New Drugs of 2018*

*Presentation by Daniel A. Hussar, Ph.D. Dean Emeritus and Remington Professor Emeritus Philadelphia College of Pharmacy University of the Sciences

Objectives:

After attending this program, the participant will be able to:

1. Identify the new therapeutic agents and explain their appropriate use. 2. Identify the indications and mechanisms of action of the new drugs. 3. Identify the most important adverse events and other risks of the new drugs. 4. State the route of administration for each new drug and the most important considerations regarding dosage and administration. 5. Compare the new therapeutic 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.

New Drug Comparison Rating (NDCR) system

5 = important advance 4 = significant advantage(s) (e.g., with respect to use/effectiveness, safety, administration) 3 = no or minor advantage(s)/disadvantage(s) 2 = significant disadvantage(s) (e.g., with respect to use/effectiveness, safety, administration) 1 = important disadvantage(s)

Additional information

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Erenumab-aooe (Aimovig – Amgen; Novartis) Agent for Migraine

2018 New Drug Comparison Rating (NDCR) =

Indication: Administered subcutaneously for the preventive treatment of migraine in adults

Comparable drugs: Beta-adrenergic blocking agents (e.g., propranolol); (fremanezumab [Ajovy] and galcanezumab [Emgality] have been subsequently marketed)

Advantages: --Is more effective in some patients --Has a unique mechanism of action (calcitonin gene-related peptide [CGRP] receptor antagonism) --Is less likely to cause adverse events and interact with other drugs --Is administered less frequently (once a month)

Disadvantages: --Is administered subcutaneously (whereas beta-blockers are administered orally) --Effectiveness and safety have not been established in pediatric patients --Has not been directly compared with other medications in clinical studies --Is much more expensive

Most important risks/adverse events: Clinical studies excluded patients with medication overuse headache, as well as patients with myocardial infarction, stroke, transient ischemic attacks, unstable angina, coronary artery bypass surgery, or other revascularization procedures within 12 months prior to screening; latex allergy

Most common adverse events: Injection site reactions (6%)

Usual dosage: Administered subcutaneously; 70 mg once a month; some patients may benefit from a dosage of 140 mg once a month, which is administered as two consecutive injections of 70 mg each

Products: Injection in single-dose prefilled syringes and prefilled autoinjectors containing 70 mg of the drug per mL (products should be stored in a refrigerator and, prior to administration, should be allowed to sit at room temperature for at least 30 minutes protected from direct sunlight)

Comments: Patients who experience migraine attacks frequently are often candidates for preventive management to reduce the frequency and severity of attacks. Those who experience 4 to 14 migraine days per month (i.e., monthly migraine days [MMD]) are classified as having episodic migraines, whereas those with 15 or more headache days per month with at least 8 migraine days per month are classified as having chronic migraines. Certain beta- adrenergic blocking agents (i.e., propranolol, timolol) and certain antiepileptic drugs (i.e., divalproex sodium, topiramate) have labeled indications for migraine prevention, as does onabotulinumtoxinA (Botox; for patients with chronic migraine). Calcitonin gene-related peptide (CGRP) is a neuropeptide that is primarily distributed in the central and peripheral nervous systems and acts as a vasodilator. It is involved in the transmission of pain impulses and elevated concentrations have been associated with migraine attacks. Erenumab is a human monoclonal antibody that exhibits high affinity binding to the CGRP receptor and is the first of a new class of CGRP antagonists. The effectiveness of erenumab was demonstrated in three placebo-controlled clinical trials, two of which were conducted in patients with a history of episodic migraine. The largest of these studies was conducted over a 6- month period using erenumab in dosages of 70 mg once a month and 140 mg once a month. Patients treated with erenumab experienced, on average, one to two fewer MMD than those on placebo, and 43% and 50% of patients, respectively, experienced at least a 50% reduction from baseline in MMD, compared with 27% of those receiving placebo. The third study was conducted in patients with a history of chronic migraine and, over the course of 3 months, patients treated with erenumab experienced, on average, 2.5 fewer MMD, with dosages of 70 mg and 140 mg once a month, than those receiving placebo. Forty percent and 41%, respectively, experienced at least a 50% reduction from baseline in MMD, compared with 24% of those receiving placebo. Erenumab has not been directly compared with other agents that have been used in the prevention of migraine.

Fremanezumab-vfrm (Ajovy – Teva) Agent for Migraine

2018 New Drug Comparison Rating (NDCR) =

Indication: Administered subcutaneously for the preventive treatment of migraine in adults

Comparable drug: Erenumab (Aimovig); (galcanezumab [Emgality] has been subsequently marketed)

Advantages: --May be administered less frequently (every month or every 3 months, whereas erenumab is administered every month) --Product does not contain latex derivatives (to which some patients may be sensitive)

Disadvantages: --May be more likely to cause injection site reactions (although incidence is similar to that with placebo, but may also be related to the larger volume of the dose [1.5 mL compared with 1 mL with erenumab]) --May be more likely to cause hypersensitivity reactions

Most important risks/adverse events: Hypersensitivity reactions; clinical studies excluded patients with a history of significant cardiovascular disease, vascular ischemia, or thrombotic events, such as cerebrovascular accidents, transient ischemic attacks, deep vein thrombosis, or pulmonary embolism

Most common adverse events: Injection site reactions (45%, compared with 38% with placebo)

Usual dosage: Administered subcutaneously; 225 mg once a month or 675 mg every 3 months (quarterly); the 675 mg dose is administered as 3 consecutive injections of 225 mg each

Product: Injection in single-dose prefilled syringes – 225 mg/1.5 mL (should be stored in a refrigerator and, prior to administration, should be allowed to sit at room temperature for 30 minutes protected from direct sunlight)

Comments: Calcitonin gene-related peptide (CGRP) is a neuropeptide that is involved in the transmission of pain impulses, and elevated concentrations have been associated with migraine attacks. Fremanezumab is a human monoclonal antibody that binds to CGRP ligand and blocks its binding to the receptor. It is the second CGRP antagonist approved for the preventive treatment of migraine, joining erenumab. The effectiveness of fremanezumab was demonstrated in two placebo-controlled studies. One study was conducted in patients with episodic migraine (i.e., 4 to 14 migraine days per month [MMD]). Patients treated with fremanezumab experienced, on average, one to two fewer MMD than those on placebo with dosages of both 225 mg once a month and 675 mg once every 3 months, over a 3-month treatment period. Approximately 46% of patients experienced at least a 50% reduction from baseline in MMD, compared with 28% of those receiving placebo. The second study was conducted in patients with chronic migraine (i.e., 15 or more headache days per month with at least 8 migraine days per month). Patients treated with fremanezumab (in both dosage regimens) experienced, on average, two fewer MMD, than those receiving placebo. Approximately 39% of patients experienced at least a 50% reduction in monthly average number of headache days of at least moderate severity, compared with 18% of those receiving placebo.

Galcanezumab-gnim (Emgality – Lilly) Agent for Migraine

2018 New Drug Comparison Rating (NDCR) =

Indication: Administered subcutaneously for the preventive treatment of migraine in adults

Comparable drugs: Erenumab (Aimovig), fremanezumab (Ajovy)

Advantages: --Product does not contain latex derivatives (compared with erenumab)

Disadvantages: --Is administered more frequently (compared with fremanezumab that may be administered once every 3 months) --May be more likely to cause hypersensitivity reactions (compared with erenumab)

Most important risks/adverse events: Hypersensitivity reactions; clinical studies excluded patients with a history of stroke, myocardial infarction, unstable angina, percutaneous coronary intervention, coronary artery bypass grafting, deep vein thrombosis, or pulmonary embolism within 6 months of screening

Most common adverse events: Injection site reactions (18%, compared with 13% with placebo)

Usual dosage: Administered subcutaneously; loading dose of 240 mg (administered as two consecutive injections of 120 mg each), followed by 120 mg once a month

Products: Injection in single-dose prefilled pens and prefilled syringes containing 120 mg of the drug per mL (products should be stored in a refrigerator and, prior to administration, should be allowed to sit at room temperature for 30 minutes protected from direct sunlight)

Comments: Calcitonin gene-related peptide (CGRP) is a neuropeptide that is involved in the transmission of pain impulses, and elevated concentrations have been associated with migraine attacks. Galcanezumab is a human monoclonal antibody that binds to CGRP ligand and blocks its binding to its receptor. It is the third CGRP antagonist approved for the preventive treatment of migraine, joining erenumab and fremanezumab. The effectiveness of galcanezumab was demonstrated in three placebo-controlled clinical studies, two of which were conducted in patients with episodic migraine (i.e., 4 to 14 migraine days per month [MMD]) for a period of 6 months. Patients treated with galcanezumab experienced, on average, two fewer MMD than those on placebo, and 62% and 59% of patients, respectively, experienced at least a 50% reduction from baseline in MMD, compared with 39% and 26% of those receiving placebo. The third study was conducted in patients with chronic migraine (i.e., 15 or more headache days per month with at least 8 MMD) for a period of 3 months. Patients treated with galcanezumab experienced, on average, two fewer MMD, than those receiving placebo. Twenty-eight percent experienced at least a 50% reduction from baseline in MMD, compared with 15% of those receiving placebo.

Cannabidiol (Epidiolex – Greenwich) Antiepileptic Drug

2018 New Drug Comparison Rating (NDCR) =

Indications: Treatment of seizures associated with Dravet syndrome or Lennox-Gastaut syndrome in patients 2 years of age and older

Comparable drugs: None

Advantages: --Is the first drug to be approved for the treatment of patients with Dravet syndrome --Is the first natural product to be derived from marijuana to be approved --Is not likely to be associated with dependence and addiction (is classified in Schedule V)

Limitations: --Causes central nervous system depressant effects in many patients --May interact with numerous other medications

Most important risks/adverse events: Central nervous system depressant effects (e.g., sedation); suicidal behavior and ideation; hypersensitivity reactions; hepatic adverse events (may cause elevations of liver transaminases [ALT, AST]; serum transaminases and total bilirubin concentrations should be determined prior to starting treatment, at 1, 3, and 6 months after initiation of treatment, and periodically thereafter); pregnancy (studies in animals suggest a risk of adverse developmental effects; patients who are pregnant should be encouraged to enroll in the North American Antiepileptic Drug Pregnancy Registry); dosage should be reduced in patients with moderate or severe hepatic impairment; activity may be increased by the concurrent use of moderate or strong CYP3A4 and/or CYP2C19 inhibitors, and decreased by strong CYP3A4 and/or CYP2C19 inducers (adjustment of dosage should be considered); concurrent use with clobazam (Onfi) may increase activity of both drugs; may increase the activity of phenytoin and diazepam; product labeling should be consulted for additional information regarding interactions

Most common adverse events: Somnolence (25%), fatigue/asthenia (12%), lethargy (8%), sedation (6%), decreased appetite (22%), diarrhea (20%), rash (13%), infections (40%), liver transaminase elevations (16%)

Usual dosage: Exposure is increased 4-fold when it is administered with a high fat/high calorie meal; initially, 2.5 mg/kg twice a day; after one week, dosage can be increased to a maintenance dosage of 5 mg/kg twice a day; may be further increased to a maximum maintenance dosage of 10 mg/kg twice a day, in weekly increments of 2.5 mg/kg twice a day; dosage should be decreased in patients with moderate or severe hepatic impairment; when treatment is to be discontinued, dosage should be reduced gradually to reduce risk of increased seizure frequency

Product: Oral solution – 100 mg/mL in bottles containing 100 mL; inactive ingredients include sesame seed oil; any solution remaining 12 weeks after first opening the bottle should be discarded

Comments: Dravet syndrome is a rare genetic epileptic disease that appears during the first year of life and is associated with frequent seizures. Lennox-Gastaut syndrome is a rare epileptic disease in which children usually begin having frequent seizures between ages 3 and 5. Cannabidiol (CBD) is a natural component of the Cannabis sativa plant (marijuana) that exhibits anticonvulsant activity. However, unlike tetrahydrocannabinol (THC), the major psychoactive component of marijuana, CBD does not cause euphoria or intoxication. CBD is the first drug to be approved for the treatment of patients with Dravet syndrome, and joins 6 other antiepileptic drugs (clobazam, valproate, lamotrigine, rufinamide, topiramate, felbamate) that have been approved for the treatment of Lennox- Gastaut syndrome. The mechanism through which CBD exerts its anticonvulsant action is not known, but it does not appear to be related to interaction with cannabinoid receptors. Its effectiveness was demonstrated in 14-week placebo-controlled trials in which either CBD or placebo was added to existing treatment (most often clobazam). In patients with Dravet syndrome, the median percent reduction in the frequency of convulsive seizures (39%) was significantly greater than in those receiving placebo (13%). In patients with Lennox-Gastaut syndrome, the median percent reduction in the frequency of drop seizures (43%) was significantly greater than in those receiving placebo (20%). CBD was reclassified by the Drug Enforcement Administration from Schedule I to Schedule V. Lofexidine hydrochloride (Lucemyra – US WorldMeds; Salix) Agent for Opioid Withdrawal

2018 New Drug Comparison Rating (NDCR) =

Indication: Mitigation of opioid withdrawal symptoms to facilitate abrupt opioid discontinuation in adults

Comparable drugs: Buprenorphine, methadone (although the properties of lofexidine are most similar to those of clonidine, the latter agent does not have a labeled indication for the management of opioid withdrawal symptoms)

Advantages: --Is the first non-opioid treatment for the management of opioid withdrawal symptoms --Increases the likelihood of successful opioid discontinuation --May reduce the need for continued use of opioid agonist substitutes (i.e., buprenorphine, methadone) in treatment plans

Disadvantages: --Greater risk of cardiovascular adverse events (e.g., hypotension) --Is administered frequently (4 times a day)

Most important risks/adverse events: Hypotension/orthostatic hypotension, bradycardia, syncope (should be avoided in patients with severe coronary insufficiency, recent myocardial infarction, cerebrovascular disease, chronic renal failure, those with marked bradycardia, and those taking other medications that decrease pulse or blood pressure); prolongation of QT interval (should be avoided in patients with congenital long QT syndrome, and should be closely monitored in patients with other risk factors including concurrent use of other medications that may cause QT prolongation [e.g., methadone, moxifloxacin]; hypokalemia or hypomagnesemia should be corrected prior to initiating treatment); may increase the CNS depressive effect of benzodiazepines, barbiturates, alcohol, and other sedating agents (patients should be cautioned about activities such as driving or operating machinery); action may be increased by the concurrent use of a CYP2D6 inhibitor (e.g., paroxetine); efficacy of orally-administered naltrexone may be reduced if it is administered within 2 hours of lofexidine

Most common adverse events: Hypotension (30%), orthostatic hypotension (29%), bradycardia (24%), dizziness (19%), sedation (13%), somnolence (11%), dry mouth (10%)

Usual dosage: Recommended starting dosage – 0.54 mg (3 tablets) 4 times daily during the period of peak withdrawal symptoms (e.g., the first 5 to 7 days following the last dose of the opioid); a period of 5 to 6 hours should separate doses; no single dose should exceed 0.72 mg (4 tablets) and the total daily dosage should not exceed 2.88 mg (16 tablets); dosage adjustments should be guided by the symptoms, and treatment may be continued for up to 14 days; when treatment is to be discontinued, the dosage should be reduced gradually over a 2- to 4-day period to mitigate withdrawal symptoms of the drug (e.g., reducing by 1 tablet per dose every 1 to 2 days); product labeling should be consulted for dosage recommendations for patients with impaired hepatic or renal function

Product: Film-coated tablets – 0.18 mg lofexidine

Comments: Opioids (e.g., morphine) reduce norepinephrine concentrations and, with continued use, the brain establishes a new equilibrium by increasing norepinephrine production in order to maintain normal functioning. When the use of an opioid is discontinued or its dosage is significantly reduced, the brain’s increased norepinephrine concentrations are no longer offset by the presence of the opioid. This results in a norepinephrine surge that produces the acute symptoms of withdrawal (e.g., pain, muscle spasms, stomach cramps, nausea, agitation, drug craving). For patients with opioid use disorder, addiction and withdrawal are often managed with the partial opioid agonist buprenorphine (e.g., Suboxone) or the opioid agonist methadone. The central alpha-2 adrenergic agonist clonidine has also been used in the management of withdrawal symptoms but this is not a labeled indication. The actions of lofexidine are most similar to those of clonidine. It binds to receptors on adrenergic neurons and reduces the release of norepinephrine. It is used as part of a broad, long-range treatment plan. Its effectiveness was evaluated in two placebo-controlled studies and patients treated with lofexidine experienced less severe withdrawal symptoms, and a higher proportion of patients completed the period of treatment. Revefenacin (Yupelri – Theravance; Mylan) Bronchodilator

2018 New Drug Comparison Rating (NDCR) =

Indication: For oral inhalation via nebulization for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD)

Comparable drug: Glycopyrrolate (Lonhala Magnair inhalation solution for nebulization)

Advantages: --Is administered once a day (whereas glycopyrrolate is administered twice a day) --May be used with any standard jet nebulizer (whereas glycopyrrolate should only be used with the Magnair system)

Disadvantages: --Has not been directly compared with glycopyrrolate or other long-acting muscarinic antagonists (LAMAs) in clinical studies --Administration of a dose requires a longer period of time (approximately 8 minutes; compared with 2 to 3 minutes with glycopyrrolate via nebulization) --Use should be avoided in patients with hepatic impairment --Concurrent use with certain organic anion-transporting polypeptide (OATP) inhibitors (e.g., cyclosporine, rifampin) is not recommended

Most important risks/adverse events: Must not be used for the treatment of acute symptoms or in patients with acutely deteriorating COPD; hypersensitivity reactions; paradoxical bronchospasm (treatment should be discontinued); worsening of urinary retention; worsening of narrow-angle glaucoma; action may be increased by other agents with anticholinergic activity (e.g., tiotropium, tolterodine, diphenhydramine), and concurrent use should be avoided; should not be used in patients with hepatic impairment because exposure of active metabolite may be increased; active metabolite is a substrate of OATP1B1 and OATP1B3 and action may be increased by inhibitors of these transporters (e.g., cyclosporine, rifampin; concurrent use should be avoided)

Most common adverse events: Cough (4%), nasopharyngitis (4%), headache (4%), upper respiratory tract infection (3%), back pain (2%)

Usual dosage: 175 mcg once a day using a mouthpiece and a standard jet nebulizer connected to an air compressor

Product: Inhalation solution for oral inhalation: polyethylene unit-dose vials – 175 mcg in 3 mL of sterile, aqueous solution; vials are wrapped in a foil pouch and should only be removed from the pouch and opened immediately before use

Comments: Revefenacin is the fifth long-acting muscarinic antagonist (LAMA) to be approved for use via oral inhalation as bronchodilators in the treatment of patients with COPD, joining tiotropium (Spiriva Respimat), aclidinium (Tudorza Pressair), umeclidinium (Incruze Ellipta), and glycopyrrolate (Seebri Neohaler). The LAMAs are most often administered via oral inhalation using metered-dose delivery devices. However, the effective use of these devices requires manual dexterity and coordination of actuation of the device and inhalation that deviates from regular breathing, which present a challenge for some patients. Approximately 10% of the patients treated for COPD in the United States administer bronchodilators by oral inhalation using a nebulizer. Glycopyrrolate was the first nebulized LAMA to be approved for the treatment of COPD, and it is administered over a period of 2 to 3 minutes twice a day. Revefenacin is the second LAMA to be approved for oral inhalation using nebulization, and the first to be administered once a day. The effectiveness of revefenacin was evaluated in two 12-week, placebo- controlled studies in patients with moderate to very severe COPD. The primary endpoint was the change from baseline in trough (predose) forced expiratory volume in one second (FEV1). In both studies, revefenacin demonstrated significant improvement in lung function compared to placebo. Following oral inhalation, revefenacin is rapidly hydrolyzed to a major active metabolite that can potentially contribute to systemic anticholinergic effects at therapeutic doses. Benralizumab (Fasenra – AstraZeneca) Antiasthmatic Agent

2018 New Drug Comparison Rating (NDCR) =

Indication: Administered subcutaneously for the add-on maintenance treatment of patients with severe asthma aged 12 years and older, and with an eosinophilic phenotype; Is not indicated for the treatment of other eosinophilic conditions, or for the relief of acute bronchospasm

Comparable drugs: Mepolizumab (Nucala), reslizumab (Cinqair); (dupilumab [Dupixent], an interleukin-4 inhibitor which is available for the treatment of atopic dermatitis, has been subsequently approved for the treatment of moderate to severe asthma with an eosinophilic phenotype or with oral corticosteroid-dependent asthma)

Advantages: --Is administered less frequently (every 8 weeks for maintenance treatment, compared with every 4 weeks with comparable drugs) --Formulation is more convenient to administer (is supplied in prefilled syringes whereas mepolizumab requires reconstitution and reslizumab is administered by intravenous infusion) --Is indicated for patients as young as 12 years of age (compared with reslizumab that is indicated for patients 18 years and older) --May be less likely to cause serious hypersensitivity reactions (compared with reslizumab that has a boxed warning regarding this risk in its labeling)

Disadvantages: --Labeled indications are more limited (compared with mepolizumab that is also indicated for the treatment of adult patients with eosinophilic granulomatosis with polyangiitis)

Most important risks/adverse events: Hypersensitivity reactions; reduction in dosage or discontinuation of systemic or inhaled corticosteroids (to avoid systemic withdrawal symptoms and/or unmasking of conditions previously suppressed by systemic corticosteroid therapy; dosage should be reduced gradually); parasitic (helminth) infections (should be treated prior to starting benralizumab; if a helminth infection develops during treatment and does not respond to antihelminth treatment, benralizumab should be discontinued until the infection resolves)

Most common adverse events: Headache (8%), pharyngitis (5%)

Usual dosage: Administered subcutaneously – 30 mg once every 4 weeks for the first 3 doses, and then once every 8 weeks (labeling notes it should be administered by a healthcare professional)

Product: Single-dose prefilled syringes – 30 mg/1 ml (should be stored in a refrigerator)

Comments: Multiple cell types, including eosinophils, and mediators (e.g., cytokines) are involved in the inflammatory process that occurs in the airways of the lungs in patients with asthma. Interleukin-5 (IL-5) is the major cytokine that is responsible for the growth and differentiation, recruitment, activation, and survival of eosinophils. Benralizumab is the third agent that reduces the activity of IL-5 to be approved. Whereas mepolizumab and reslizumab act on IL-5 itself, benralizumab directly binds to the alpha subunit of IL-5 receptors, thereby preventing the binding of IL-5 to its receptors, leading to apoptosis of eosinophils through antibody- dependent cell-mediated cytotoxicity. The effectiveness of benralizumab was evaluated in two placebo-controlled studies in patients with severe asthma and high blood eosinophil counts who had a history of two or more asthma exacerbations in the past 12 months. The two studies were 48 and 56 weeks in duration, and the primary endpoint was the rate of asthma exacerbations. In these studies, 35% and 40% of the patients treated with benralizumab experienced an exacerbation compared with 51% of the patients in each study who received placebo. The effect of benralizumab on reducing the use of maintenance oral corticosteroids was evaluated in a third study for a period of 28 weeks. The median percent reduction in the daily oral corticosteroid dose from baseline was 75% in patients treated with benralizumab compared to 25% in patients receiving placebo. In all three studies, patients treated with the new drug experienced consistent improvements from baseline in the mean forced expiratory volume in 1 second (FEV1). Baricitinib (Olumiant – Lilly) Antiarthritic Agent

2018 New Drug Comparison Rating (NDCR) =

Indication: Treatment of adult patients with moderately or severely active rheumatoid arthritis who have had an inadequate response to one or more tumor necrosis factor (TNF) antagonist therapies

Comparable drugs: Tofacitinib (Xeljanz, Xeljanz XR)

Advantages: --Is less likely to interact with other medications

Disadvantages: --Is associated with a risk of thrombosis (identified as a boxed warning in labeling) --Labeled indication for rheumatoid arthritis is more limited (tofacitinib is indicated in patients who have had an inadequate response or intolerance to methotrexate) --Labeled indications are more limited (tofacitinib is also indicated for patients with psoriatic arthritis or ulcerative colitis) --Use is not recommended in patients with moderate or severe renal impairment (whereas tofacitinib is used in a reduced dosage)

Most important risks/adverse events: Serious infections (boxed warning; treatment should not be initiated in patients with an active serious infection, including localized infections; patients should be evaluated for active or latent tuberculosis infection; should not be used concurrently with another Janus kinase inhibitor, a biologic disease- modifying antirheumatic drug [DMARDs; e.g., TNF inhibitors], or a potent immunosuppressant [e.g., azathioprine, cyclosporine]; live vaccines should not be used concurrently); lymphoma and other malignancies (boxed warning; risk should be evaluated in patients with a known malignancy other than a successfully treated non-melanoma skin cancer); thrombosis, including deep venous thrombosis, pulmonary embolism, arterial thrombosis (boxed warning); gastrointestinal perforation (caution should be exercised in patients at increased risk such as those with a history of diverticulitis); hematologic laboratory abnormalities (neutropenia, lymphopenia, anemia; treatment should not be initiated, or should be interrupted, in patients with an absolute neutrophil count less than 1000 cells/mm3, an absolute lymphocyte count less than 500 cells/mm3, or hemoglobin less than 8g/dL); elevated liver enzymes; elevated lipid concentrations (should be evaluated 12 weeks following initiation of treatment); women with infants should be advised not to breastfeed; action may be increased by strong organic anion transporter 3 (OAT3) inhibitors (e.g., probenecid) and concurrent use is not recommended; use in patients with moderate or severe renal impairment or severe hepatic impairment is not recommended

Most common adverse events: Upper respiratory tract infections (16%), nausea (3%), herpes simplex (1%), herpes zoster (1%), multiple laboratory abnormalities

Usual dosage: 2 mg once a day, with or without food

Product: Film-coated tablets – 2 mg

Comments: Janus kinase (JAK) enzymes are intracellular enzymes which transmit signals arising from cytokine or growth factor-receptor interactions on the cellular membrane to influence cellular processes of hematopoiesis and immune cell function. Inhibition of these enzymes blocks the activation of mediators of inflammation. Baricitinib is the second JAK inhibitor to be approved for the treatment of patients with rheumatoid arthritis, joining tofacitinib. It may be used as monotherapy or with methotrexate or another nonbiologic DMARD. The effectiveness of baricitinib was evaluated in placebo-controlled studies in which the primary endpoint was the proportion of patients who achieved an ACR20 response (i.e., a 20% improvement in criteria established by the American College of Rheumatology) at 12 weeks. One of the studies was conducted in patients who had an inadequate response or intolerance to nonbiologic DMARDs (e.g., methotrexate), and another study was conducted in patients who had been treated with one or more TNF inhibitors. Patients treated with baricitinib achieved ACR20 responses of 66% and 49%, respectively, at Week 12, compared with 39% and 27% in those receiving placebo. Tildrakizumab-asmn (Ilumya – Sun) Agent for Psoriasis

2018 New Drug Comparison Rating (NDCR) =

Indication: Administered subcutaneously for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy

Comparable drugs: Guselkumab (Tremfya), Ustekinumab (Stelara)

Advantages: --Is administered less frequently (every 12 weeks for maintenance treatment compared with guselkumab that is administered every 8 weeks) --One dosage regimen is appropriate for all adult patients (compared with ustekinumab that is used in two dosage regimens based on patient weight)

Disadvantages: --May be less effective (compared with guselkumab based on results of noncomparative studies of the individual agents) --Labeled indications are more limited (compared with ustekinumab that is also indicated for patients with active psoriatic arthritis and patients with moderately to severely active Crohn’s disease) --Labeled indications do not include pediatric patients (compared with ustekinumab that is indicated for the treatment of patients 12 years of age and older with plaque psoriasis) --Is administered by a healthcare provider (compared with guselkumab that may also be self-administered by patients)

Most important risks/adverse events: Infections (treatment should not be initiated in patients with any clinically important active infection until the infection resolves or is adequately treated; if a serious infection occurs during treatment or an infection is not responding to standard therapy, discontinuation of tildrakizumab should be considered); tuberculosis (patients should be evaluated for tuberculosis prior to initiating treatment); live vaccines should not be administered during treatment

Most common adverse events: Upper respiratory tract infections (14%), injection site reactions (3%), diarrhea (2%)

Usual dosage: Administered subcutaneously – 100 mg at Weeks 0 and 4, and every 12 weeks thereafter

Product: Single-dose prefilled syringes – 100 mg (should be stored in a refrigerator); may be stored in original carton at room temperature for up to 30 days but, once stored at room temperature, should not be placed back in the refrigerator

Comments: Certain interleukins (ILs) have been identified as having a role in the occurrence and worsening of psoriasis, and six monoclonal antibodies that inhibit specific ILs have been developed for the treatment of patients with psoriasis. Ustekinumab inhibits IL-12 and IL-23 and was the first IL inhibitor to be marketed (2009). Guselkumab also inhibits IL-23, and has also been reported to reduce serum concentrations of several other interleukins, including IL-17A. Tildrakizumab is the third IL-23 inhibitor and acts by binding to the p19 subunit of IL-23. The three other IL inhibitors indicated for the treatment of patients with psoriasis inhibit IL-17A and include secukinumab (Cosentyx), ixekizumab (Taltz), and brodalumab (Siliq). The effectiveness of tildrakizumab was evaluated in two placebo-controlled studies. The primary endpoints were a reduction in the Psoriasis Area and Severity Index (PASI) score of at least 75% (PASI 75) from baseline to Week 12 and an improvement in the Physician Global Assessment (PGA) to clear or minimal. Of the patients treated with tildrakizumab, 64% and 61% attained a PASI 75 response, compared with 6% in each study of those receiving placebo, and 14% and 12% of those treated with the new drug attained a PASI 100 response, compared with 1% and 0% of those receiving placebo. Of the patients treated with tildrakizumab, 58% and 55% received a PGA of clear or minimal, compared with 7% and 4% of those receiving placebo. In one of the studies some patients were treated with etanercept (Enbrel), and 48% of these patients attained a PASI 75 response and a PGA of clear or minimal. Tezacaftor/ivacaftor (Symdeko – Vertex) Agents for Cystic Fibrosis

2018 New Drug Comparison Rating (NDCR) =

Indication: Treatment of patients with cystic fibrosis aged 12 years and older who are homozygous for the F508del mutation or who have at least one mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that is responsive to tezacaftor/ivacaftor based on in vitro data and/or clinical evidence

Comparable drugs: Lumacaftor/ivacaftor (Orkambi)

Advantages: --Labeled indication includes a larger patient population (indication for lumacaftor/ivacaftor is limited to patients who are homozygous for F508del mutation in the CFTR gene) --May be less likely to cause adverse events (labeling for lumacaftor/ivacaftor also includes precautions regarding respiratory events and hypertension) --Interacts with fewer medications

Disadvantages: --Has not been studied in patients less than 12 years (whereas lumacaftor/ivacaftor is indicated for children as young as 6 years)

Most important risks/adverse events: Elevated transaminases (ALT and AST should be assessed prior to initiating treatment, every 3 months during the first year, and annually thereafter); non-congenital lens opacities/cataracts (baseline and follow-up ophthalmological examinations are recommended in pediatric patients); action is reduced by CYP3A inducers (e.g., carbamazepine, rifampin), and concurrent use should be avoided; action is increased by CYP3A inhibitors (e.g., fluconazole, clarithromycin) and dosage of tezacaftor/ivacaftor should be reduced when used concurrently (consumption of grapefruit products and Seville oranges should be avoided); dosage should be reduced in patients with moderate or severe hepatic impairment

Most common adverse events: Headache (15%), nausea (9%), sinus congestion (4%), dizziness (4%)

Usual dosage: Should be administered with fat-containing food (e.g., eggs, cheeses, nuts, whole milk, meats); 100 mg tezacaftor/150 mg ivacaftor in the morning and 150 mg ivacaftor in the evening, approximately 12 hours apart; product labeling should be consulted for the recommendations for dosage adjustment in patients with hepatic impairment or who are also being treated with a CYP3A inhibitor

Products: Combination tablets containing 100 mg of tezacaftor and 150 mg of ivacaftor that are co-packaged with tablets containing 150 mg of ivacaftor

Comments: Cystic fibrosis (CF) is caused by a mutation in a gene that encodes for the protein cystic fibrosis transmembrane conductance regulator (CFTR) that regulates chloride and water transport in the body. Children must inherit two defective CFTR genes, one from each parent, to have CF. The F508del mutation is the most common cause of CF and people who have two copies of the F508del mutation account for approximately one-half of the CF population in the US. Defective functioning of the CFTR protein results in the formation of thick mucus in the affected areas, and manifestations include chronic cough and persistent lung and sinus infections, pancreatic insufficiency and other severe digestive problems, and other complications. Tezacaftor facilitates the cellular processing and trafficking of normal and mutant forms of CFTR to increase the amount of mature CFTR delivered to the cell surface. Ivacaftor is a CFTR potentiator that facilitates increased chloride transport by potentiating the gating of the CFTR protein at the cell surface. The use of tezacaftor and ivacaftor in combination results in a further enhancement of chloride transport than that provided with either agent given alone. The effectiveness of the tezacaftor/ivacaftor regimen was demonstrated in two placebo- controlled trials in which patients treated with the combination therapy experienced statistically significant and clinically meaningful improvements in lung function and other measures of disease that were sustained for up to 48 weeks of treatment.

Sodium zirconium cyclosilicate (Lokelma – AstraZeneca) Agent for Hyperkalemia

2018 New Drug Comparison Rating (NDCR) =

Indication: Treatment of hyperkalemia in adults; should not be used as an emergency treatment for life-threatening hyperkalemia because of its delayed onset of action

Comparable drug: Patiromer sorbitex calcium (Veltassa)

Advantages: --Is not likely to cause hypomagnesemia --Product does not require refrigeration

Disadvantages: --Is more likely to cause edema

Most important risks/adverse events: Gastrointestinal adverse events in patients with motility disorders (should be avoided in patients with severe constipation or bowel obstruction or impaction, including abnormal post-operative bowel motility disorders); edema (patients should be monitored for signs of edema, particularly those who should restrict their sodium intake or are vulnerable to fluid overload [e.g., heart failure, kidney disease]; as appropriate, dietary sodium should be adjusted and the dosage of diuretics increased); interactions with other oral medications (in general, other oral medications should be administered at least 2 hours before or 2 hours after the new drug; may transiently increase gastric pH and change the absorption of co-administered drugs that exhibit pH-dependent solubility [systemic exposure of weak acids such as furosemide and atorvastatin is increased and that of weak bases such as dabigatran {Pradaxa} is decreased])

Most common adverse events: Edema (6% -11%), hypokalemia (4%)

Usual dosage: Initial treatment – 10 grams three times a day for up to 48 hours; maintenance treatment – 10 grams once a day; during maintenance treatment the dosage may be increased based on serum potassium concentrations at intervals of 1 week or longer and in increments of 5 grams; dosage may be decreased or discontinued if the serum potassium is below the desired target range; recommended maintenance dosage range is 5 grams every other day to 15 grams daily

Product: Powder for oral suspension – packets containing 5 grams and 10 grams; contents of a packet should be emptied into a drinking glass containing 3 tablespoonfuls or more of water; mixture should be stirred well and patient should drink immediately; procedure should be repeated as needed so that the patient drinks the entire dose

Comments: Hyperkalemia is characterized by elevated serum potassium concentrations (generally above 5 mEq/L). It is most often experienced by patients with kidney disease or heart failure, particularly in those who are taking medications that inhibit the renin-angiotensin-aldosterone system (RAAS) such as angiotensin-converting enzyme inhibitors (ACEIs; e.g., lisinopril), angiotensin receptor blockers (ARBs; e.g., losartan), the direct rennin inhibitor aliskiren (Tekturna), and aldosterone antagonists (e.g., spironolactone, eplerenone). The cation-exchange resin sodium polystyrene sulfonate (e.g., Kayexalate) has been available for more than 50 years and has been used orally or as an enema in the treatment of hyperkalemia. Patiromer sorbitex calcium was marketed in 2016 and consists of the active moiety, patiromer, a non-absorbed potassium-binding polymer, and a calcium-sorbitol counterion. When administered orally, the counterion is exchanged for potassium that binds with patiromer, resulting in increased fecal potassium excretion and reduced serum potassium concentrations. Sodium zirconium cyclosilicate is a non-absorbed zirconium silicate that preferentially captures potassium in exchange for hydrogen and sodium. It has a high affinity for potassium even in the presence of other cations. It was evaluated in placebo-controlled studies in multiple phases. In the acute phase (the first 48 hours), patients treated with a dosage of 10 grams three times daily had a mean serum potassium reduction of -0.7mEq/L, compared with -0.2 mEq/L in those receiving placebo. Patients with higher starting concentrations of potassium (>5.5 mEq/L) had a greater response. Continued efficacy was demonstrated in longer studies (e.g., 29 days, 12 months). Angiotensin II acetate (Giapreza – La Jolla) Vasopressor

2018 New Drug Comparison Rating (NDCR) =

Indication: Administered intravenously to increase blood pressure in adults with septic or other distributive shock

Comparable drugs: Other vasopressors (e.g., norepinephrine, phenylephrine, vasopressin)

Advantages: --May further increase blood pressure and reduce mortality in patients in shock --Increases blood pressure by a different mechanism of action

Disadvantages: --May be more likely to cause thrombotic and thromboembolic events

Most important risks/adverse events: Risk for thrombosis (patients should receive concurrent venous thromboembolism prophylaxis); response may be increased by the concurrent use of an angiotensin-converting enzyme inhibitor, and decreased by the concurrent use of an angiotensin receptor blocker

Most common adverse events: Thromboembolic events (13%), thrombocytopenia (10%), tachycardia (9%), fungal infection (6%), delirium (6%), acidosis (6%)

Usual dosage: Administered by continuous intravenous infusion, preferably through a central venous line; starting dosage – 20 nanograms (ng)/kg/min; blood pressure response should be monitored and the dosage of the drug titrated every 5 minutes by increments of up to 15 ng/kg/min as needed to achieve or maintain target blood pressure; a dosage of 80 ng/kg/min should not be exceeded in the first 3 hours of treatment; maintenance doses should not exceed 40 ng/kg/min; once the underlying shock has sufficiently improved, the dosage should be down-titrated every 5 to 15 minutes by increments of up to 15 ng/kg/min based on blood pressure

Product: Vials – 2.5 mg, 5 mg (should be stored in a refrigerator); contents of a vial must be diluted in 0.9% Sodium Chloride Injection to achieve a final concentration of 5,000 ng/mL or 10,000 ng/mL

Comments: The treatment of patients in shock usually includes the administration of intravenous fluids and vasopressors (e.g., norepinephrine, vasopressin, phenylephrine, epinephrine, dopamine). However, in some patients, these measures are insufficient to prevent irreversible organ damage and/or death. Angiotensin II is a naturally occurring peptide hormone of the renin-angiotensin-aldosterone system (RAAS) that causes vasoconstriction and an increase in blood pressure. The plasma half-life of angiotensin II is less than one minute which necessitates administration via continuous intravenous infusion. The effectiveness of angiotensin II was evaluated in a study of 321 adults with shock who remained hypotensive despite fluid and vasopressor therapy. More than 90% of the patients had septic shock, and 83% had received two or more vasopressors and 47% three or more vasopressors prior to the administration of angiotensin II. Doses of angiotensin II or placebo were titrated to a target mean arterial pressure (MAP) of at least 75 mmHg during the first 3 hours of treatment while doses of other vasopressors were maintained. From Hour 3 to Hour 48, angiotensin II or placebo was titrated to maintain MAP between 65 and 70 mmHg while reducing doses of other vasopressors. The primary endpoint was the percentage of patients who achieved either a MAP of at least 75 mmHg or at least a 10 mmHg increase in MAP without an increase in baseline vasopressor therapy at 3 hours. The primary endpoint was achieved by 70% of patients treated with angiotensin II, compared with 23% of those receiving placebo. Mortality through Day 28 was 46% of the patients on angiotensin II and 54% of those on placebo.

Ertugliflozin L-pyroglutamic acid (Steglatro – Merck) Antidiabetic Agent

2018 New Drug Comparison Rating (NDCR) = 3 (no or minor advantages/disadvantages)

Indication: Adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus

Comparable drugs: Canagliflozin (Invokana), dapagliflozin (Farxiga), empagliflozin (Jardiance)

Advantages: --Warning in labeling regarding risk of lower limb amputation is not as definitive (compared with canagliflozin that has a boxed warning in its labeling regarding this risk) --Has not been associated with reports of patients experiencing bladder cancer (compared with dapagliflozin)

Disadvantages: --Labeled indications are more limited (compared with empagliflozin that is also indicated to reduce the risk of cardiovascular death in adult patients with type 2 diabetes mellitus and established cardiovascular disease); (the labeled indications for canagliflozin have been subsequently revised to include use to reduce the risk of major adverse cardiovascular events in these patients)

Most important risks/adverse events: Renal function impairment (contraindicated in patients with severe renal impairment); hypersensitivity reactions (contraindicated in patients with a history of a serious reaction); hypotension (risk is increased in patients with impaired renal function or low systolic blood pressure, the elderly, and in patients treated with a diuretic); lower limb amputation (patients should be monitored for infections or ulcers of lower limbs); ketoacidosis; urinary tract infections; hypoglycemia (when used concomitantly with insulin or an insulin secretagogue [e.g., a sulfonylurea]); pregnancy (use is not recommended during the second and third trimesters); nursing mothers (use is not recommended); positive urine glucose test results; (the labeling for the SGLT2 inhibitors has been subsequently revised to include a warning about necrotizing fasciitis of the perineum [Fournier’s gangrene])

Most common adverse events: Female genital mycotic infection (12%), male genital mycotic infection (4%), urinary tract infection (4%), headache (3%), back pain (3%), increased LDL-C concentrations (5%)

Usual dosage: Initially - 5 mg once a day in the morning; in patients who tolerate treatment and require additional glycemic control, dosage may be increased to 15 mg once a day; treatment should not be initiated in patients with an estimated glomerular filtration rate (eGFR) of 30 to <60 mL/minute/1.73m2); in patients in whom the eGFR falls to and persists within this range during treatment, continued use of the drug is not recommended

Products: Film-coated tablets – 5 mg, 15 mg; combination formulations with metformin (Segluromet: 2.5 mg/500 mg, 2.5 mg/1,000 mg, 7.5 mg/500 mg, 7.5 mg/1,000 mg); combination formulations with sitagliptin (Steglujan; 5 mg/100 mg, 15 mg/100 mg)

Comments: Sodium-glucose cotransporter 2 (SGLT2) is expressed in the proximal renal tubules and is responsible for the reabsorption of the majority of glucose filtered by the kidneys. Ertugliflozin is the fourth SGLT2 inhibitor, joining canagliflozin, dapagliflozin, and empagliflozin, and these agents reduce the reabsorption of filtered glucose, thereby increasing urinary glucose excretion and lowering blood glucose and glycosylated hemoglobin (A1C) concentrations. Its effectiveness has been demonstrated in studies in which it was used as monotherapy, or in combination with regimens with metformin and/or other antidiabetic agents. In the placebo-controlled study of ertugliflozin monotherapy (in doses of 5 mg and 15 mg once a day), the reduction in A1C at week 26 was -0.7% and -0.8%, respectively, compared with -0.2% in the patients receiving placebo. The percentage of patients achieving an A1C of less than 7% was 30% and 39%, respectively, for the two doses of ertugliflozin, compared with 17% of those receiving placebo. Similar reductions in A1C attributed to ertugliflozin were also reported in studies in which it was used in combination with metformin and/or sitagliptin (Januvia). In patients with type 2 diabetes and moderate renal impairment (eGFR 30 to <60 mL/minute/1.73m2), reductions of A1C were not significantly different between the drug and placebo, and efficacy of the drug was not demonstrated in these patients. None of the SGLT2 inhibitors should be used in the treatment of patients with type 1 diabetes or diabetic ketoacidosis. Semaglutide (Ozempic – Novo Nordisk) Antidiabetic Agent

2018 New Drug Comparison Rating (NDCR) =

Indication: Administered subcutaneously as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus

Comparable drugs: Exenatide (Byetta), exenatide extended-release (Bydureon), liraglutide (Victoza), lixisenatide (Adlyxin), dulaglutide (Trulicity); (albiglutide [Tanzeum] has also been available but marketing has been discontinued)

Advantages: --Is administered less frequently (once a week compared with liraglutide and lixisenatide that are administered once a day and the Byetta formulation of exenatide that is administered twice a day) --Is more effective in reducing hemoglobin A1C concentrations (compared with exenatide extended-release) --May be associated with a greater loss of weight

Disadvantages: --Labeled indications are more limited (compared with liraglutide for which indications also include use to reduce the risk of major adverse cardiovascular events in patients with diabetes and established cardiovascular disease) --Dosage titration requires an additional step (compared with dulaglutide)

Most important risks/adverse events: Thyroid C-cell tumors (reported in studies in rodents but risk in humans is not known; boxed warning; contraindicated in patients with a personal or family history of medullary thyroid carcinoma or in patients with multiple endocrine neoplasia syndrome type 2); pancreatitis (other antidiabetic agents should be considered in patients with a history of pancreatitis; treatment should be discontinued if pancreatitis is suspected); hypersensitivity reactions; acute kidney injury and worsening of chronic renal failure (risk is increased in patients who have experienced gastrointestinal adverse events [e.g., diarrhea, dehydration]); diabetic retinopathy complications (patients with a history of diabetic retinopathy should be monitored); hypoglycemia (when used concurrently with insulin or an insulin secretagogue [e.g., sulfonylureas]); women should discontinue treatment at least 2 months before a planned pregnancy; delays gastric emptying and may alter the absorption of oral medications

Most common adverse events: Nausea (20%), vomiting (9%), diarrhea (9%), abdominal pain (6%)

Usual dosage: Administered subcutaneously in the abdomen, thigh, or upper arm; initially, 0.25 mg once a week for 4 weeks (this dosage is subtherapeutic and is used only for treatment initiation); after 4 weeks, the dosage is increased to 0.5 mg once a week; if additional glycemic control is needed after at least 4 weeks on the 0.5 mg dose, dosage may be increased to 1 mg once a week

Products: Injection supplied in prefilled single-patient-use pens containing 2 mg/1.5 mL; pens deliver 0.25 mg, 0.5 mg, or 1 mg of the drug per injection (should be stored in a refrigerator prior to first use)

Comments: Semaglutide is the sixth glucagon-like peptide-1 (GLP-1) receptor agonist to be approved in the United States. These agents have multiple actions that include suppression of glucagon secretion, stimulation of glucose- dependent insulin secretion, slowing gastric emptying, and promoting satiety. The effectiveness of semaglutide was demonstrated in studies in which it was used as monotherapy and in combination with metformin, metformin and sulfonylureas, metformin and/or a thiazolidinedione, and basal insulin. It reduced hemoglobin A1C and fasting plasma glucose concentrations, and the mean changes in weight from baseline were a weight loss of 4 to 5 kg. Semaglutide (in a dosage of 1 mg once a week) provided a greater reduction in A1C concentrations than sitagliptin (-1.5% vs. -0.7% at week 56), exenatide extended-release (-1.4% vs. -0.9% at week 56), and insulin glargine (-1.5% vs. -0.9% at week 30). Semaglutide has also been evaluated in a cardiovascular outcomes trial in patients with diabetes and a high risk of cardiovascular events. The primary composite endpoint was the time to first occurrence of a major adverse cardiovascular event. The number of these experiences was lower in patients treated with semaglutide compared with placebo (6.6% vs. 8.9%), suggesting an advantage for the medication. However, the design of the trial limits the conclusion to semaglutide being noninferior to placebo. Elagolix sodium (Orilissa – AbbVie) Agent for Endometriosis

2018 New Drug Comparison Rating (NDCR) =

Indication: Management of moderate to severe pain associated with endometriosis

Comparable drugs: Gonadotropin-releasing hormone (GnRH) receptor agonists (leuprolide [e.g., Lupron], nafarelin [Synarel])

Advantages: --Is administered orally (whereas leuprolide is administered intramuscularly and nafarelin is administered intranasally) --Does not cause initial flare of symptoms --Labeled dosage recommendations permit use (150 mg once a day) for up to 24 months (whereas, when used for treating endometriosis, leuprolide should not be used for longer than 12 months and nafarelin should not be used for more than 6 months)

Disadvantages: --Interacts with more medications --Has not been directly compared with other therapies in clinical studies --Labeled indications are more limited (leuprolide and nafarelin are indicated for use in children with central precocious puberty, and leuprolide is also indicated for the treatment of uterine fibroids and prostate cancer) --Is administered once a day (compared with leuprolide depot 11.25 mg that is administered every 3 months)

Most important risks/adverse events: Bone loss (causes dose- and duration-dependent decreases in bone mineral density [BMD]; contraindicated in women with osteoporosis; BMD should be assessed in women with additional risk factors for bone loss); contraindicated in pregnant women (risk of pregnancy loss may be increased; change in menstrual bleeding may reduce the ability to recognize the occurrence of pregnancy in a timely manner; women who are sexually active should use non-hormonal contraception during treatment and for one week following discontinuation of treatment; estrogen-containing contraceptives should not be used); suicidal ideation and mood disorders (patients with depressive symptoms should be promptly evaluated and appropriate actions taken); action may be increased in patients with hepatic impairment and is contraindicated in patients with severe hepatic impairment); may cause elevations of hepatic enzymes and blood lipids; action may be increased by organic anion transporting polypeptide (OATP) 1B1 inhibitors (concurrent use of strong OATP1B1 inhibitors such as cyclosporine and gemfibrozil is contraindicated), as well as by strong CYP3A inhibitors; action may be reduced by CYP3A inducers; may reduce the action of CYP3A substrates such as oral midazolam, and increase the action of digoxin and rosuvastatin

Most common adverse events (and incidence with a dosage of 150 mg once a day): hot flush/night sweats (24%), headache (17%), nausea (11%), insomnia (6%), mood alteration/swings (6%), amenorrhea (4%), depression (3%)

Usual dosage: 150 mg once a day for up to 24 months; in patients with dyspareunia, treatment with a dosage of 200 mg twice a day for up to 6 months should be considered; product labeling should be consulted for recommended dosage adjustments in patients with moderate hepatic impairment or who are taking interacting drugs

Products: Tablets – 150 mg, 200 mg

Comments: Elagolix is a gonadotropin-releasing hormone (GnRH) receptor antagonist that binds to GnRH receptors in the pituitary gland. It causes a dose-dependent suppression of luteinizing hormone and follicle- stimulating hormone, leading to decreased blood concentrations of the ovarian sex hormones, estradiol and progestin. The GnRH agonists also reduce estrogen concentrations with continued use, but only following an initial increase in estrogen concentrations that may be poorly tolerated. The effectiveness of elagolix was demonstrated in two placebo-controlled studies in which the new drug was significantly more effective than placebo in reducing dysmenorrhea and nonmenstrual pelvic pain. Patients with dyspareunia experienced improvement with a dosage of 200 mg twice a day but statistical significance was not achieved with a dosage of 150 mg once a day. Eravacycline dihydrochloride (Xerava – Tetraphase) Antibacterial Agent

2018 New Drug Comparison Rating (NDCR) =

Indication: Administered intravenously for the treatment of complicated intra-abdominal infections caused by susceptible microorganisms: Escherichia coli, Klebsiella pneumoniae, Citrobacter freundii, Enterobacter cloacae, Klebsiella oxytoca, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Streptococcus anginosus group, Clostridium perfringens, Bacteroides species, and Parabacteroides distasonis in patients 18 years or older

Comparable drugs: Other tetracyclines (e.g., doxycycline, minocycline)

Advantages: --Is active against strains of certain bacteria that are resistant to other tetracyclines --Is more effective in some patients with complicated intra-abdominal infections (cIAI)

Disadvantages: --Labeled indications are much more limited (doxycycline and minocycline have labeled indications for numerous types of infections) --Is not available in an oral formulation (whereas doxycycline and minocycline are administered orally and parenterally) --Effectiveness and safety have not been evaluated in patients less than 18 years of age (whereas doxycycline and minocycline are used in patients 8 years and older)

Most important risks/adverse events: Hypersensitivity reactions including anaphylaxis (use is contraindicated in patients with known hypersensitivity to any of the tetracyclines); tooth discoloration and enamel hypoplasia (use in infants and children younger than 8 years, nursing mothers, or during the second or third trimester of pregnancy is not recommended); inhibition of bone growth; Clostridium difficile-associated diarrhea (should be considered in any patient who develops diarrhea); potential for tetracycline class adverse events (e.g., photosensitivity, anti-anabolic effects); action may be reduced by concurrent use of a strong CYP3A inducer (e.g., rifampin; dosage of eravacycline should be increased); may increase action of anticoagulants that may require reduction of anticoagulant dosage; dosage should be reduced in patients with severe hepatic impairment

Most common adverse events: Infusion site reactions (8%), nausea (7%), vomiting (4%), diarrhea (2%)

Usual dosage: Administered by intravenous infusion over approximately 60 minutes: 1 mg/kg every 12 hours for 4 to 14 days; if a strong CYP3A inducer is being used concurrently, the dosage should be increased to 1.5 mg every 12 hours; in patients with severe hepatic impairment the dosage should be 1 mg/kg every 12 hours on Day 1 and then decreased to 1 mg/kg every 24 hours

Product: For injection: lyophilized powder (50 mg) in single-dose vials (should be stored in a refrigerator); contents of a vial should be reconstituted with 5 mL of Sterile Water for Injection and swirled gently, but not shaken; reconstituted solution is then diluted to a target concentration of 0.3 mg/mL in a 0.9% Sodium Chloride Injection infusion bag

Comments: cIAI include infections such as appendicitis, diverticulitis, peritonitis, intra-abdominal abscess, and perforations of the gastrointestinal tract. Infections are usually polymicrobial and caused by gram-negative, gram- positive, and/or anaerobic bacteria, and are associated with systemic symptoms. Empiric treatment with a broad- spectrum antibacterial regimen often includes a beta-lactam antibiotic (carbapenems, cephalosporins, penicillins [sometimes with a beta-lactamase inhibitor]) but some patients are hypersensitive to these agents or experience infections caused by strains of bacteria that are resistant. Eravacycline is a tetracycline class antibacterial agent that is also designated as a fluorocycline because its structure includes a fluorine substituent. It exhibits activity against strains of bacteria that are resistant to other tetracyclines. The effectiveness of eravacycline was demonstrated in two studies in which it was compared with ertapenem or meropenem. Clinical cures were achieved in 87% of the patients treated with eravacycline or ertapenem, and 91% of patients treated with eravacycline or meropenem. However, it did not meet non-inferiority endpoints in a study in patients with complicated urinary tract infections. Plazomicin sulfate (Zemdri – Achaogen) Antibacterial Agent

2018 New Drug Comparison Rating (NDCR) =

Indication: Administered intravenously in patients 18 years of age or older for the treatment of complicated urinary tract infections (cUTI), including pyelonephritis caused by the following susceptible organisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Enterobacter cloacae

Comparable drugs: Other aminoglycoside antibacterial agents (e.g., amikacin, gentamicin, tobramycin)

Advantages: --Is more effective in some patients --Cross-resistance with other aminoglycosides is not likely --Is administered once a day (whereas other aminoglycosides are often administered more frequently)

Disadvantages: --Labeled indication does not include infections caused by Pseudomonas aeruginosa --Labeled indications are more limited (e.g., other aminoglycosides are also indicated for the treatment of infections such as septicemia, respiratory, central nervous system, skin and soft tissue, and intra-abdominal infections) --Has not been evaluated in pediatric patients

Most important risks/adverse events: Nephrotoxicity (boxed warning; risk is greater in patients with impaired renal function, the elderly, and those receiving concomitant nephrotoxic medications); ototoxicity (boxed warning); neuromuscular blockade (boxed warning); pregnancy (boxed warning; may cause harm to the unborn child); contraindicated in patients with known hypersensitivity to any aminoglycoside; hypersensitivity reactions; Clostridium difficile-associated diarrhea

Most common adverse events: Decreased renal function (4%), diarrhea (2%), hypertension (2%)

Usual dosage: Administered by intravenous infusion over 30 minutes; in patients with a creatinine clearance of at least 90 mL/min, the recommended dosage is 15 mg/kg every 24 hours for 4 to 7 days; in patients with a creatinine clearance of at least 15 to less than 90 mL/min, therapeutic drug monitoring is recommended to maintain plasma trough concentrations below 3 mcg/mL; product labeling should be consulted for recommended dosage adjustments based on creatinine clearance and trough concentrations

Product: Injection - single-dose vials – 500 mg/10 mL (should be stored in a refrigerator); appropriate volume to provide the required dose should be diluted in 0.9% Sodium Chloride Injection or Lactated Ringer’s Injection to achieve a final volume of 50 mL

Comments: Although a beta-lactam antibiotic or fluoroquinolone would usually be used in the treatment of complicated urinary tract infections caused by Enterobacteriaceae, the emergence of carbapenem-resistant and other resistant strains of these bacteria has resulted in additional challenges in treating these infections. Plazomicin is a semi-synthetic aminoglycoside antibacterial agent that, like the other aminoglycosides, binds to bacterial 30S ribosomal subunits, thereby inhibiting protein synthesis and exhibiting a bactericidal action. It is primarily active against gram-negative aerobic bacteria. Its action is not inhibited by most of the aminoglycoside modifying enzymes that may result in resistance to other aminoglycosides, and cross-resistance is unlikely. Activity of plazomicin has also been demonstrated in vitro in the presence of certain carbapenemases. The effectiveness of plazomicin was evaluated in a study of hospitalized adults with cUTI, in which it was compared with meropenem (administered IV every 8 hours). At Day 5 of treatment the rates of resolution or improvement of symptoms and microbiological eradication were 88% and 94%, respectively. A Test of Cure (resolution of symptoms [i.e., cure] and microbiological eradication) visit was scheduled for at least 2 weeks following the first dose of treatment. These results for plazomicin and meropenem were 82% and 70%, respectively. Some of the patients who were effectively treated with plazomicin had cUTI that were caused by isolates of bacteria that were resistant to gentamicin and tobramycin.

Ozenoxacin (Xepi – Medimetricks) Antibacterial Agent

2018 New Drug Comparison Rating (NDCR) =

Indication: Topical treatment of impetigo due to Staphylococcus aureus or Streptococcus pyogenes in adults and pediatric patients 2 months of age and older

Comparable drugs: Mupirocin (e.g., Bactroban), retapamulin (Altabax)

Advantages: --Is active against methicillin-resistant S. aureus (MRSA)(compared with retapamulin that is indicated for methicillin-susceptible isolates only) --Is indicated for pediatric patients as young as 2 months of age (compared with retapamulin that is not indicated for patients younger than 9 months) --Is less likely to cause adverse events --Is applied less frequently (twice a day compared with mupirocin that is applied three times a day)

Disadvantages: --Has not been directly compared with comparable drugs in clinical studies --May be less effective --Labeled indications and formulations are more limited (compared with mupirocin that is also indicated for the treatment of secondarily infected traumatic skin lesions, and is also available in a nasal ointment formulation for the eradication of nasal colonization with MRSA in adult patients and health care workers as part of an infection control program during institutional outbreaks of MRSA infection)

Most important risks/adverse events: Potential for microbial overgrowth of nonsusceptible bacteria and fungi (if such infections occur, use should be discontinued and alternative therapy instituted)

Most common adverse events: Rare reports of rosacea and seborrheic dermatitis

Usual dosage: A thin layer of cream is applied to the affected area twice a day for 5 days; affected area may be up to 100 cm2 in adult and pediatric patients 12 years of age and older, or 2% of the total body surface area and not exceeding 100 cm2 in pediatric patients less than 12 years of age; treated area may be covered with a sterile bandage or gauze dressing to protect the area and avoid accidental transfer of the cream to the eyes or other areas

Product: Cream – 1% (10 mg/gram)

Comments: Impetigo is a highly contagious bacterial skin infection that is usually caused by S. aureus or S. pyogenes. It occurs most often in infants and young children, and spreads easily in child care settings and schools. Impetigo that is localized and involves limited areas of skin is usually treated with a topically-applied antibacterial agent (i.e., mupirocin, retapamulin), and more extensive lesions are usually treated with an oral antibiotic. Ozenoxacin is a quinolone antibacterial agent that is applied topically and exhibits a bactericidal action. Its action against S. aureus includes both methicillin-susceptible and methicillin-resistant isolates. Its effectiveness was evaluated in two placebo-controlled clinical trials in which overall success was defined as no need for additional antimicrobial therapy of the baseline affected area(s) and absence/reduction in clinical signs and symptoms assessed at the end of therapy (Day 6-7). Clinical success was demonstrated in 35% and 54% of the patients treated with ozenoxacin, compared with 19% and 38%, respectively, of those on placebo. Ozenoxacin has not been directly compared with mupirocin or retapamulin, but a comparison of the results of the studies of the individual drugs suggests that the new drug is less effective. For the treatment of impetigo, ozenoxacin is used in a cream formulation, whereas mupirocin and retapamulin are used in ointment formulations.

Baloxavir marboxil (Xofluza – Genentech; Shionogi) Antiviral Agent

2018 New Drug Comparison Rating (NDCR) =

Indication: Treatment of acute uncomplicated influenza in patients 12 years of age and older who have been symptomatic for no more than 48 hours

Comparable drug: Oseltamivir (e.g., Tamiflu)

Advantages: --Is a single-dose treatment (whereas oseltamivir is usually administered twice a day for 5 days) --Has a unique mechanism of action (is a polymerase acidic endonuclease inhibitor) --May be effective in some patients with influenza that is resistant to oseltamivir --Use has not been associated with neuropsychiatric adverse events --Dosage adjustment is not necessary in patients with renal impairment

Disadvantages: --Effectiveness and safety have not been evaluated in patients less than 12 years of age (whereas oseltamivir is indicated for the treatment of patients 2 weeks of age and older) --May be less effective against influenza B viruses --Has not been evaluated for the prophylaxis of influenza (whereas oseltamivir is indicated for the treatment and prophylaxis of influenza) --Absorption and activity may be reduced by coadministration with polyvalent cation-containing products

Most important risks/adverse events: Bacterial infection (may coexist with or occur as a complication of influenza); absorption and activity may be reduced by polyvalent cation-containing products (e.g., antacids), and coadministration should be avoided; may decrease the effectiveness of intranasal live attenuated influenza vaccine

Most common adverse events: Diarrhea (3%), bronchitis (2%)

Usual dosage: For patients weighing 40 kg to less than 80 kg – single dose of 40 mg; for patients weighing at least 80 kg – single dose of 80 mg

Products: Film-coated tablets – 20 mg, 40 mg; supplied in blister card packaging

Comments: Baloxavir marboxil is a prodrug that is almost completely converted by hydrolysis to its active metabolite, baloxavir, that exerts activity against influenza A and influenza B viruses. Baloxavir inhibits the endonuclease activity of the polymerase acidic protein, an influenza virus-specific enzyme in the viral RNA polymerase complex required for viral gene transcription, resulting in inhibition of influenza virus replication. Oseltamavir and related agents act by inhibiting influenza neuraminidase. The effectiveness of baloxavir was evaluated in two clinical studies in which the primary endpoint was the time to alleviation of symptoms, defined as the time when all seven symptoms (cough, sore throat, nasal congestion, headache, feverishness, myalgia, and fatigue) had been assessed by the patient as none or mild for a duration of at least 21.5 hours. The first study was conducted in 400 adult patients and was placebo-controlled. The median time to alleviation of symptoms in patients treated with a single dose of 40 mg of baloxavir was 50 hours, compared with a median time of 78 hours in those receiving placebo. The second study was an active- and placebo-controlled trial in 1,436 adult and adolescent patients. The median time to alleviation of symptoms in patients treated with a single dose of 40 mg or 80 mg of baloxavir was 54 hours, compared with a median time of 80 hours in those receiving placebo. The second study included a group of patients who were treated with oseltamivir (twice a day for 5 days). There was no difference in the median time to alleviation of symptoms (i.e., 54 hours) between patients who received a single dose of baloxavir and those who received oseltamivir. The infections of most patients in the clinical studies were caused by influenza A viruses. The subset of patients with influenza B infections in the first study had a shorter median time to alleviation of symptoms than those in the placebo group, but in the subset of patients in the second study with influenza B infections, the median time to alleviation of symptoms was longer in those receiving baloxavir than in those receiving placebo. Doravirine (Pifeltro – Merck) Antiviral Agent

2018 New Drug Comparison Rating (NDCR) =

Indication: In combination with other antiretroviral agents for the treatment of HIV-1 infection in adult patients with no prior antiretroviral treatment history

Comparable drugs: Other non-nucleoside reverse transcriptase inhibitors (NNRTI; rilpirivine [Edurant] is the NNRTI used for the basis of the following comparisons)

Advantages: --Labeled indication is less restrictive (rilpivirine is indicated in patients with HIV-1 RNA less than or equal to 100,000 copies/mL) --Is less likely to cause depressive disorders, hepatotoxicity, or prolongation of the QT interval --Is not likely to interact with drugs that increase gastric pH (whereas these agents may reduce plasma concentrations of rilpivirine)

Disadvantages: --Has not been evaluated in patients less than 18 years of age (whereas rilpivirine is indicated in patients 12 years of age and older)

Most important risks/adverse events: Action may be significantly reduced by strong CYP3A inducers (e.g., carbamazepine, enzalutamide, rifampin, St. John’s wort) and concurrent use is contraindicated, and at least a 4-week cessation period is recommended prior to initiation of treatment with doravirine; action may be reduced by efavirenz, etravirine, and nevirapine, and concurrent use is not recommended; dosage should be increased if rifabutin is used concurrently; immune reconstitution syndrome

Most common adverse events: Nausea (7%), headache (6%), fatigue (6%), diarrhea (5%), abdominal pain (5%)

Usual dosage: 100 mg once a day; in patients also treated with rifabutin, the recommended dosage is 100 mg twice a day (approximately 12 hours apart)

Products: Film-coated tablets – 100 mg; a combination product, Delstrigo tablets, contains doravirine (100 mg), lamivudine (300 mg), and tenofovir disoproxil fumarate (300 mg), and is administered once a day as a complete regimen in patients with no antiretroviral treatment history

Comments: Doravirine is the sixth non-nucleoside reverse transcriptase inhibitor (NNRTI) to be marketed for the treatment of HIV infection, joining delavirdine (Rescriptor), efavirenz (Sustiva), etravirine (Intelence), nevirapine (Viramune), and rilpivirine. The effectiveness of doravirine was evaluated in two 48-week active controlled clinical studies. In the first study either doravirine or darunavir plus ritonavir was administered once daily in combination with emtricitabine/tenofovir disoproxil fumarate or abacavir/lamivudine. At Week 48 the percentages of patients with virologic outcomes of HIV-1 RNA of less than 50 copies/mL were 84% for the doravirine regimen and 80% for the darunavir/ritonavir regimen. In the second study the combination product (Delstrigo) with doravirine/lamivudine/tenofovir disoproxil fumarate was compared with a combination of efavirenz, emtricitabine, and tenofovir disoproxil fumarate. At Week 48, the percentages of patients with less than 50 copies/mL were 84% and 81%, respectively. Although the new regimens are highly effective, they may not be as effective as regimens that include an HIV-1 integrase strand transfer inhibitor (INSTI; i.e., bictegravir, dolutegravir, elvitegravir, raltegravir). Biktarvy and Genvoya are INSTI-containing complete regimen combination formulations that include tenofovir alafenamide instead of tenofovir disoproxil fumarate as the prodrug for tenofovir. Tenofovir alafenamide is less likely than tenofovir disoproxil fumarate to cause renal toxicity and affect bone mineral density, although it may be more likely to increase blood lipid concentrations.

Bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate (Biktarvy – Gilead) Antiviral Agents 2018 New Drug Comparison Rating (NDCR) =

Indications: A complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults who have no antiretroviral treatment history or to replace the current antiretroviral regimen in those who are virologically-suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen for at least 3 months with no history of treatment failure and no known substitutions associated with resistance to the individual components of Biktarvy

Comparable drugs: Elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (Genvoya)

Advantages: --Formulation does not include cobicistat that may interact with numerous other medications --Indicated as a replacement regimen in patients with no history of treatment failure for at least 3 months (compared with at least 6 months with Genvoya)

Disadvantages: --Is not indicated for pediatric patients (whereas Genvoya is indicated in pediatric patients weighing at least 25 kg)

Most important risks/adverse events: Severe acute exacerbations of hepatitis B virus (HBV) in patients who are coinfected with HIV-1 and HBV upon discontinuation of products containing emtricitabine and tenofovir disoproxil fumarate (boxed warning; hepatic function should be closely monitored for at least several months in patients who discontinue treatment); immune reconstitution syndrome; lactic acidosis/severe hepatomegaly with steatosis; new onset or worsening renal impairment (use is not recommended in patients with estimated creatinine clearance less than 30 mL per minute); women should not breastfeed due to the potential for HIV transmission; may increase the action of dofetilide and concurrent use is contraindicated; may increase the action of metformin; bictegravir is a substrate for the CYP3A and UGT1A1 pathways and action may be reduced by inducers of these pathways (concurrent use with rifampin is contraindicated, and use with rifampin, rifabutin, or St. John’s wort is not recommended; in patients treated with carbamazepine, oxcarbazepine, phenobarbital, or phenytoin, alternative anticonvulsants should be considered); action of bictegravir may be reduced by polyvalent cations (may be administered under fasting conditions 2 hours before an antacid containing aluminum, magnesium, and/or calcium; may be administered together with supplements containing calcium or iron with food); because it is a complete regimen, concurrent use of other antiretroviral medications for HIV-1 infection is not recommended

Most common adverse events: Headache (5%), diarrhea (5%), nausea (4%)

Usual dosage: One tablet once a day with or without food

Product: Film-coated tablets – bictegravir 50 mg, emtricitabine 200 mg, tenofovir alafenamide 25 mg

Comments: Bictegravir is the fourth HIV-1 integrase strand transfer inhibitor to be approved, joining raltegravir (Isentress), elvitegravir (e.g., in the combination formulation Genvoya), and dolutegravir (Tivicay). Bictegravir is not available as a single agent but in a combination formulation with the HIV-1 nucleoside analog reverse transcriptase inhibitors emtricitabine and tenofovir alafenamide. Tenofovir alafenamide is a prodrug that is metabolized much more efficiently than the prodrug tenofovir disoproxil fumarate to the active tenofovir diphosphate. Tenofovir alafenamide may be used in a much lower dosage and its lower systemic exposure is less likely to be associated with renal toxicity and a reduction in bone mineral density. The effectiveness of Biktarvy was evaluated in two studies in adults with no antiretroviral treatment history, in which it was compared with a regimen of dolutegravir, abacavir, and lamivudine, as well as a regimen of dolutegravir, emtricitabine, and tenofovir alafenamide. The new combination formulation was similarly effective and the percentages of patients with HIV-1 RNA less than 50 copies/mL at Week 48 exceeded 90% for all regimens. Biktarvy was also studied in two studies in virologically-suppressed patients who were switched to Biktarvy, and compared with other HIV-1 antiretroviral regimens. The new combination formulation was similarly effective in maintaining virologic suppression at Week 48 in more than 90% of patients. Ibalizumab-uiyk (Trogarzo – TaiMed; Thera) Antiviral Agent

2018 New Drug Comparison Rating (NDCR) =

Indication: In combination with other antiretroviral(s), administered intravenously for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in heavily treatment-experienced adults with multidrug resistant HIV-1 infection failing their antiretroviral regimen

Comparable drugs: Other HIV-1 antiretroviral agents

Advantages: --Is effective in some patients who have failed other treatments --Has a unique mechanism of action (is a CD4-directed post-attachment HIV-1 inhibitor) --Causes fewer adverse events and is less likely to interact with other medications --Is administered less frequently (once every two weeks)

Disadvantages: --Is administered intravenously (whereas most comparable agents are administered orally) --Is not indicated for use in pediatric patients

Most important risks/adverse events: Immune reconstitution inflammatory syndrome; infusion-associated adverse events; women should not breastfeed because of the potential for HIV transmission

Most common adverse events: Diarrhea (8%), dizziness (8%), nausea (5%), rash (5%), elevated creatinine concentrations (10%)

Usual dosage: Administered by a trained medical professional as an intravenous infusion in the cephalic vein of the patient’s right or left arm; initial loading dose of 2,000 mg (10 vials) followed by maintenance doses of 800 mg (4 vials) every 2 weeks; duration of the loading dose infusion should be no less than 30 minutes, and patients should be observed for one hour following administration for at least the first dose

Product: Single-dose vials that deliver approximately 1.33 mL containing 200 mg of the drug; (vials should be stored in a refrigerator); contents of the appropriate number of vials needed to provide the recommended dose should be diluted in 250 mL of 0.9% Sodium Chloride Injection

Comments: Most patients with HIV-1 infection can be successfully treated with a combination of two or more antiretroviral drugs such as integrase strand transfer inhibitors (INSTIs), nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTI), and HIV-1 protease inhibitors (PIs). However, as many as 25,000 patients in the United States have multidrug resistant (MDR) HIV-1 infection that is associated with a high risk of complications and death. Ibalizumab is a humanized monoclonal antibody and the first biologic drug to be approved for the treatment of HIV-1 infection. It is designated as a CD4-directed post-attachment HIV-1 inhibitor, and blocks HIV-1 from infecting CD4+ T cells by binding to domain 2 of CD4 and interfering with post- attachment steps required for the entry of HIV-1 virus particles into host cells and preventing the viral transmission that occurs via cell-cell fusion. The binding specificity of ibalizumab to domain 2 of CD4 allows it to block viral entry into host cells without causing immunosuppression and, therefore, it does not interfere with CD4–mediated immune functions. It is active against HIV-1 resistant to all approved antiretroviral agents, and studies have not revealed cross-resistance with other agents. Ibalizumab was evaluated in a clinical trial of 40 patients with MDR HIV-1 infection who had a viral load greater than 1,000 copies/mL and documented resistance to at least one drug in each of the NRTI, NNRTI, and PI classes. Fifty-three percent of the patients had been treated with 10 or more antiretroviral drugs. The primary efficacy endpoint was a significant decrease in the viral load (HIV-RNA), and 83% of the patients experienced this endpoint one week after the loading dose of ibalizumab was added to their failing antiretroviral regimen. At week 25 of treatment with ibalizumab in combination with other antiretroviral drugs, 43% of patients achieved virologic suppression (HIV-1 RNA less than 50 copies/mL). Treatment was discontinued in 13% of patients as a consequence of adverse events or death. Tafenoquine succinate (Krintafel – GlaxoSmithKline) Antiparasitic Agent

2018 New Drug Comparison Rating (NDCR) =

Indication: For the radical cure (prevention of relapse) of Plasmodium vivax malaria in patients aged 16 years and older who are receiving appropriate antimalarial therapy for acute P. vivax infection; is NOT indicated for the treatment of acute P. vivax malaria

Comparable drug: Primaquine

Advantages: --Is effective as a single-dose treatment (whereas primaquine is used in a 14-day course of treatment)

Disadvantages: --May be more likely to cause psychiatric adverse events

Most important risks/adverse events: Hemolytic anemia (patients with glucose-6-phosphate dehydrogenase [G6PD] deficiency are at particular risk; is contraindicated in patients with G6PD deficiency or unknown G6PD status); pregnancy (is not recommended during pregnancy; women of reproductive potential should be advised to avoid pregnancy or use effective contraception for 3 months after the dose of tafenoquine; a woman with normal concentrations of G6PD could give birth to a G6PD infant); lactation (a G6PD-deficient infant could be at risk of hemolytic anemia from exposure through breast milk; is contraindicated in breastfeeding women when the infant is found to be G6PD-deficient or the G6PD status is unknown; women should be advised to not breastfeed for 3 months after the dose of tafenoquine); methemoglobinemia; hypersensitivity reactions (is contraindicated in patients with known hypersensitivity to any 8-aminoquinoline derivative); psychiatric effects (e.g., anxiety, insomnia; in patients with a psychiatric illness, anticipated benefit must be weighed against the risk of psychiatric adverse events); has a long half-life (approximately 15 days) and adverse events may be delayed in onset and/or duration; inhibits the activity of organic cation transporter-2 (OCT2) and multidrug and toxic extrusion (MATE) transporters (concentration and activity of substrates of these transporters [e.g., dofetilide, metformin] may be increased and concurrent use should be avoided)

Most common adverse events: Dizziness (8%), nausea (6%), vomiting (6%), headache (5%), decreased hemoglobin (5%)

Usual dosage: Single dose of 300 mg administered as two tablets taken together with food; should be coadministered on the first or second day of appropriate antimalarial therapy (e.g., chloroquine) for acute P. vivax malaria; tablets should be swallowed whole; if vomiting occurs within 1 hour of administration, a repeat dose should be given

Product: Film-coated tablets – 150 mg

Comments: Following a bite of an infected mosquito, P. vivax infects the blood and causes an acute malaria episode. It also has the ability to lie dormant in the liver from where it periodically reactivates to cause relapses of malaria. Most antimalarial drugs are active against the blood-stage of the parasite but are not very effective against the dormant forms in the liver. The 8-aminoquinoline derivative, primaquine, is the only previous antiparasitic agent to be approved to target the dormant liver stage to prevent relapse. Like primaquine, tafenoquine is an 8- aminoquinoline antimalarial agent. Its effectiveness was demonstrated in two clinical trials in patients positive for P. vivax who received a 3-day regimen of chloroquine to treat the acute infection in addition to a single dose of tafenoquine, an active control, or placebo. Patients were considered recurrence-free at 6 months if they demonstrated initial parasite clearance, took no subsequent antimalarial medication, and were confirmed parasite- free at the 6-month final assessment. In the largest study, recurrence-free efficacy occurred in 60% of the patients treated with chloroquine and tafenoquine, and in 26% of the patients treated with chloroquine and placebo. In patients in whom chloroquine/tafenoquine and chloroquine/primaquine regimens were compared, the efficacy rates at 6 months were generally similar (approximately 70%). The FDA has subsequently approved another tafenoquine product (Arakoda 100-mg tablets) that is indicated for the prophylaxis of malaria in a different dosage regimen. Netarsudil dimesylate (Rhopressa – Aerie) Agent for Glaucoma

2018 New Drug Comparison Rating (NDCR) =

Indication: For ophthalmic administration for the reduction of intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension

Comparable drugs: Ophthalmic beta-adrenergic blocking agents (e.g., timolol)

Advantages: --Is less likely to cause systemic adverse events --Has a unique mechanism of action (is a rho kinase inhibitor)

Disadvantages: --Is less effective in lowering IOP in some patients --Is more likely to cause ocular adverse events

Most important risks/adverse events: Bacterial keratitis; contact lenses should be removed prior to administration, and may be reinserted 15 minutes following administration

Most common adverse events: Conjunctival hyperemia (53%); corneal verticillata (opacities), instillation site pain, conjunctival hemorrhage, each occurring in approximately 20% of patients; instillation site erythema, corneal staining, blurred vision, increased lacrimation, erythema of eyelid, reduced visual acuity, each occurring in 5-10% of patients

Usual dosage: One drop in the affected eye(s) once a day in the evening; if a dose is missed, treatment should continue with the next dose in the evening; twice a day dosing is not well tolerated and is not recommended; should be administered at least 5 minutes apart from another ophthalmic medication

Product: Ophthalmic solution – 0.02% (0.2 mg/mL); unopened bottles should be stored in a refrigerator; after opening, may be stored at room temperature for up to 6 weeks; formulation contains benzalkonium chloride as a preservative, which may be absorbed by soft contact lenses (contact lenses should be removed prior to administration)

Comments: Netarsudil has a unique mechanism of action as a rho kinase inhibitor. It is thought to reduce IOP by increasing the outflow of aqueous humor through the trabecular meshwork, but its exact mechanism of action is not known. Following ophthalmic administration, it is metabolized by esterases in the eye, and one of its metabolites is pharmacologically active. The effectiveness of netarsudil (0.02% once daily in the evening) was demonstrated in three controlled trials in which it was compared with timolol (0.5% twice a day). Patients treated with netarsudil experienced up to 5 mmHg reductions in IOP. In patients with a baseline IOP <25 mmHg, the IOP reductions were similar to those of timolol. However, in patients with baseline IOP 25 mmHg or greater, the mean IOP reductions were smaller with netarsudil than with timolol. Although timolol was administered twice a day in these clinical studies, some formulations of timolol (e.g., Timolol XE) may be administered once a day. The ophthalmic use of beta-adrenergic blocking agents has been associated with the occurrence of systemic adverse events (e.g., pulmonary, cardiovascular, central nervous system) in some patients and their labeling includes contraindications, warnings, and precautions regarding certain of these risks. In contrast, netarsudil appears unlikely to cause systemic adverse events and its labeling does not identify such risks. However, the incidence of ocular adverse events with netarsudil is higher than that reported with ophthalmic beta-blockers or with the prostaglandin analogs such as latanoprost (e.g., Xalatan).

Voretigene neparvovec-rzyl (Luxturna – Spark) Agent for Retinal Dystrophy

2018 New Drug Comparison Rating (NDCR) =

Indication: Administered by subretinal injection for the treatment of patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy; patients must have viable retinal cells

Comparable drug: None

Advantages: --Is the first drug to be demonstrated to be effective in the treatment of biallelic RPE65 mutation-associated retinal dystrophy --Is the first gene therapy that targets a disease caused by mutations in a specific gene

Limitations: --Duration of treatment benefit has not yet been determined

Most important risks/adverse events: Endophthalmitis; decreased visual acuity; retinal abnormalities; cataract formation; increased intraocular pressure; expansion of intraocular air bubbles (patients should be instructed to avoid air travel, travel to high elevations, or scuba diving until the intraocular air bubble following administration has completely dissipated [may take one week or more]); treatment is not recommended in patients younger than 12 months of age because the drug would potentially be diluted or lost during cell proliferation

Most common adverse events: Conjunctival hyperemia (22%), cataract (20%), increased intraocular pressure (15%), retinal tear (10%), dellen (thinning of the corneal stroma; 7%), macular hole (7%), subretinal deposits (7%)

Usual dosage: 1.5 x 1011 vector genomes (vg) in each eye, administered by subretinal injection in a total volume of 0.3 mL; a single injection should be made in each eye on separate days within a close interval, but no fewer than 6 days apart; a systemic oral corticosteroid (equivalent to prednisone at 1 mg/kg/day [maximum of 40 mg/day]) should be given for a total of 7 days (starting 3 days before administration of the drug in the first eye), and followed by tapering the dose during the following 10 days; the same corticosteroid regimen should be used for treatment in the second eye

Product: Intraocular suspension for subretinal injection in a 0.5 mL extractable volume in a single-dose 2 mL vial for a single administration in one eye; vial and the two vials of diluents provided should be stored in the frozen state; drug is supplied in a concentration of 5 x 1012 vg/mL that requires a 1:10 dilution prior to administration; product labeling should be consulted for specific recommendations for diluting, preparing, and administration of injection; universal biohazard precautions should be observed during handling for up to 7 days following administration

Comments: Hereditary retinal dystrophies are a group of genetic retinal disorders that are associated with worsening visual dysfunction . The human retinal pigment epithelial 65 kDa gene (RPE65) provides instructions for making an enzyme that is essential for normal vision. Mutations in the RPE65 gene lead to reduced or absent levels of RPE isomerohydrolase activity resulting in impairment of vision. The loss of vision often occurs during childhood or adolescence, and may eventually result in complete blindness. Biallelic RPE65 mutation-associated retinal dystrophy affects up to 2,000 individuals in the US. Biallelic mutation carriers have a mutation, but not necessarily the same mutation, in both copies of a particular gene. Voretigene is provided in a suspension of an adeno-associated virus vector-based gene therapy for subretinal injection. It uses a naturally-occurring, live, non-replicating adeno-associated virus serotype 2, which has been genetically modified using recombinant techniques, to deliver the normal human RPE65 gene to the retinal cells. Its effectiveness was evaluated in a study of 31 patients, with almost two-thirds of the patients being less than 18 years of age. Significant improvements in functional vision, as assessed by the ability of a patient to navigate an obstacle course accurately and at a reasonable pace at different levels of environmental illumination, were demonstrated in the patients treated with voretigene, compared to those in the control group. The benefit was sustained over the two-year period of the study. Patients who were initially in the control group were treated with the drug after one year, following which they experienced similar improvement with the drug.