2015 new drug update.

in Practice

2015 New Drug Update Six new drugs approved within the last two years, which are used for medical problems often experienced by the elderly, have been selected for consideration in this review. The uses and most important properties of these agents are discussed, and a rating for each new drug is determined using the New Drug Comparison Rating system developed by the author. Advantages, disadvantages, and other important information regarding the new drug are identified and used as the basis for determining the rating. The drugs include two antidiabetic agents, one bronchodilator, one antidepressant, one for erectile dysfunction, and one for menopause-associated conditions. KEY WORDS: Albiglutide, Antidepressant, Antidiabetic agent, Avanafil, Bazedoxifene, Bronchodilator, Chronic obstructive pulmonary disease, Conjugated estrogens, Diabetes, Elderly, Empagliflozin, Erectile dysfunction, Estrogens, Menopause, Muscarinic antagonist, Umeclidinium, Vilanterol, Vortioxetine. Abbreviations: A1c = Hemoglobin A1c, BPH = Benign prostatic hyperplasia, cGMP = Cyclic guanosine monophosphate, COPD = Chronic obstructive pulmonary disease, CV = Cardiovascular, CYP = Cytochrome P450, DPP-4 = Dipeptidyl peptidase 4, eGFR = Estimated glomerular filtration rate, FDA = Food and Drug Administration, GLP-1 = Glucagon-like peptide 1, HbA1c = Hemoglobin A1c, LABA = Long-acting beta2-adrenergic agonist, LAMA = Long-acting muscarinic antagonist, MAOI = Monoamine oxidase inhibitor, MTC = Medullary thyroid carcinoma, NDCR = New Drug Comparison Rating, NO = Nitric oxide; PDE5 = Phosphodiesterase type 5, SGLT2 = Sodium-glucose cotransporter 2, SNRI = Serotonin norepinephrine reuptake inhibitor, SSRI = Selective serotonin reuptake inhibitor, T2DM = Type 2 diabetes mellitus, UGT = Uridine diphosphate glucuronosyl transferase, UTI = Urinary tract infection, 5-HT = 5-hydroxytryptamine.

Daniel A. Hussar

Introduction

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ix new drugs approved within the last two years, which are used for medical problems often experienced by the elderly, have been selected for consideration in this review. The uses and most important properties of these agents are discussed, and a rating for each new drug is determined using the New Drug Comparison Rating (NDCR) system developed by the author.

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In the NDCR system, a rating from 1 to 5 (5 being the highest rating) is assigned for each new drug. The rating is based on a comparison of the new drug with related drugs already marketed. Advantages, disadvantages, and other important information regarding the new drug are identified and used as the basis for determining the rating. The overall opinions that correspond to the numerical ratings are noted below:

The Consultant Pharmacist april 2015 Vol. 30, No. 4

5 = Important advance (e.g., the first drug approved for the indication) 4 = Significant advantage(s) (e.g., with respect to use/ effectiveness, safety, administration) 3 = No or minor advantage(s)/disadvantage(s), or advantage(s) and disadvantage(s) of similar importance 2 = Significant disadvantage(s) (e.g., with respect to use/effectiveness, safety, administration) 1 = Important disadvantage(s) The rating is determined at the time the drug is first marketed. In this paper, NDCRs are provided for the six new drugs considered along with the advantages and disadvantages identified and used in the determination of the rating.

Antidiabetic Agents1,2 The number of therapeutic options for the treatment of patients with type 2 diabetes mellitus (T2DM) continues to increase, and two new drugs are considered individually in the following discussions.

Empagliflozin Empagliflozin (Jardiance—Boehringer-Ingelheim; Lilly) is the third drug in a new class of orally administered antidiabetic agents designated as sodium-glucose cotransporter 2 (SGLT2) inhibitors, joining canagliflozin (Invokana), which was marketed in 2013, and dapagliflozin (Farxiga), which was marketed in early 2014. SGLT2 is expressed in the proximal renal tubules and is responsible for the reabsorption of the majority of glucose that is filtered by the kidneys. By inhibiting SGLT2, empagliflozin and the other agents in this class reduce the reabsorption of filtered glucose, increase urinary glucose excretion, and reduce blood glucose and hemoglobin A1c (A1c) concentrations. Like canagliflozin and dapagliflozin, empagliflozin is specifically indicated as an adjunct to diet and exercise to improve glycemic control in adults with T2DM. Its effectiveness has been demonstrated in studies in which it was used as monotherapy, or in combination regimens with metformin, glimepiride, pioglitazone, or insulin. The use of empagliflozin resulted in reductions in A1c and fasting plasma glucose (FPG) concentrations and, in

many patients, weight reduction. In a placebo-controlled study, the percentage of patients achieving an A1c of less than 7% at week 24 was 35% and 44% in patients receiving daily doses of 10 mg and 25 mg of empagliflozin, respectively, compared with 12% of those receiving placebo. Patients treated with empagliflozin lost an average of approximately 3 kg of body weight, compared with an average loss of 0.4 kg in those receiving placebo. The reductions in A1c and FPG in patients treated with combination regimens that included empagliflozin, as well as the percentage of patients achieving an A1c of less than 7%, were generally similar to those attained with empagliflozin monotherapy. Approximately one-third of the patients in the clinical studies were 65 years of age or older, and 6% were 75 years of age and older. It is not necessary to adjust the dosage based on the patient’s age. The use of empagliflozin is not recommended for the treatment of patients with type 1 diabetes mellitus or diabetic ketoacidosis. As with the other SGLT2 inhibitors, empagliflozin increases serum creatinine concentrations and decreases estimated glomerular filtration rate (eGFR). Older patients and those with impaired renal function are more susceptible to associated risks. The use of empagliflozin is contraindicated in patients with severe renal impairment (eGFR < 30 mL/min/1.73 m2) or end-stage renal disease, or patients on dialysis. Renal function should be evaluated before initiating treatment and periodically thereafter. Treatment should not be initiated in patients with an eGFR less than 45 mL/min/1.73 m2, and if the eGFR is persistently less than this value during treatment, the drug should be discontinued. These recommendations are the same as for the use of canagliflozin, whereas treatment with dapagliflozin should not be initiated in patients with an eGFR less than 60 mL/min/1.73 m2. The SGLT2 inhibitors cause intravascular volume contraction that may result in symptomatic hypotension. Volume status should be assessed, and corrected if necessary, in all older patients, paying special attention to those with impaired renal function or low systolic blood pressure, and in patients treated with a diuretic.


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Although empagliflozin is not likely to cause hypoglycemia, it can increase the risk of hypoglycemia when used in combination with insulin or an insulin secretagogue (e.g., a sulfonylurea). Therefore, a lower dosage of the latter agent may be necessary when such combination regimens are used. The most commonly experienced adverse events in the clinical studies of empagliflozin (and the incidence in patients treated with a dosage of 10 mg daily) include urinary tract infection (UTI) (9%), female genital mycotic infection (5%; e.g., vulvovaginal candidiasis), dyslipidemia (4%; e.g., increased low-density lipoprotein cholesterol), increased urination (3%), male genital mycotic infection (3%; e.g., balanitis), and upper respiratory tract infection (3%). The risk of UTIs and volume depletion-related adverse events is greater in patients 75 years of age and older. The labeling for dapagliflozin includes a warning regarding infrequent reports of bladder cancer experienced by patients in the clinical studies. However, there have not been reports of this problem in the studies of empagliflozin or canagliflozin. The effect of food on empagliflozin pharmacokinetics is not considered clinically relevant and it may be administered without regard to food. The primary route of metabolism is thought to be glucuronidation via uridine diphosphate glucuronosyl transferase (UGT) pathways. Three glucuronide conjugates are the most abundant metabolites, but the systemic exposure of each of these metabolites is less than 10% of total drug-related material. Approximately 55% and 40% of a dose of the drug is eliminated in the urine and feces, respectively. Most of the drug recovered in the feces is in the unchanged form, whereas approximately one-half of the drug excreted in the urine is unchanged drug. An adjustment of dosage is not necessary in patients with an eGFR greater than or equal to 45 mL/ min/1.73 m2, or in patients with hepatic impairment. Because the SGLT2 inhibitors increase urinary glucose excretion, positive urine glucose tests will result. Therefore, urine glucose tests are not recommended to monitor glycemic control, and alternative methods should be used. The recommended dosage of empagliflozin is 10 mg once a day in the morning. In patients who tolerate this

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dosage well but need additional glycemic control, the dosage may be increased to 25 mg once a day. Empagliflozin tablets are supplied in 10 mg and 25 mg potencies. NDCR = 3 (no or minor advantage[s]/disadvantage[s]) Comparable drugs: Canagliflozin (Invokana), dapagliflozin (Farxiga)

Advantages • Recommendations for use in patients with impaired renal function are less restrictive (compared with dapagliflozin) • May be used in patients with severe hepatic impairment (compared with canagliflozin that has not been studied in patients with severe hepatic impairment and for whom use is not recommended) • Has not been associated with reports of patients experiencing bladder cancer (compared with dapagliflozin) Disadvantages • Additive benefit when used in combination regimens may be less pronounced (although agents have not been directly compared in clinical studies) • Not available in a combination formulation with metformin (a combination formulation of empagliflozin and linagliptin has been subsequently approved) Albiglutide Albiglutide (Tanzeum—GlaxoSmithKline) is the third glucagon-like peptide-1 (GLP-1) receptor agonist to be approved by the Food and Drug Administration (FDA), joining exenatide (Byetta; exenatide extended-release [Bydureon]) and liraglutide (Victoza). These agents augment glucose-dependent insulin secretion and also slow gastric emptying, resulting in lower fasting glucose and reduced postprandial glucose excursions in patients with T2DM. Albiglutide is a recombinant fusion protein comprising two tandem copies of modified human GLP-1 genetically fused in tandem to human albumin. A human GLP-1 fragment sequence has been modified to confer resistance to dipeptidyl peptidase 4 (DPP-4)-mediated proteolysis. The human albumin moiety of the protein, together with the DPP-4 resistance, provides a longer



half-life that permits administration of doses just once a week. The exenatide extended-release formulation is also administered once a week, whereas liraglutide is administered once a day and exenatide twice a day. Like the other GLP-1 agonists, albiglutide is administered subcutaneously and is indicated as an adjunct to diet and exercise to improve glycemic control in adults with T2DM. Its effectiveness was demonstrated in eight clinical trials that included more than 2,300 patients with T2DM. Albiglutide was evaluated as a stand-alone therapy, as well as in combination with other antidiabetic agents including metformin, glimepiride, pioglitazone, and/or insulin (but not prandial insulin). Its use resulted in an improvement (lowering) of HbA1c (hemoglobin A1c, glycosylated hemoglobin) concentrations and fasting plasma glucose concentrations. In a study in which albiglutide was compared with liraglutide, the new drug provided less of an A1c reduction (0.8%) than liraglutide (1.0%), and the between-treatment difference did not meet the prespecified, noninferiority margin. Of the patients in the eight clinical trials, 19% were 65 years of age and older, and fewer than 3% were 75 years of age and older. No overall differences in safety or effectiveness were observed between these patients and younger patients. The limitations of use, warnings, and other risks associated with the use of albiglutide are generally similar to those for the other GLP-1 agonists. It is not indicated in the treatment of patients with type 1 diabetes or patients with diabetic ketoacidosis, and is not recommended as first-line therapy for patients inadequately controlled on diet and exercise. Albiglutide has not been studied in patients with severe gastrointestinal (GI) disease including severe gastroparesis, and its use is not recommended in patients with preexisting problems of this type. Acute pancreatitis has been infrequently experienced with the use of the GLP-1 agonists, including albiglutide, and treatment should be promptly discontinued if pancreatitis is suspected. Albiglutide was not studied in patients with a history of pancreatitis, and other antidiabetic agents should be considered in patients with a history of pancreatitis. There have been reports of thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in studies

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of GLP-1 agonists in rodents. Although it is not known whether albiglutide causes these tumors in humans, its use is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2, and these risks are also included in a boxed warning in its labeling. The adverse events most often reported in the clinical studies of albiglutide include upper respiratory tract infection (14%), diarrhea (13%), nausea (11%), and injection site reaction (11%). One patient experienced a serious hypersensitivity reaction, and treatment should be discontinued if such a response occurs. Many patients with diabetes are overweight, and some antidiabetic agents such as the sulfonylureas (e.g., glimepiride) have been associated with weight gain during treatment. Conversely, many patients treated with a GLP-1 agonist experience weight loss although, in the study in which albiglutide was compared with liraglutide, the weight loss from baseline to week 32 was less with the new drug (0.6 kg) than with liraglutide (2.2 kg). When used as monotherapy, albiglutide is not likely to cause hypoglycemia. However, there is an increased risk of this response when it is used in combination with an insulin secretagogue (e.g., a sulfonylurea) or insulin, and a reduction in dosage of the latter agents may be necessary. Because albiglutide causes a delay in gastric emptying, a potential exists for alteration of the absorption and activity of concomitantly administered oral medications. Although clinically important changes of this type were not identified in several studies that have been conducted, caution should be exercised when oral medications are used concurrently, particularly if their absorption is incomplete and/or not highly predictable when they are used alone. Following subcutaneous administration, maximum concentrations of albiglutide are reached at three to five days. As an albumin fusion protein, the expected metabolic pathway is degradation to small peptides and individual amino acids by proteolytic enzymes. It has an elimination half-life of approximately five days that makes it suitable for once-a-week administration. Dosage adjustment is not necessary in patients with impaired renal


function. However, the frequency of GI adverse events (e.g., nausea, vomiting, diarrhea, dehydration) has been reported to increase as renal function declines. Because these reactions may worsen renal function, caution should be exercised when initiating treatment or increasing the dosage of albiglutide in patients with renal impairment. Albiglutide is administered by subcutaneous injection in the abdomen, thigh, or upper arm region. The recommended dosage is 30 mg once a week on the same day each week. Doses may be administered at any time of the day without regard to meals. The dosage may be increased to 50 mg once a week if the glycemic response is not adequate. If a dose is missed, the patient should administer it as soon as possible within three days after the missed dose. Thereafter, doses should be administered on the usual day of administration. If it is more than three days after the missed dose, patients should wait until their next regularly scheduled weekly dose. Albiglutide for injection is supplied as a lyophilized powder in 30 mg and 50 mg doses in single-dose Pens (pen injectors) for reconstitution. Prior to dispensing, the Pens should be stored in the refrigerator. Following dispensing, the Pens may be stored at room temperature for up to four weeks prior to use. The product labeling should be consulted for information regarding reconstitution of the powder and administration of the injection. The diluent is supplied in the Pen and the cartridge on the Pen is turned to the position that permits mixing the diluent with the powder. The reconstituted solution should be administered within eight hours following preparation. The exenatide extended-release formulations for onceweekly administration also require reconstitution, whereas the formulations of exenatide and liraglutide are premixed. NDCR = 3 (no or minor advantage[s]/disadvantage[s]) Comparable drugs: Exenatide (Byetta), exenatide extended-release (Bydureon), liraglutide (Victoza)

Advantages • Less-frequent administration (once a week, compared with liraglutide [once a day] and exenatide [twice a day]; exenatide extended-release is also administered once a week)

Disadvantages • Less reduction in glycosylated hemoglobin (HbA1c) and fasting plasma glucose (compared with liraglutide; comparative studies with exenatide have not been conducted) • Less weight loss (compared with liraglutide) • More likely to cause injection-site reactions (compared with exenatide and liraglutide) • Formulation requires reconstitution (compared with exenatide and liraglutide; exenatide extended-release also requires reconstitution) In late 2014, dulaglutide (Trulicity) was approved and marketed as the fourth GLP-1 receptor agonist.

Bronchodilator3 Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the United States; cigarette smoking is the most common cause. The maintenance treatment of COPD often involves the use of a long-acting beta2-adrenergic agonist (LABA; i.e., salmeterol [Serevent], formoterol [Foradil], indacaterol [Arcapta], vilanterol [in combination with fluticasone - Breo Ellipta]) and/or a long-acting muscarinic antagonist (LAMA; i.e., tiotropium [Spiriva HandiHaler], aclidinium [Tudorza Pressair]) via oral inhalation. Both the LABAs and LAMAs provide a bronchodilating action, and an inhaled corticosteroid may also be added to the regimen.

Umeclidinium Bromide Umeclidinium bromide joins tiotropium and aclidinium in the group of LAMAs, also designated as long-acting anticholinergic or antimuscarinic agents. It was initially approved in a formulation with the LABA vilanterol trifenatate (Anoro Ellipta—GlaxoSmithKline), and is the first combination formulation to include both a LAMA and LABA. Therefore, patients who do not experience adequate benefit with the use of one inhaled bronchodilator can be treated with two bronchodilators with different mechanisms of action with one dose from the same delivery device. Although a combination formulation (Combivent Respimat) of ipratropium and albuterol is also available, these agents have a shorter duration of action and must be administered more frequently.


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The umeclidinium/vilanterol combination is administered by oral inhalation, and its specific indication is for the long-term, once-daily maintenance treatment of airflow obstruction in patients with COPD, including chronic bronchitis and/or emphysema. The effectiveness of the combination was demonstrated in studies in which the new formulation provided a larger increase in forced expiratory volume in the first second of expiration at 24 weeks than either of the individual components or placebo. The studies included 2,143 individuals 65 years of age and older, of whom 478 (22.3%) were 75 years of age and older. No overall differences in effectiveness or safety were observed between these patients and younger patients. The indication for tiotropium also includes use for reducing COPD exacerbations. However, this is not a labeled indication for umeclidinium/vilanterol or for aclidinium. The new combination formulation is not indicated for the relief of acute bronchospasm or in patients with acutely deteriorating COPD, or for the treatment of asthma. The risks and precautions with the use of umeclidinium/vilanterol are very similar to those of the other LAMAs and LABAs that are administered by oral inhalation. The product is contraindicated in patients with severe hypersensitivity to milk proteins or any other ingredients of the formulation. Paradoxical bronchospasm has been experienced infrequently, and treatment should be discontinued if this response occurs. Because of its anticholinergic action, umeclidinium may cause worsening of urinary retention or narrow-angle glaucoma, and patients should be advised to immediately consult their physician if signs or symptoms of these complications occur. The activity of umeclidinium may be increased by the use of other medications with anticholinergic activity (e.g., tolterodine [e.g., Detrol], diphenhydramine [e.g., Benadryl]), and the concurrent use of these agents should be avoided. Other precautions must also be observed because of the inclusion of vilanterol in the formulation. Like the other LABAs, its use is associated with an increased risk of asthma-related death, and this is the subject of a boxed warning in its labeling that also includes multiple observations that the new product is not indicated for

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the treatment of asthma. The beta2-agonists must also be used with caution in patients with cardiovascular (CV) disorders, convulsive disorders, thyrotoxicosis, and diabetes. The new product should not be used concurrently with another LABA because of the risk of an excessive response. A beta-adrenergic blocking agent can inhibit the bronchodilating action of vilanterol and may produce severe bronchospasm. Accordingly, concurrent use is best avoided. Vilanterol is a substrate for the CYP3A4 pathway, and its exposure and activity may be increased by the concurrent use of ketoconazole or another strong CYP3A4 inhibitor (e.g., clarithromycin). Caution must be exercised if a CYP3A4 inhibitor is used concomitantly with umeclidinium/vilanterol. The risk of CV adverse events may be increased by a monoamine oxidase inhibitor (MAOI) or tricyclic antidepressant. Their concurrent use with vilanterol or another beta-agonist is best avoided, but if treatment with the potentially interacting drugs is considered necessary, extreme caution must be exercised. The most commonly experienced adverse events in the clinical studies of umeclidinium/vilanterol include pharyngitis (2%), diarrhea (2%), and pain in extremity (2%). Following oral inhalation, both umeclidinium and vilanterol are mostly absorbed from the lung with minimum contribution from oral absorption. Umeclidinium is a substrate for the CYP2D6 metabolic pathway and the P-glycoprotein transporter. However, clinically important pharmacokinetic interactions involving umeclidinium are unlikely. Patients with impaired hepatic or renal function experience little change in exposure of umeclidinium. Umeclidinium bromide and vilanterol trifenatate are supplied in a plastic inhaler containing two double-foil blister strips, each with 30 blisters. An institutional pack containing 7 blisters per strip is also available. Each blister on one strip contains a powder mix that includes micronized umeclidinium bromide in an amount equivalent to 62.5 mcg of umeclidinium. Each blister on the other strip contains a powder mix that includes micronized vilanterol trifenatate in an amount equivalent to 25 mcg of vilanterol. When the inhaler is activated, the powder within both blisters is exposed and available for dispersion into the airstream created by the patient inhaling



through the mouthpiece. The powder mixes of the two drugs also include lactose monohydrate, which contains milk proteins. The recommended dosage of umeclidinium/vilanterol is one oral inhalation containing 62.5 mcg of umeclidinium and 25 mcg of vilanterol once a day. The product should be administered at the same time every day, and should not be used more than one time every 24 hours. The umeclidinium/vilanterol inhalation system is supplied in a moisture-protective foil tray and should only be removed from the tray immediately before initial use. The inhaler should be discarded when the dose counter reads “0” after all blisters have been used (presumably after 30 days when used once daily as recommended) or six weeks after opening the foil tray, whichever comes first. Subsequent to the approval of the combination of umeclidinium and vilanterol, FDA approved a formulation of umeclidinium as a single agent (Incruse Ellipta) for oral inhalation. Vilanterol continues to be available only in combination formulations (Anoro Ellipta and Breo Ellipta). NDCR = 4 (Significant advantages) Comparable drugs: Other LAMAs that are used as bronchodilators via oral inhalation: Aclidinium (Tudorza Pressair), tiotropium (Spiriva HandiHaler)

Advantages • Is the first combination formulation for oral inhalation that includes a LAMA and a LABA • More convenient administration and lesser likelihood of problems associated with administration (compared with tiotropium, which is supplied in capsules that are placed in a device for oral inhalation) • Is administered less frequently (compared with aclidinium, which is administered twice a day) Disadvantages • Indication does not include use to reduce exacerbations of COPD (whereas the labeled indication for tiotropium includes use to reduce exacerbations) • Umeclidinium is not available as a single agent (has been subsequently approved in a formulation as a single agent [Incruse Ellipta])

Antidepressant4 An estimated 14 million Americans are experiencing major depressive disorder (depression) with symptoms ranging from mild in severity to severe and disabling. The medications most often prescribed for the treatment of depression include the selective serotonin reuptake inhibitors (SSRIs; citalopram [e.g., Celexa], escitalopram [e.g., Lexapro], fluoxetine [e.g., Prozac], paroxetine [e.g., Paxil], sertraline [e.g., Zoloft]) and the serotonin norepinephrine reuptake inhibitors (SNRIs; duloxetine [Cymbalta], venlafaxine [e.g., Effexor], desvenlafaxine [Pristiq], levomilnacipran [Fetzima]). Vilazodone (Viibryd) was marketed in 2011, and this agent acts as a serotonin (5-HT) reuptake inhibitor and as a partial agonist at 5-HT1A receptors.

Vortioxetine Hydrobromide Vortioxetine hydrobromide (Brintellix – Lundbeck; Takeda) was marketed in late 2013, and its primary mechanism of antidepressant action is thought to be inhibition of serotonin reuptake. In addition, it acts as an agonist at 5-HT1A receptors, a partial agonist at 5-HT1B receptors, and an antagonist at 5-HT3, 5-HT1D, and 5-HT7 receptors. Although it is the only medication with this combination of actions at serotonin receptors, the contribution of any of these additional actions to the antidepressant effect of the drug has not been established and the clinical relevance is unknown. Vortioxetine is indicated for the treatment of patients with depression, and its effectiveness has been demonstrated in six placebo-controlled, short-term (6 to 8 weeks) clinical studies, one of which was conducted in elderly patients. No overall differences in effectiveness or safety were observed between elderly and younger patients, and dosage adjustment is not necessary on the basis of age. Vortioxetine was also evaluated in a long-term (24 to 64 weeks) maintenance study in which its use resulted in a statistically significant longer time to recurrence of depressive episodes, compared with placebo. Although duloxetine was used as an active comparator in several studies, there are insufficient data to compare the effectiveness of vortioxetine and duloxetine, and there are no data that suggest that the new drug is more effective than other


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antidepressants. However, some patients have not experienced sufficient benefit with the use of one or more other antidepressants, and the potential exists for vortioxetine to be effective in some patients who have not experienced an adequate response with other agents. Most antidepressants have been approved for other indications in addition to depression. Although vortioxetine is being evaluated in patients with generalized anxiety disorder, as well as its potential to improve cognitive function, these are not labeled indications at the present time. The drug-related problems, warnings, and precautions associated with the use of vortioxetine are generally similar to those for the serotonin reuptake inhibitors. The labeling for each of these agents includes a boxed warning regarding the increased risk of suicidal thinking and behavior in children, adolescents, and young adults (ages 18 to 24 years). Depression itself is associated with an increased risk of suicide, and all patients being treated with an antidepressant should be closely observed for clinical worsening, suicidality, or unusual changes in behavior. The use of an MAOI (e.g., tranylcypromine) for the treatment of a psychiatric disorder with or within 21 days after stopping treatment with vortioxetine is contraindicated because of an increased risk of serotonin syndrome. The use of vortioxetine within 14 days of stopping treatment with an MAOI is also contraindicated. The concurrent use of vortioxetine with other MAOIs such as linezolid (Zyvox) or intravenous methylene blue is also contraindicated because of the risk of serotonin syndrome. Because treatment with linezolid or intravenous methylene blue must sometimes be initiated on an urgent basis, patients being treated with vortioxetine should promptly stop treatment with the antidepressant, and linezolid or methylene blue can then be administered with monitoring for symptoms of serotonin syndrome for 21 days or until 24 hours after the last dose of the MAOI, whichever comes first. The risk of serotonin syndrome is also increased by the concurrent use of vortioxetine and other agents having serotonergic activity (e.g., SSRIs, SNRIs, tricyclic antidepressants, triptans, tramadol, tryptophan, fentanyl, lithium, buspirone, St. John’s wort). In patients in whom the use of such combinations is clinically warranted, treatment

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must be closely monitored. If symptoms suggestive of serotonin syndrome occur (e.g., mental status changes [e.g., agitation, hallucinations], autonomic instability [e.g., tachycardia, dizziness, flushing], neuromuscular effects [e.g., tremor, rigidity, incoordination], seizures, GI symptoms), treatment should be discontinued. The use of vortioxetine and other serotonergic antidepressants has been associated with the activation of mania/hypomania and the occurrence of hyponatremia and abnormal bleeding. The risk of bleeding is increased in patients who are also being treated with an anticoagulant, aspirin, or a nonsteroidal anti-inflammatory drug, and patients should be cautioned regarding this possibility. The adverse events experienced most often in the clinical studies of vortioxetine (and their incidence in patients treated with a dosage of 20 mg a day) include nausea (32%), vomiting (6%), dizziness (9%), and constipation (6%). Sexual dysfunction was reported in 5% of the patients treated with the new drug, compared with 2% of those receiving placebo. Treatment was discontinued because of an adverse event in 8% of the patients treated with vortioxetine (20 mg a day), most often as a result of nausea, compared with 4% of those receiving placebo. Vortioxetine was not observed to have any significant effect on body weight. Because vortioxetine may cause central nervous system effects (e.g., dizziness), patients should not engage in activities such as driving or operating machinery until they have determined how the medication may affect their alertness and judgment. The Medication Guide for vortioxetine includes a recommendation that patients avoid drinking alcohol while taking the drug. However, the labeling includes the results of a clinical study in which a single dose of 20 mg or 40 mg of vortioxetine did not increase the impairment of mental and motor skills caused by alcohol (single dose of 0.6 g/kg). Following oral administration, the absolute bioavailability of vortioxetine is 75%. The consumption of food does not significantly affect its bioavailability, and it may be administered without regard to meals. The new drug is extensively metabolized, primarily via the CYP2D6 pathway, to a pharmacologically inactive metabolite.


Most of a dose is eliminated in the urine as metabolites. Adjustment of dosage is not necessary in patients with renal impairment or in patients with mild or moderate hepatic impairment. Vortioxetine has not been studied in patients with severe hepatic impairment. The concurrent use of a strong CYP2D6 inhibitor (e.g., bupropion, fluoxetine, paroxetine, quinidine) may increase the action of vortioxetine, and a reduction in dosage of the latter agent by one-half is recommended. Conversely, the action of vortioxetine may be reduced by the concomitant use of a strong CYP inducer (e.g., carbamazepine, phenytoin, rifampin), and an increase in dosage of the antidepressant should be considered, but not to exceed three times the initial dosage. The recommended starting dosage of vortioxetine is 10 mg once a day. The dosage should be subsequently increased to 20 mg once a day, as tolerated. For patients who do not tolerate a higher dosage, a reduction in dosage to 5 mg once a day may be considered. In patients who are known poor CYP2D6 metabolizers, the maximum recommended dosage is 10 mg once a day. The dosage should be reduced by one-half in patients who are also being treated with a strong CYP2D6 inhibitor. If a strong CYP inducer is used concurrently for more than 14 days, an increased dosage of vortioxetine should be considered. Although treatment with vortioxetine can be abruptly discontinued, some patients in the clinical studies experienced transient adverse events (e.g., headache, muscle tension) when higher dosages (15 mg or 20 mg a day) were abruptly discontinued. Accordingly, it is recommended that the dosage be reduced to 10 mg once a day for one week before full discontinuation of treatment with higher dosages. Vortioxetine hydrobromide is supplied in tablets in amounts equivalent to 5 mg, 10 mg, 15 mg, and 20 mg of vortioxetine. NDCR = 3 (No or minor advantage[s]/disadvantage[s]) Comparable drugs: Other drugs that inhibit serotonin reuptake (e.g., SSRIs; escitalopram [e.g., Lexapro] is the specific agent to which comparisons are made)

Advantages • In addition to inhibiting serotonin reuptake, has a unique combination of actions on multiple serotonin receptor types • May be more effective in some patients (however, the contribution of its additional actions on serotonin receptors has not been established and the clinical relevance is not known) • May be less likely to cause sexual dysfunction Disadvantages • Has not been directly compared with other antidepressants in clinical studies • Labeled indications are more limited (escitalopram is also indicated for the treatment of generalized anxiety disorder, and fluoxetine, paroxetine, and sertraline have multiple additional labeled indications) • Has not been evaluated in patients younger than 18 years of age (whereas escitalopram is indicated in the treatment of depression in adolescent patients aged 12 to 17 years) • Interacts with CYP2D6 inhibitors (e.g., quinidine) and CYP inducers (e.g., carbamazepine) • Dosage titration is needed

Agent for Erectile Dysfunction5 Avanafil Avanafil (Stendra—Auxilium; Vivus) is the fourth phosphodiesterase type 5 (PDE5) inhibitor to be approved for the treatment of erectile dysfunction, joining sildenafil (Viagra), tadalafil (Cialis), and vardenafil (Levitra, Staxyn). The physiologic mechanism of erection of the penis involves release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. NO then activates the enzyme guanylate cyclase that results in increased concentrations of cyclic guanosine monophosphate (cGMP), producing smooth muscle relaxation in the corpus cavernosum and allowing increased blood flow into the penis and erection. PDE5 is responsible for degradation of cGMP in the corpus cavernosum, and the inhibition of PDE5 enhances the effect of NO. Because


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sexual stimulation is required to initiate the local release of NO, the inhibition of PDE5 has no effect in the absence of sexual stimulation. Each of the PDE5 inhibitors has been demonstrated to be significantly more effective than placebo in the treatment of erectile dysfunction in clinical trials. Men who have experienced benefit with the use of these agents include those with diseases or clinical situations associated with a higher frequency of erectile dysfunction (e.g., diabetes, radical prostatectomy). The PDE5 inhibitors have not been directly compared with each other, but they appear to be similar in efficacy. Preference for one of these agents sometimes will be based on its onset of action or duration of action. Tadalafil has a longer duration of action and more dosage/treatment options, which may be an advantage in permitting greater spontaneity in facilitating intercourse. However, it has a slower onset of action than the other agents. Avanafil appears to have a faster onset of action than the other agents and most patients can take the new drug approximately 15 minutes before sexual activity. Sildenafil and vardenafil are usually taken approximately 60 minutes before sexual activity. In the clinical studies of avanafil, approximately 23% of the participants were 65 years of age and older. No overall differences in efficacy or safety were observed between individuals compared with younger subjects. The PDE5 inhibitors are used on an as-needed basis for the treatment of erectile dysfunction. However, tadalafil is also used in a lower dosage once a day without regard to timing of sexual activity. Tadalafil is also indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH), as well as for the treatment of both BPH and erectile dysfunction. Erectile dysfunction is the only labeled indication for avanafil at the present time. The risks and adverse events associated with the use of avanafil are generally similar to those for sildenafil, tadalafil, and vardenafil. As with the other PDE5 inhibitors, the use of avanafil with any form of an organic nitrate (e.g., nitroglycerin), either regularly and/or intermittently, is contraindicated because it may potentiate the hypotensive effects of nitrates. If a nitrate is considered necessary in a life-threatening situation, at least 12 hours should

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elapse after a dose of avanafil before nitrate administration is considered. If a nitrate is used in these circumstances, it should be administered under close medical supervision with appropriate hemodynamic monitoring. The PDE5 inhibitors exhibit a vasodilating action and can also increase the blood pressure-lowering effect of alpha-adrenergic blocking agents (e.g., tamsulosin), as well as other antihypertensive agents. In patients who are stabilized on alpha-blocker therapy, the use of a PDE5 inhibitor should be initiated at the lowest dose (i.e., 50 mg of avanafil). In patients already using a PDE5 inhibitor, treatment with an alpha-blocker should be initiated at the lowest dose. Alcohol also has a vasodilating action and patients should be advised that substantial consumption of alcoholic beverages (e.g., greater than 3 units [i.e., glasses of wine, shots of whiskey]) in combination with avanafil may increase the potential for orthostatic signs and symptoms (e.g., decrease in standing blood pressure, dizziness). Because of a potential for cardiac risk during sexual activity in patients with preexisting CV disease, avanafil should not be used in men for whom sexual activity is inadvisable because of their underlying CV status. The clinical studies of avanafil did not include patients who had suffered an acute myocardial infarction, stroke, life-threatening arrhythmia, or coronary revascularization during the last six months, patients with resting hypotension (blood pressure less than 90/50 mmHg) or hypertension (greater than 170/100 mmHg), or patients with unstable angina. The use of the PDE5 inhibitors has been infrequently associated with prolonged erection greater than four hours and priapism (painful erections greater than six hours in duration). If an erection persists for longer than four hours, the patient should seek immediate medical assistance. Avanafil and the other PDE5 inhibitors should be used with caution in patients who have conditions that may predispose them to priapism (e.g., sickle cell anemia, multiple myeloma) or who have anatomical deformation of the penis (e.g., Peyronie’s disease). There have been rare occurrences of a sudden loss of vision in one or both eyes in patients treated with a PDE5 inhibitor, and this may be a sign of nonarteritic anterior


ischemic optic neuropathy, which has been reported in temporal association with the use of these agents. Patients who experience such a reaction should discontinue use of the drug and seek medical attention. The PDE5 inhibitors have also been associated with a sudden decrease or loss of hearing, which may be accompanied by tinnitus or dizziness. If this occurs, the drug should be discontinued and medical attention sought. The most commonly experienced adverse events (and their incidence with a dose of 100 mg) in the clinical studies of avanafil include headache (7%), flushing (4%), nasal congestion (3%), nasopharyngitis (3%), and back pain (2%). Hypersensitivity reactions (pruritus, eyelid swelling) have been reported with avanafil and it is contraindicated in patients with a known hypersensitivity to any component of the tablet formulation. The safety of the new drug in patients with bleeding disorders or active peptic ulceration is not known. Following oral administration, avanafil is rapidly absorbed and the maximum concentration is usually attained in 30 to 45 minutes when administered in the fasting state. Although consumption of a high-fat meal may reduce the rate of absorption, it may be administered without regard to food. It is extensively metabolized in the liver, primarily via the CYP3A4 pathway, and its metabolites have weak or no pharmacologic activity. Avanafil is excreted as metabolites predominantly in the feces (approximately 62% of a dose) and to a lesser extent in the urine (approximately 21%). Dosage adjustment is not necessary in patients with mild-to-moderate hepatic impairment or mild-to-moderate renal impairment. However, it has not been studied in patients with severe hepatic or renal impairment and is not recommended for use in these patients. The action of avanafil is increased by the concurrent use of a CYP3A4 inhibitor. Its use should be avoided in patients being treated with a strong CYP3A4 inhibitor (e.g., clarithromycin, itraconazole, ritonavir). In patients being treated with a moderate CYP3A4 inhibitor (e.g., diltiazem, fluconazole, verapamil), the maximum recommended dose of avanafil is 50 mg and it should not be used more than once every 24 hours.

The recommended starting dose of avanafil is 100 mg and, when it was initially approved, it was recommended that it be taken as needed approximately 30 minutes before sexual activity. The consideration of additional studies has resulted in a revision of this recommendation so that it now indicates that the drug can be taken approximately 15 minutes before sexual activity. Based on individual efficacy and tolerability, the dose may be increased to a maximum dose of 200 mg or reduced to 50 mg. The maximum recommended dosing frequency is once a day. Avanafil tablets are supplied in 50 mg, 100 mg, and 200 mg potencies. NDCR = 3 (no or minor advantage[s]/disadvantage[s]) Comparable drugs: Sildenafil (Viagra), tadalafil (Cialis), vardenafil (Levitra, Staxyn)

Advantages • May have a faster onset of action (is administered approximately 15 minutes before sexual activity, whereas sildenafil and vardenafil are usually taken approximately 60 minutes before sexual activity) • Less risk of problems associated with QT-interval prolongation (compared with vardenafil) • Dosage adjustment is not needed in patients with mild-to-moderate hepatic impairment (compared with sildenafil and tadalafil, with which dosage adjustment may be needed) Disadvantages • Labeled indications are more limited (compared with tadalafil, which is also indicated for use once a day in a lower dosage for erectile dysfunction, and for the treatment of BPH) • Has a shorter duration of action (compared with tadalafil) • Use is not recommended in patients with severe renal impairment (whereas comparable drugs can be used with dosage adjustments and/or appropriate precautions)


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Agent for Menopause-Associated Conditions6 There are approximately 33 million women in the United States between the ages of 45 and 59, and the average age of menopause in this country is 51. Menopause is associated with reduced functioning of the ovaries during aging that results in lower concentrations of estrogens and other hormones. The reduction of estrogen concentrations is often accompanied by moderate-to-severe vasomotor symptoms (hot flashes), and followed by bone loss and an increased risk of osteoporosis. Approximately 50% of women in the United States 50 years of age or older have low bone mass that places them at higher risk for osteoporosis. Estrogens have been used for more than 60 years as a hormonal replacement therapy to manage menopausal symptoms. Although estrogen is effective in reducing menopausal symptoms, when used alone it increases the risk of endometrial hyperplasia that may be a precursor to endometrial cancer. To reduce this risk of endometrial problems, a progestin has been used in combination with an estrogen.

Conjugated Estrogens and Bazedoxifene Acetate A combination of conjugated estrogens and bazedoxifene acetate (Duavee—Pfizer) has recently been approved for the treatment of menopause-associated conditions. Products containing conjugated estrogens (e.g., Premarin) have been available for decades, but bazedoxifene is a new therapeutic agent. Bazedoxifene is an estrogen agonist/ antagonist, also designated as a selective estrogen receptor modulator, which activates estrogen receptors in some tissues while inhibiting estrogen activity in others (e.g., the uterus). The combination product is the first to be approved that includes an estrogen agonist/antagonist instead of a progestin to reduce the risk of endometrial hyperplasia associated with the use of estrogen alone for the treatment of menopause-associated conditions. The combination of conjugated estrogens and bazedoxifene is specifically indicated in women with a uterus for the treatment of moderate-to-severe vasomotor symptoms associated with menopause, and for the prevention of postmenopausal osteoporosis. As with other products

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containing estrogen, conjugated estrogens/bazedoxifene should be used for the shortest duration consistent with treatment goals and risks for the individual woman. When treatment is considered solely for the prevention of postmenopausal osteoporosis, the new product should only be used in women at significant risk of osteoporosis, and nonestrogen medication should be carefully considered. The effectiveness of conjugated estrogens/bazedoxifene in the treatment of vasomotor symptoms was demonstrated in a placebo-controlled study in which the new product significantly reduced the number and severity of hot flashes. In studies in which the new product was evaluated for the prevention of postmenopausal osteoporosis, it significantly increased lumbar spine bone mineral density and total hip bone mineral density. Approximately 5% of the women in the clinical studies were 65 years of age or older. No overall differences in effectiveness or safety were observed between women 65 to 74 years of age and younger women. The product was not studied in women 75 years of age and older, and it is not recommended for use in women in this age group. Bazedoxifene joins several other agents that are classified as estrogen agonist/antagonists and that are indicated for use in postmenopausal women. Raloxifene (Evista) is indicated for the treatment and prevention of osteoporosis, and for the reduction in risk of invasive breast cancer in postmenopausal women with osteoporosis or who are at high risk for invasive breast cancer. Ospemifene (Osphena) was marketed in 2013 for the treatment of moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy, as a result of menopause. The most commonly experienced adverse events in the placebo-controlled trials of conjugated estrogens/ bazedoxifene include muscle spasms (8%), nausea (8%), diarrhea (8%), dyspepsia (7%), upper abdominal pain (7%), oropharyngeal pain (7%), neck pain (5%), and dizziness (5%). The contraindications and other risks associated with the use of the conjugated estrogens/bazedoxifene combination include potential problems that could result from the use of estrogen alone (i.e., the conjugated estrogens component of the combination product). The new


product is contraindicated in patients with undiagnosed abnormal uterine bleeding; known, suspected, or past history of breast cancer; known or suspected estrogendependent neoplasia; active or past history of venous or arterial thromboembolism; known protein C, protein S, or antithrombin deficiency or other known thrombophilic disorder; known hepatic impairment or disease; and those who are hypersensitive to any component of the product. The product is classified in Pregnancy Category X and is contraindicated in women who are pregnant or who may become pregnant. Studies that have evaluated estrogen-alone treatment have reported increased risks of stroke and deep vein thrombosis, as well as probable dementia in postmenopausal women 65 years of age and older, and these concerns are included as boxed warnings in the labeling for the conjugated estrogens/bazedoxifene combination. There are also boxed warnings in the labeling that estrogen therapy should not be used for the prevention of CV disease or dementia and that there is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogen. Estrogen therapy has also been associated with an increased risk of CV disorders, hypertriglyceridemia, gallbladder disease, visual abnormalities, and hypothyroidism. Thyroid function should be monitored as women who are being treated with thyroid replacement therapy who are also receiving estrogens may require increased doses of thyroid-replacement therapy. Women for whom the conjugated estrogens/bazedoxifene combination is prescribed should not take additional estrogens or estrogen agonist/ antagonists, or progestins. Following oral administration, conjugated estrogens are well absorbed, but the absolute bioavailability of bazedoxifene is approximately 6%. Estrogens are partially metabolized via the CYP3A4 pathway, whereas bazedoxifene undergoes metabolism by UGT enzymes in the intestinal tract and liver. The conjugated estrogen components are excreted in the urine, and bazedoxifene is primarily eliminated via biliary excretion, followed by elimination in the feces. The product has not been studied in women with renal impairment or women older

than 75 years of age, and its use is not recommended in these patients. The concurrent use of a CYP3A4 inhibitor (e.g., clarithromycin, itraconazole, grapefruit juice) may increase the exposure of conjugated estrogens, and CYP3A4 inducers (e.g., carbamazepine, rifampin, St. John’s wort) may reduce plasma concentrations of estrogens. Inducers of UGTs (e.g., carbamazepine, rifampin) may increase the metabolism of bazedoxifene and reduce its exposure. Duavee tablets each contain 0.45 mg of conjugated estrogens and a quantity of bazedoxifene acetate equivalent to 20 mg of bazedoxifene. The recommended dosage is one tablet daily. In women who are taking the product for the prevention of postmenopausal osteoporosis, supplemental calcium and/or vitamin D should be taken if daily intake is not adequate. NDCR = 4 (Significant advantages) Comparable drug: Raloxifene (Evista)

Advantages • Labeled indications include treatment of vasomotor symptoms associated with menopause • Is the only combination formulation with an estrogen agonist/antagonist and estrogen Disadvantages • Labeled indication for postmenopausal osteoporosis is limited to prevention (whereas the indication for raloxifene also includes treatment) • Labeled indications do not include a reduction in risk of invasive breast cancer • Labeling includes a boxed warning regarding an increased risk of endometrial cancer • Bazedoxifene is only available in a fixed-dose combination product and not as a single agent


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Daniel A. Hussar, PhD, is the Remington Professor of Pharmacy at the Philadelphia College of Pharmacy at the University of the Sciences in Philadelphia, Philadelphia, Pennsylvania. For correspondence: Daniel A. Hussar, PhD, Philadelphia College of Pharmacy at the University of the Sciences in Philadelphia, 600 South 43rd Street, Philadelphia, PA 19104-4495; Phone: 215-596-8880; Fax: 215-596-8685; E-mail: [email protected]. Acknowledgement: This paper is based on a presentation at the American Society of Consultant Pharmacists’ Annual Meeting in Orlando, Florida, November 2014. Some of the content of the paper is adapted from works previously published in the Journal of the American Pharmacists Association and Pharmacy Today. Disclosure: No funding was received for the development of this manuscript. The author has no potential conflicts of interest. Consult Pharm 2015;30:192-208. © 2015 American Society of Consultant Pharmacists, Inc. All rights reserved. Doi:10.4140/TCP.n.2015.192.

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