currently there are other GLP-1 agonists already available to patients. Some medications in the class have longer dosing intervals (up to once weekly), more significant A1c decreases, better cardiovascular benefits and significantly more weight loss. No significant cost savings is associated with using lixisenatide alone compared to other GLP-1 agonists, which may limit lixisenatide s ultimate impact on patient care. Combination Products New combination injectable medications approved for Type 2 diabetes also exist, which are GLP-1 agonists with long-acting insulin, or LAI. Lixisenatide was formulated with insulin glargine (Soliqua, Sanofi), and liraglutide was formulated with insulin degludec, (Xultophy, Novo Nordisk. These products bring the total amount of injectable GLP-1 agonists to eight, including combination products. Insulin glargine and lixisenatide injection (Soliqua, Sanofi) is available in 100/33 3mL pens 100 units/ml insulin glargine and 33 units/ml lixisenatide and five pens per package. 9 This formulation is indicated for patients who are inadequately controlled on a basal insulin dose of less than 60 units daily. Insulin glargine and lixisenatide injection can be administered as three-fixed doses of 15 units/5 mcg, 30 units/10 mcg and a maximum of 60 units/20 mcg per injection. Pharmacists need to ensure that patients are at an appropriate starting dose based on their current basal insulin dose. The 15/5 formulation is the starting dose for patients who previously used less than 30 units of basal insulin. The 30/10 formulation is appropriate for patients using between 30-to-60 units daily. Dosing is consistent with lixisenatide and should be admistered once daily one hour before the first meal. Injection technique, contraindications, adverse reactions and drug interactions are all consistent with previously approved lixisenatide and insulin glargine. 9 Similar considerations are true for insulin degludec and liraglutide injection (Xultophy, Novo Nordisk). Insulin degludec and liraglutide injection is available in a 3-mL pen as a 100/ units/ml insulin degludec and 3.6 mg/ml liraglutide dispensed in a five-pen package. 10 The pen dose counter, and subsequent liraglutide component dose, is measured via the amount of insulin degludec prescribed for the patient. The pen allows for dosing from 10-to-50 units of a maximum daily dose per injection, with the recommended starting dose of 16 units/0.58 mg. While this dos- FEBRUARY

3 ing provides patients with more flexibility, pharmacists should counsel patients to ensure appropriate initial dosing and titration to reduce the risk for hypoglycemia. Another significant difference between GLP-1/insulin combination injections is that insulin degludec and liraglutide can be administered once daily without regard to meals. However, it only is indicated for patients who have a high basal daily dose of insulin that is less than 50 units daily. 10 Injection technique, contraindications, adverse reactions and drug interactions are all consistent with previously approved Insulin degludec and liraglutide. Three-combination oral products to treat Type 2 diabetes were approved in 2016: empagliflozin/metformin, (Synjardy XR, Boehringer Ingelheim); linagliptin/ metformin (Jentadueto XR, Boehringer Ingelheim) and canagliflozin/metformin (Invokamet XR, Janssen). Empagliflozin/ metformin and canagliflozin/metformin are sodium-glucose co-transporter 2, or SGLT2 inhibitors used in combination with metformin, and linagliptin/metformin is a dipeptidyl peptidase-4, or DPP-4, inhibitor used in combination with metformin. All three have similar benefits in reducing pill burden. If patients have sufficient insurance coverage, all three combination products can be dosed once daily. Hepatitis C Specialty pharmacy, particularly in the community-outpatient setting, continues PATIENT SCENARIO 1 Mrs. Peters is a 59-year-old female diagnosed with Type 2 diabetes and hypertension. Her current medications include lisinopril 20 mg, one tablet by mouth once daily; metformin 1,000 mg, one tablet by mouth in the morning and in the evening; and insulin glargine 22 units, injected subcutaneously every day at bedtime. Her A1c from her most recent laboratory work was 7.6%. She stated that her physician wants her to start a GLP-1 agonist to lower her A1c below 7%. However, Mrs. Peters already reluctantly committed to a daily insulin injection and is very hesitant to commit to another daily injection. What options are available for Mrs. Peters, and what are the advantages/disadvantages to each therapy? Discussion The pharmacist should first inform the patient about two options currently approved that would allow her to start a GLP-1 agonist in combination with a long-acting insulin, while not adding to her daily injection burden. Both insulin glargine/lixisenatide injection and insulin degludec/liraglutide injection are options for Mrs. Peters. Since she is uncontrolled at her current dose of 22 units/day of insulin glargine means that she is a candidate to switch to either therapy, as patients must be lower than 50 units for insulin degludec/liraglutide and 60 units for insulin glargine/lixisenatide. While lixisenatide is the newest GLP-1 inhibitor approved, its combination with insulin glargine could serve well in clinical predictability with this patient. However, it can only be dosed at three distinct doses. Since the patient is starting a new therapy, the recommendations for Mrs. Peters should be to start at the 15 units/5 mcg dose once daily within the first hour of the day and titrated as appropriate. Insulin degludec/liraglutide also is an option with a starting dose of 16 units/0.58 mg dose taken once daily and titrating to effect. Insulin degludec/liraglutide has more dosing flexibility and can be dosed between 10 to 50 total units of basal insulin. Any patient starting a GLP-1 agonist should be counseled on increased nausea/vomiting and potential for hypoglycemia when dosed with insulin. Mrs. Peters should also be assessed for a history of pancreatitis or renal failure for either medication. to drive significant revenue growth for pharmacies and pharmaceutical manufacturers. 11 A main growth area is the treatment of hepatitis C virus, or HCV, where approximately 2.7-to-3.9 million Americans are estimated to be infected. 12 While these medications come at a high cost to patients, pharmacies and insurance companies, the medication outcomes for patients continue to improve. Two NMEs were approved for the treatment of HCV: elbasvir/grazoprevir, (Zepatier, Merck) and velpatasvir/sofosbuvir, or (Epclusa, Gilead Sciences). Elbasvir and grazoprevir, approved in January, is a fixed-dose combination of an NS5A inhibitor and an NS3/4A protease inhibitor indicated for HCV genotypes 1 and Elbasvir and grazoprevir is dosed for 12-to-16 weeks with or without ribavirin based on the patients genotype and level of cirrhosis exact dosing regimens should be determined using the package insert. Outcomes from clinical trials were significant and comparable to other oral fixed-dose combination regimens for hepatitis C sustained virologic response, or SVR, rates of 95% in genotype 1, including patients with cirrhosis and 97% to 100% SVR rates in small cohorts of genotype 4 patients. 13 Adverse events more than 5% were consistent with other medications approved to treat HCV fatigue, headache and nausea. Grazoprevir is a substrate of OATP transporters, or1b1/3, which means it should not be administered with certain HIV medications like atazanavir, darunavir or immunosuppressant, such as cyclosporine, due to risk OTAP inhibition resulting in ALT elevations. Sofosbuvir/velpatasvir was approved in June 2016 as a fixed-dose combination of a NS5B polymerase inhibitor and NS5A inhibitor indicated for all genotypes of HCV (one to six) with and without cirrhosis. This is the first medication to treat all genotypes of HCV with a standard recommended treatment regimen of 12 weeks, and only patients with decompensated cirrhosis child-pugh scores B and C require the addition of ribavirin for the course of therapy. 14 Sofosbuvir/velpatasvir is well tolerated, with the main adverse reactions were headache and fatigue as the main adverse reactions for more than 10% of patients. As expected, increased adverse events like anemia, nausea, insomnia and diarrhea occurred when the regimen was dosed with ribavirin. Sofosbuvir and velpatasvir are substrates of P-glycoprotein, or P-gp, and were moderately metabolized by CYP2B6, 2C8 and 3A4. Solubility of velpatasvir is affected by gastric ph. Therefore, antacids should not be used within four hours; H 2 -receptor antagonists should be either administered simultaneously or separated by 12 hours; and the use of proton pump inhibitors is not recommended. While approved prior to 2016, a new extended-release formulation of dasabuvir/ombitasvir/paritaprevir/ritonavir (Viekira XR, AbbVie) was approved. The original formulation was reduced to three tablets taken once daily with food. Many of the same considerations still apply, including an indication for genotype 1 HCV, significant drug interactions (ritonavir and paritaprevir are metabolized by CYP3A enzymes; Dasabuvir is a substrate of CYP2C8; all are substrates of P-gp, all but ritonavir are substrates of BCRP; and paritaprevir is a substrate of OATP1B1/3) and risk of hepatic failure, but the regimen is comparable to other fixed-dose combination tablets in that it does not require a second daily dose to fully adhere to the regimen. 15 Pharmacists can make a significant impact on patient outcomes with HCV treatment. Given the extremely high cost of these medications, pharmacists can work with patients to ensure that they adhere to therapy, as well as follow abstinence requirements such as alcohol or IV drug use required by payers. Many of these regimens can interact with patients regular maintenance medications. Pharmacists should monitor for drug interactions with each patient s medications, particularly for HCV treatment regimens that require the use of ribavirin or ritonavir. The addition of these medications changes the drug interaction and adverse event profile signifi- 3 FEBRUARY

4 cantly, and pharmacists should consult the package insert for regimen-specific interactions. Lastly, pharmacists can work with local health departments to promote screening opportunities in their area, or host them where allowed by state law. CLIA-waived point of care, or POC, tests are available to detect HCV with high accuracy. Rheumatoid Arthritis Three of the four total biosimilar agents approved by the FDA to date were approved in The FDA definition of biosimilar is: the biological product is approved based on data demonstrating that it is highly similar to an FDA-approved biological product, known as a reference product, and that there are no clinically meaningful differences between the biosimilar product and the reference product. 3 This is an important distinction for pharmacists and patients, as the biosimilar designation does not consider these products to be interchangeable. The determination of biosimilar as documented by the FDA s purple book specifically distinguishes between biosimilars and interchangeable biologic products. The important distinction is that interchangeable products must produce similar clinical outcomes, while the biosimilar distinction is based on similarity to the reference product. In addition to other diseases, all three biosimilars are indicated for the treatment of rheumatoid arthritis in adults and work as an immunosuppressant blocking the cytokine response of Tumor Necrosis Factor, or TNF-alpha. Etanercept-szzs (Erelzi, Sandoz) is a biosimilar to etanercept (Enbrel, Amgen). Infliximab-dyyb, (Inflectra, Celltrion) is a biosimilar to Infliximab (Remicade, Janssen). Adalimumab-atto, (Amievita, Amgen) is a biosimilar to adalimumab, (Humira, AbbVie). All three medications contain consistent black-box warnings for serious infections and malignancy as the original biologic counterparts. The clinical data, including indications, dosing, contraindications/warnings, drug interactions and adverse reactions listed in the standard product labeling, are the same as the original medications. As more biosimilar medications are produced and brought to market, it is critical for pharmacists to work with patients and prescribers to ensure that they are prescribed and recommended appropriately as the regulatory framework becomes clearer. Other therapies for rheumatoid arthritis approved in 2016 include an extended-release formulation of the first janus kinase, or JAK, inhibitor, tofacitinib, (Xeljanz XR,Pfizer). 16 The dose of 11 mg taken once daily replaces the original tofacitinib dose of 5 mg taken twice daily. There are no known clinical differences between the extended-release and standard formulations outside of the dosing requirements. However, it is important for pharmacists to help patients who may require a lower dose of tofacitinib to not use the XR product. Patients with renal and hepatic impairment, or patients taking a potent CYP 3A4 inhibitor, such as ketoconazole, should not use the XR product in order to appropriately reduce the dose. Patients with these considerations should use the standard tofacitinib dose to 5 mg taken once daily. 16 Human Immunodeficiency Virus, or HIV-1, Infection No new NMEs were approved for the treatment of HIV-1 infection in However, the approval of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide, (Genvoya, Gilead Sciences) in 2015 drove innovation for patients with HIV/AIDS in The tenofovir alafenamide, or TAF, component of the single-tablet regimen replaced the traditional tenofovir disoproxil fumarate that was included for years in previous combination treatments. The new formulation of tenofovir has the same nucleoside reverse transcriptase inhibitor, or NRTI, mechanism as the original formulation, but is a prodrug that is converted from TAF to tenofovir intracellularly. TAF allows for a more concentrated dose to be delivered to the patient in an effort to reduce systemic exposure and negative effects of bone mineral density loss, and worsening kidney function. Co-formulation with TAF resulted in PATIENT SCENARIO 2 changes to three prominent single-tablet combination regiments used to treat HIV. In addition to Genvoya, which replaced the previous formulation with tenofovir disoproxil fumarate (Stribild, Gilead Sciences), emtricitabine/tenofovir alafenamide (Descovy, Gilead Sciences) and emtricitabine/rilpivirine/tenofovir alafenamide (Odefsey, Gilead Sciences) were approved in 2016 to replace Truvada (Gilead Sciences) and Complera (Gilead Sciences), respectively. Due to similar dosing burden and the potential for improved longterm adverse event outcomes, pharmacists should encourage patients to switch to TAF-based formulations of these HIV-1 treatment regimens, even if well controlled. Tenofovir alafenamide (Vemlidy, Gilead Sciences) also was approved as a treatment for hepatitis B to be used in similar fashion to tenofovir disoproxil fumarate (Viread, Gilead Sciences). Dry Eye Disease Lifitegrast ophthalmic solution 5% (Xiidra, Shire) is a lymphocyte function-associated antigen-1 antagonist that was approved in 2016 for the treatment of dry eye disease, or DED. 18 LFA-1 is a protein found on leukocyctes that interact with ligand intercellular adhesion molecule-1, or ICAM- 1. ICAM-1 is highly expressed in patients with DED. While the exact mechanism of action is unknown, antagonism of LFA-1 may reduce the expression of ICAM-1 and inhibition functions of the immune system, including T-cell adherence to ICAM-1. Lifitegrast is dosed as a single, one-use Mr. Stevens is a 36-year-old male with a history of moderate-to-severe rheumatoid arthritis. He has been well-controlled on his regimen of methotrexate, eight 2.5mg tablets 20 mg taken orally once a week; folic acid, a once daily 1-mg tablet taken orally; and adalimumab, 40 mg administered subcutaneously every other week. He recently read in the newspaper that a new product called Amjevita was approved. He arrived at the pharmacy with questions about the article. Specifically, he wanted to know if he needed to speak with his physician about it. He also was curious about the product, and if it was similar to his generic methotrexate. What should Mr. Stevens know about biosimilars? Discussion The pharmacist should explain that the FDA approval of these biosimilar products does not necessarily guarantee their arrival to market. To date, four biosimilars have been approved, and varying degrees of litigation determine when they are allowed to reach the market. To explain how biosimilars work to patients, the pharmacist should begin with the FDA-approval process that was revised at nearly the same time as the Affordable Care Act. Since these medications have unique biological qualities, there are two ways that biologic products are approved: as a biosimilar product or as an interchangeable biological product. Using an analogy with Mr. Steven s methotrexate, an interchangeable biological product is a standard similar to the generic substitution, so there is no need to contact the healthcare provider to substitute for the reference product. However, since these have been approved as biosimilars, these medications exist in parallel to their original products because they have not yet met the standard required for interchangeability. If adalimumab-atto were to reach the market, the pharmacist would work with the patient s prescriber to seek a different prescription in order for the patient to use the biosimilar product. FEBRUARY

5 container that can provide one drop for each affected eye every 12 hours for treatment of DED. Pharmacists should counsel patients who use this product on consistent administration technique, and recommend patients administer the solution at least 15 minutes prior to using contact lenses. The main adverse events of more than 5% for lifitegrast were instillation site irritation, taste abnormalities and reduced visual acuity. 18 Clinical studies used to approve this medication only compared it to with placebo, so it is difficult to recommend as firstline therapy since it has not been compared to other agents for the same indication. Many patients can treat DED with over-thecounter, or OTC, therapy. Given the potential cost of treatment with lifitegrast, pharmacists should recommend that patients attempt to treat DED with OTC medications, if they have not had prior treatment. Atopic Dermatitis A topical treatment for mild-to-moderate atopic dermatitis, or eczema, was approved in Crisaborole ointment 2% (Eucrisa, Anacor Pharmceuticals) is a phosphodiesterase 4, or PDE-4, inhibitor indicated for treatment for patients ages 2 years old and older. 19 Generally well tolerated in clinical trials, crisaborole improved investigator s static global assessment, or ISGA, scores after 28 days of treatment scores range from 0-clear to 4-severe disease. All patients enrolled had a score of 2-mild or 3-moderate, and the outcome was a percentage of patients who achieved a score of 1 or 0 compared to placebo. In the two trials, crisaborole achieved ISGA scores in 32.8% and 31.4% of patients, compared to placebo, with 25.4% and 18.0%, respectively. 20 Crisaborole should be applied as a thin layer to affected areas twice daily, and is available in 60- and 100-g tubes. The only warnings or contraindications are known hypersensitivity to crisaborole, and the only adverse reaction that occurred in more than 1% of patients was pain at the application site. 19 Due to the increased cost, it is likely the crisaborole will be used after a regimen of moisturizers and topical corticosteroids in the treatment of mild-to-moderate atopic dermatitis. This novel mechanism increases the options for patients with eczema and is well tolerated, especially for patients who are not achieving an adequate response from standard initial therapy. Dyspareunia Prasterone (Intrarosa, Endoceutics) vaginal inserts were approved to treat dyspareunia, or painful sexual intercourse, in patients who experienced vulvar and vaginal atrophy due to menopause.21 Prasterone is a steroid that is converted into active androgens and estrogens the exact mechanism of how prasterone treats dyspareunia is unknown. In clinical trials, treatment was measured for 12 weeks based on four outcomes: patient reported severity of symptoms, measured vaginal superficial cells, percentage of parabasal cells and vaginal ph. Treatment with prasterone showed increases in superficial cells, decreases in parabasal cells and vaginal ph resulting in statistically significant decreases in patientreported symptoms compared to placebo. Prasterone is supplied as 28 vaginal inserts with 4-weekly packs of seven that can be stored at room temperature. 21 Pharmacists should counsel patients to wash their hands and urinate prior to administration. It is important to remind patients that this should be taken nightly at bedtime and not as needed, or only prior to sexual intercourse. The main adverse events were vaginal discharge and changes on pap smears. Ensure that patients share any abnormal bleeding with their prescribing provider. Since daily use can affect androgen and estrogen levels, prasterone should not be used by patients who have, or think they may have, breast cancer, as well as patients who are pregnant and breastfeeding. The place in therapy for prasterone is not exactly clear. While able to be delivered locally, many other options exist, including topical or locally delivered estrogen to improve vaginal atrophy. Pharmacists should counsel patients on all their available options, beginning with vaginal moisturizers or lubricants to potential estrogen, ospemifene and prasterone. It is very important that patients are appropriately referred so an accurate diagnosis can be made to guide treatment for dyspareunia. Epilepsy Brivaracetam, (Briviact, UCB) was approved as an adjunct therapy for the treatment of partial-onset seizures in patients age 16 years old or older. 22 While the exact mechanism is unknown, brivaracetam has affinity to synaptic vesicle protein 2A, or SV2A, similar to levetiracetam. It is unknown at this time if brivaracetam has similar activity on GABA receptors. Brivaracetam was approved based on clinical trials that revealed decreased seizure frequency in patients taking two separate doses of brivaracetam compared to placebo. The recommended dose for brivaracetam is 50 mg taken orally, twice daily. Since the tablets are available in 10 mg, 25 mg, 50 mg, 75 mg and 100 mg, patient s doses can be titrated to effect up to a max dose of 100 mg taken twice daily, or adjusted down to 25 mg in patients with hepatic impairment or drug interactions. Brivaracetam is partially metabolized by CYP2C19, but has multiple interactions with other anticonvulsants, including increasing the plasma concentration of phenytoin and carbamazepine. Other CYP2C19 inducers resulted in decreased concentrations of brivaracetam. Pharmacists need to counsel patients for somnolence, fatigue and nausea hypersensitivity reactions in the clinical trials included examples of bronchospasm and angioedema. All patients should be monitored for signs of depression, as well as other psychiatric effects such as anxiety. 22 Parkinson s Disease Psychosis Pimavanserin (Nuplazid, Acadia) is an atypical antipsychotic used for the treatment of delusions and hallucinations associated with Parkinson s disease psychosis.23 Pimavanserin is an agonist/ antagonist at serotonin 5-HT2A receptors with some activity in 5-HT 2C serotonin receptors that are thought to be responsible for delusions associated with Parkinson s psychosis. Pimavanserin was approved with an FDA black-box warning related to the use of atypical antipsychotics in elderly patients with dementia-related psychosis. Pharmacists should ensure that patients who receive pimavanserin have a diagnosis of Parkinson s with known psychosis prior to dispensing. The dosing regimen is fixed: two 17-mg tablets taken once daily with or without food. The only dosing adjustments are for patients taking concurrent CYP3A4 inhibitors, where the dose is reduced to one 17- mg tablet taken once daily. Pimavanserin is heavily metabolized by CYP 3A4/5 enzymes, and while it is not an inhibitor or inducer, pharmacists should monitor closely for medications that affect metabolism. The most common adverse events for more than 5% include peripheral edema and a confusional state. Pharmacists should monitor for worsening hallucination, urinary tract infections and fatigue as these were responsible for treatment discontinuation in clinical trials. 23 Pharmacists should be vigilant in their assessment of patients who have worsening symptoms of Parkinson s disease. Many causes of psychosis or worsening of symptoms are because the medications used to improve motor function, such as dopamine, or D2, can increase delusions. However, changes in functional status can be caused by OTC anticholinergic medications, such as diphenhydramine or changes in functional status. Communication with patients and their provider can supply alternative options to prevent delusions and reduce the potential risk of antipsychotic use with the elderly. VACCINES There were no biological, or BLA, approvals for new vaccine products in However, ACIP and CDC recommended 5 FEBRUARY

6 changes that impact community pharmacy practice during the calendar year. While these recommendations are not covered in depth because these are not newly approved medications, a summary of changes in recommendations is included below: HPV vaccination schedules were updated to add a two-dose schedule for both boys and girls ages nine years old to 14 years old. The new schedule includes the initial vaccine and the second dose scheduled 6-to-12 months after the original vaccination to complete the series. For adolescents older than 15 years old, the three-dose series is still recommended. The 9-valent version of the HPV, or 9vHPV, (Gardasil, Merck) vaccine continues to be the recommended vaccine of choice. 24 According to the new guidelines, any patients who began the series prior to their 15th birthday and received two doses of any HPV vaccine at the new recommended dosing schedule zero and six-to-12 months) are considered vaccinated. Additionally, if patients started the series prior to their 15th birthday, one more vaccination is required to catch up at least six months after their original dose. All HIV-infected patients should receive two doses of the meningococcal conjugate vaccine, or MCV. Patients who were previously vaccinated after the age of seven should receive one booster dose five years after the previous dose, and every five years after. 25 Annual influenza recommendations were updated, including changes to vaccine composition and addition of two vaccines approved by the FDA in The MF59-adjuvanted trivalent inactivated influenza vaccine, or aiiv3 (Fluad, Sequris) is indicated for people ages 65 years old and older. The quadrivalent cell culture-based inactivated influenza vaccine, or cciiv4, Flucelvax, Sequris) was indicated for children ages 4 years old and older. The most notable updated was a recommendation preference that the live attenuated influenza vaccine, or LAIV, not be used due to decreased efficacy. Outside of LAIV change, the ACIP and CDC continue to not prefer one formulation over another in the absence of contraindications to vaccine. 26 Routine vaccination of smallpox for laboratory workers who directly handle cultures or animals that are infected with orthopoxviruses. 27 The recommendation that has the largest impact on community pharmacy is the HPV vaccination. Pharmacists can communicate with providers to ensure that patients who are less than 15 years old only need two total vaccinations. Pharmacists can serve an important role to ensure the appropriate subsequent doses are given as indicated. PRESCRIPTION-TO-OTC SWITCHES In 2016, the FDA approved two prescription-to-otc switches: fluticasone furoate (Flonase Sensimist Allergy Relief, GSK) and adapalene gel 0.1% (Differin Gel, Galderma).28,29 Fluticasone furoate is a distinct formulation of fluticasone propionate (Flonase Allergy Relief, GSK), approved for OTC use in Fluticasone furoate was known as Veramist as a prescription, but will be marketed under the Flonase branding as an OTC product. Because of the brand extensions, it is important to discuss each specific product with patients when recommending. Fluticasone propionate is marketed as both an adult and pediatric product, and fluticasone furoate will be the third fluticasone product marketed OTC. For pharmacists and patients, the main distinction is the appropriate age of use. Fluticasone furoate can be used in children age two years old and older, while fluticasone propionate is only labeled for use in children older than four years old. This is consistent with the starting age of triamcinolone, or Children s Nasacort, but significantly younger than budesonide (Rhinocort ) that is indicated for patients 6 years old. Both dosing regimens and delivery mechanisms are consistent with their prescription counterparts. Patients who use fluticasone OTC for treatment of allergic rhinitis should be referred to a physician after seven days of use if their symptoms do not improve. Current labeling still recommends following up with a physician Table 2 Pharmacist and patient resources Food and Drug Administration (FDA) Novel Drug Approvals: if medication is needed for six months of chronic use. 28 Adapalene gel 0.1% is the first topical retinoid to be approved for OTC acne treatment.29. It will be available commercially in 0.5 oz, or 15g, and 1.5 oz, or 45 g, tubes indicated for a 30- and 90-day supply, respectively. The OTC indication is for children and adults ages 12 years old and older, and is to be applied to the affected area once daily at the same time of day. Pharmacists can recommend that patients use it at night to reduce potential sun exposure, and that patients should use sunscreen when they will be outside while using this product. Many moisturizers available contain sunscreen at an SPF 15 level that can help patients avoid both sun sensitivity and dryness associated with adapalene use. It is indicated for 12 weeks of treatment prior to a provider referral, and patients should be adequately educated that it may take up to three months to see the full effect of treatment. While there is no evidence that adapalene causes birth defects, patients should see a provider if they are pregnant or breastfeeding before use. With the release of adapalene, Galderma also released a skin wash containing alpha hydroxy acids and a non-medicated moisturizer. While these could be appropriate agents to be used with adapalene gel, they are marketed under the same brand name, and pharmacists should ensure that patients are selecting the correct gel product if intending to treat acne with adapalene. 29 RESOURCES FOR THE PHARMACIST The majority of information about new therapies available for patients is included in the standard product labeling, or SPL, re- FDA Purple Book for Biosimilars: TherapeuticBiologicApplications/Biosimilars/ucm htm Prescription to Over-the-Counter (OTC) Switch List: ACIP Vaccine Recommendations: PRACTICE POINTS Ensure appropriate basal insulin dose prior to switching to GLP-1 agonist/lai combination injection Sofosbuvir/velpatasvir was the first agent to treat HCV that can be given to any genotype 1-6 Patients with HIV regimens that contain tenofovir disoproxil fumarate can be safely switched to tenofovir alafenamide for potential long-term safety improvements. HPV vaccination should now be a two-dose series if began prior to age 15 years old Adapalene gel 0.1% is the first retinoid to be approved for OTC acne treatment in the United States FEBRUARY

7 quired for approval by the FDA. SPL information, commonly referred to as the package insert for prescription medications, details much of the information required to adequately prescribe and educate patients. Table 2 summarizes FDA and other resources needed to access up-to-date information on new therapeutics. CONCLUSION Despite the low number of drugs approved in 2016, it is likely that advances in treatments, including the approval of more biosimilars, will have a significant impact on practice in the future. While many approved products are infused or limited in target patient population, the continued development of specialty medications that can be taken orally or injected by the patient will continue to drive the role of the community pharmacist in 2017 and beyond. 1 U.S. Food and Drug Administration. Novel Drug Approvals for Available at: Accessed January 26th, U.S. Food and Drug Administration. Novel Drug Summary Available at: DrugInnovation/ucm htm Accessed February 3rd, U.S. Food and Drug Administration Biological Approvals. Available at: BiologicsBloodVaccines/DevelopmentApprovalProcess/BiologicalApprovalsbyYear/ucm htm. Accessed January 9th, U.S. Food and Drug Administration. Drugs@FDA: FDA Approved Drug Products. Available at: Last accessed February 4th, Adlyxin [package insert]. Bridgewater, NJ: Sanofi-Aventis U.S. LLC; Ahrén B, Leguizamo dimas A, Miossec P, et al. Efficacy and safety of lixisenatide once-daily morning or evening injections in type 2 diabetes inadequately controlled on metformin (GetGoal-M). Diabetes Care. 2013;36(9): Pinget M, Goldenberg R, Niemoeller E, et al. Efficacy and safety of lixisenatide once daily versus placebo in type 2 diabetes insufficiently controlled on pioglitazone (GetGoal-P). Diabetes Obes Metab. 2013;15(11): Bentley- Lewis R, Aguilar D, Riddle MC, et al. Rationale, design, and baseline characteristics in Evaluation of LIXisenatide in Acute Coronary Syndrome, a long-term cardiovascular end point trial of lixisenatide versus placebo. American heart journal May 31;169(5): Soliqua [package insert]. Bridgewater, NJ: Sanofi-Aventis U.S. LLC; Xultophy [package insert]. Plainsboro, NJ: Novo Nordisk Inc.; QuintilesIMS. IMS Health Study: U.S. Drug Spending Growth Reaches 8.5 Percent in Available at: Accessed February 2nd, Centers for Disease Control and Prevention. Viral Hepatitis Hepatitis C Information Available at: Accessed January 27, Zepatier [package insert]. Whitehouse Station, NJ: Merck & Co. Inc.; Epclusa [package insert]. Foster City, CA: Gilead Sciences Inc.; Viekira XR [package insert]. North Chicago, IL: AbbVie Inc.; Xeljanz XR [package insert]. New York, NY: Pfizer Inc.; Genvoya [package insert]. Foster City, CA: Gilead Sciences Inc.; Xiidra [package insert]. Lexington, MA: Shire US Inc.; Eucrisa [package insert]. Palo Alto, CA: Anacor Pharmaceuticals, Inc.; Paller AS, Tom WL, Lebwohl MG, et al. Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for the topical treatment of atopic dermatitis (AD) in children and adults. J Am Acad Dermatol. 2016;75(3): e4. 21 Intrarosa [package insert]. Qubec City Canada G1V 4M7: Endoceutics Inc.; Briviact [package insert]. Smyrna, GA: UCB, Inc.; Nuplazid [package insert]. San Diego, CA: Acadia Pharmaceuticals Inc.; Meites E, Kempe A, Markowitz LE. Use of a 2-Dose Schedule for Human Papillomavirus Vaccination Updated Recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep 2016;65: MacNeil JR, Rubin LG, Patton M, et al. Recommendations for Use of Meningococcal Conjugate Vaccines in HIV-Infected Persons Advisory Committee on Immunization Practices, MMWR Morb Mortal Wkly Rep 2016;65: Grohskopf LA, Sokolow LZ, Broder KR, et al. Prevention and Control of Seasonal Influenza with Vaccines. MMWR Recomm Rep 2016;65(No. RR-5): Petersen BW, Harms TJ, Reynolds MG, et al. Use of Vaccinia Virus Smallpox Vaccine in Laboratory and Health Care Personnel at Risk for Occupational Exposure to Orthopoxviruses Recommendations of the Advisory Committee on Immunization Practices (ACIP), MMWR Morb Mortal Wkly Rep 2016;65: National Institute of Health Daily Med. Flonase Sensimist Allergy Relief Available at: nlm.nih.gov/dailymed/druginfo.cfm?setid=107100af-7ca2-44e8-b067-c0ab0a19a6dc Accessed Feburary 6th, National Institute of Health Daily Med. Differin Gel Available at: Accessed Feburary 6th, Learning Assessment Successful completion of New drugs of 2016 ( H01-P) is worth two contact hour of credit. To submit answers, visit our website at www. DrugStoreNewsCE.com. Please note: Assessment questions submitted online will appear in random order. 1. A patient diagnosed with Type 2 diabetes is currently controlled on insulin degludec. At what basal insulin dose could this patient switch to combination insulin degludec and liraglutide injection therapy? a. 45 units b. 55 units c. 65 units d. 75 units 2. What is the expected A1c reduction for a patient who has tolerated lixisenatide at the 20-mcg once-daily dose after three months of therapy? a. 0.0% to 0.5 % b. 0.5% to 1.0 % c. 1.0% to 1.5 % d. 1.5% to 2.0 % 3. Which of the following antiviral therapies approved in 2016 is indicated to treat genotype 3 HCV infection? a. Elbasvir/grazoprevir b. Velpatasvir/sofosbuvir c. Dasabuvir/ombitasvir/paritaprevir/ ritonavir d. Elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide 4. Which of the following components of dasabuvir/ombitasvir/paritaprevir/ ritonavir, or (Viekira XR, AbbVie) is a CYP2C8 substrate? a. Dasabuvir b. Ombitasvir c. Paritaprevir d. Ritonavir 5. Which of the following adverse events was most common as a result of adding ribravirin to the recommended HCV regimen? a. Fatigue b. Headache c. Nausea d. Anemia 6. By which process was adalimumabatto (Amjevita, Amgen) approved by the FDA? a. Biosimilar b. Interchangeable c. AB-rated generic d. Clinical equivalence 7. What is the FDA s key reference in providing guidance to clinicians on biosimilars? a. The pink book b. The yellow book c. The orange book d. The purple book 8. What is the appropriate dose of tofacitinib for a patient who is taking ketoconazole? a. 5 mg of Tofacitinib taken twice daily b. 11 mg of Tofacitinib taken once daily c. 5 mg of Tofacitinib taken once daily d. Tofacitinib is not recommended with coadministration of ketoconazole 7 FEBRUARY

8 Learning Assessment 9. What is a potential benefit to HIV-1 infection patients who use tenofovir alafenamide in place of tenofovir disoproxil fumarate? a. Decreased viral load b. Increased CD4+ cell count c. Decreased bone mineral density loss d. Decreased potential drug interactions 10. How long should patients wait to use contact lenses after the administration of lifitegrast? a. No delay is required b. 5 minutes c. 15 minutes d. 60 minutes 11. Which of the following investigator s static global assessment, or ISGA, scores of atopic dermatitis would prevent a patient to be a candidate for crisaborole treatment? a. 1 -Almost clear b. 2 - Mild disease c. 3 - Moderate disease d. 4 - Severe disease 12. Which medication would require a dose adjustment if administered with brivaracetam? a. Atorvastatin b. Fluconazole c. Carbamazepine d. Atazanavir 13. What is the neurologic target for pimavanserin to treat Parkinson s Disease psychosis? a. Dopamine (D2) b. Cholinesterase c. Serotonin (5-HT2A) d. Histamine (H2) 14. If a 13-year-old female patient at your pharmacy received a dose of 9vHPV today, when should the patient receive the second dose? a. In four weeks b. In eight weeks c. In six months d. In five years 15. Which of the following formulations of the influenza vaccine is indicated only for patients age 65 years old and older? a. aiiv3 (Fluad ) b. cciiv4, (Flucevax ) c. LAIV, (Flumist ) d. IIV (Fluzone ) 16. A 16-year-old male patient received a dose of HPV vaccination three years ago, but never completed the series. What is the recommended catch-up schedule to complete the series? a. one 9vHPV today b. one 9vHPV in six-to-12 months c. one 9vHPV today and one 9VHPV in six-to-12 months d. one 9vHPV in four weeks and one 9VHPV in six months 17. A 3-year-old patient suffering from nasal congestion, secondary to allergic rhinitis, can be treated with which OTC intranasal steroid? a. Fluticasone furoate (Flonase Sensimist Allergy Relief) b. Fluticasone propionate (Flonase Allergy Relief) c. Fluticasone propionate (Children s Flonase Allergy Relief) d. Budesonide (Rhinocort ) 18. What age is it appropriate to treat acne with adapalene gel 0.1%? a. 2 years old b. 6 years old c. 12 years old d. 18 years old 19. What is the appropriate length of treatment with adapalene gel 0.1% prior to consulting a provider? a. seven days b. 30 days c. three months d. 12 months 20. Which medication, if coadministered with lixisenatide, would need to be dosed separately to due to reduced gastric absorption? a. Atorvastatin b. Norgestimate and ethinyl estradiol tablets c. Metformin d. Chlorthalidone FEBRUARY