The Medical Letter ® On Drugs and Therapeutics Published by The Medical Letter, Inc • 145 Huguenot Street, New Rochelle, NY 10801 • A Nonprofit Publication IN THIS ISSUE (starts on next page) Conjugated Estrogens/Bazedoxifene (Duavee) for Menopausal Symptoms and Prevention of Osteoporosis p 33 Tasimelteon (Hetlioz) for Non-24-Hour Sleep-Wake Disorder p 34 In Brief: Enteric-Coated Aspirin as an Antiplatelet Drug p 36 Important Copyright Message The Medical Letter® publications are protected by US and international copyright laws Forwarding, copying or any distribution of this material is prohibited Sharing a password with a non-subscriber or otherwise making the contents of this site available to third parties is strictly prohibited By accessing and reading the attached content I agree to comply with US and international copyright laws and these terms and conditions of The Medical Letter, Inc For further information click: Subscriptions, Site Licenses, Reprints or call customer service at: 800-211-2769 FORWARDING OR COPYING IS A VIOLATION OF U.S AND INTERNATIONAL COPYRIGHT LAWS The Medical Letter publications are protected by US and international copyright laws Forwarding, copying or any other distribution of this material is strictly prohibited For further information call: 800-211-2769 The Medical Letter ® On Drugs and Therapeutics Published by The Medical Letter, Inc • 145 Huguenot Street, New Rochelle, NY 10801 • A Nonprofit Publication Volume 56 (Issue 1441) April 28, 2014 ALSO IN THIS ISSUE Tasimelteon (Hetlioz) for Non-24-Hour Sleep-Wake Disorder p 34 In Brief: Enteric-Coated Aspirin as an Antiplatelet Drug p 36 Conjugated Estrogens/Bazedoxifene (Duavee) for Menopausal Symptoms and Prevention of Osteoporosis The FDA has approved Duavee (Pfizer), a fixeddose combination of conjugated estrogens and the new selective estrogen receptor modulator (SERM) bazedoxifene, for treatment of moderate to severe vasomotor symptoms and for prevention of osteoporosis in postmenopausal women with an intact uterus Bazedoxifene is an estrogen agonist/antagonist with estrogen-like effects on bone and antiestrogen effects on the uterus It is the second SERM to be approved for prevention of osteoporosis; raloxifene (Evista, and generics) has been available as a single agent for this indication since 1997 HORMONAL THERAPY — Systemic estrogen is the most effective treatment for menopausal vasomotor symptoms; it decreases hot flushes by 50-100% within weeks.1 However, women with an intact uterus who take systemic estrogen are advised to also take an oral progestin to reduce the risk of developing endometrial hyperplasia or adenocarcinoma, and progestins can cause irregular vaginal bleeding, increases in breast density, and breast pain Moreover, the Women’s Health Initiative found that women 50-79 years old who took conjugated equine estrogens 0.625 mg plus medroxyprogesterone acetate 2.5 mg (Prempro) for >5 years were at increased risk for coronary heart disease, stroke, venous thromboembolism, and breast cancer.2,3 Estrogen alone, which was assigned to women without a uterus, did not increase the risk of coronary heart disease or (at years) breast cancer www.medicalletter.org Take CME Exams Conjugated estrogens with or without the progestin reduced the incidence of fractures MECHANISM OF ACTION — In vitro and in vivo studies have demonstrated that bazedoxifene inhibits the stimulating effect of conjugated estrogens on endometrial and breast tissue, but not the positive effects on vasomotor symptoms, vulvovaginal atrophy, or bone mineral density.4 Table Pharmacology Conjugated Estrogens Bazedoxifene Drug class Estrogens Estrogen agonist/ antagonist Route Oral Oral Tmax 6.5 hrs (estrone) 2.5 hrs Metabolism Primarily hepatic, partly by CYP3A4 Primarily glucuronidation Elimination Mainly in urine Feces (~85%); urine (1%) Half-life 17 hrs (estrone) 30 hrs CLINICAL STUDIES — A 12-week, randomized, double-blind trial in 332 postmenopausal women 40-65 years old with an intact uterus and >7 moderate to severe hot flushes daily compared conjugated estrogens 0.45 mg/bazedoxifene 20 mg and conjugated estrogens 0.625 mg/bazedoxifene 20 mg to placebo By week 4, the active drugs had reduced the average daily number of hot flushes by 5.9 per day, significantly more than the 2.8-reduction with placebo, and also had significantly reduced their severity At week 12, patients treated with the drug combinations still reported significantly fewer and less severe hot flushes than those who were taking placebo.5 Two larger clinical trials evaluated the efficacy of conjugated estrogens/bazedoxifene in preventing postmenopausal osteoporosis A 24-month, randomized, double-blind trial in 3397 postmenopausal women 40-75 years old with an intact uterus compared various doses of bazedoxifene combined with either 0.45 mg or 0.625 mg of conjugated estrogens to placebo, using FORWARDING OR COPYING IS A VIOLATION OF U.S AND INTERNATIONAL COPYRIGHT LAWS 33 raloxifene 60 mg as an active comparator At both 12 months and 24 months, 0.45 mg of conjugated estrogens combined with bazedoxifene 20 mg had increased lumbar spine and total hip bone mineral density significantly more than placebo or raloxifene.6 The second clinical trial evaluating the efficacy of the combination for prevention of osteoporosis was a 12-month trial in 1843 postmenopausal women 40-65 years old with an intact uterus that compared conjugated estrogens 0.45 mg/bazedoxifene 20 mg and conjugated estrogens 0.625 mg/bazedoxifene 20 mg to conjugated estrogens 0.45 mg/medroxyprogesterone acetate 1.5 mg (Prempro), bazedoxifene 20 mg alone, and placebo The conjugated estrogens 0.45 mg/ bazedoxifene 20 mg combination increased lumbar spine and total hip bone mineral density significantly more than placebo The increase in lumbar spine bone mineral density at 12 months was significantly greater with Prempro than with conjugated estrogens 0.45 mg/bazedoxifene 20 mg The increase in total hip bone mineral density was about the same with both treatments.7 A randomized, placebo-controlled, 5-year trial found that bazedoxifene 20 mg alone significantly decreased the risk of vertebral fractures in postmenopausal women.8 Duavee was not approved by the FDA for treatment of vulvovaginal atrophy or dyspareunia ADVERSE EFFECTS — In clinical trials of conjugated estrogens/bazedoxifene, the combination did not cause vaginal bleeding, increase breast density, or cause breast pain The effects of the new combination on the endometrium were similar to those with placebo The incidence of breast cancer, endometrial cancer, ovarian cancer, venous thromboembolism, stroke, myocardial infarction, and death from any cause in clinical trials was 0%, or close to it, with both conjugated estrogens/ bazedoxifene and placebo The long-term risk of venous thromboembolism and ischemic stroke with the new combination remains to be determined DRUG INTERACTIONS — Estrogens are metabolized partly by CYP3A4; concurrent administration of a CYP3A4 inhibitor or inducer could, respectively, increase or decrease serum concentrations of the hormone.9 Increases in estrogen serum concentrations could increase the risks associated with estrogen therapy, including venous thromboembolism Bazedoxifene is metabolized by uridine diphosphate glucuronosyltransferase (UGT) enzymes; UGT inducers such as rifampin could reduce serum concentrations of bazedoxifene, increasing the risk of endometrial hyperplasia 34 DOSAGE AND COST — Each Duavee tablet contains 0.45 mg of conjugated estrogens and 20 mg of bazedoxifene The recommended dosage for treatment of vasomotor symptoms or prevention of osteoporosis is one tablet daily Thirty Duavee tablets cost $111.40, compared to $198.00 for 30 tablets of Evista (60 mg) and $103.90 for 28 tablets of Prempro (0.45 mg/1.5 mg).10 CONCLUSION — The combination of conjugated estrogens with the estrogen agonist/antagonist bazedoxifene (Duavee) is effective for treatment of menopausal vasomotor symptoms and prevention of postmenopausal osteoporosis, without the short-term adverse effects of estrogen/progestin combinations Its long-term safety is unknown; venous thromboembolism and stroke could occur □ Drugs for menopausal symptoms Med Lett Drugs Ther 2012; 54:41 JE Rossouw et al Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial JAMA 2002; 288:321 JE Manson et al Estrogen plus progestin and the risk of coronary heart disease N Engl J Med 2003; 349:523 S Mirkin and BS Komm Tissue-selective estrogen complexes for postmenopausal women Maturitas 2013; 76:213 JV Pinkerton et al Relief of vasomotor symptoms with the tissueselective estrogen complex containing bazedoxifene/conjugated estrogens: a randomized, controlled trial Menopause 2009; 16:1116 R Lindsay et al Efficacy of tissue-selective estrogen complex of bazedoxifene/conjugated estrogens for osteoporosis prevention in at-risk postmenopausal women Fertil Steril 2009; 92:1045 JV Pinkerton et al Effects of bazedoxifene/conjugated estrogens on the endometrium and bone: a randomized trial J Clin Endocrinol Metab 2014; 99:E189 SL Silverman et al Sustained efficacy and safety of bazedoxifene in preventing fractures in postmenopausal women with osteoporosis: results of a 5-year, randomized, placebo-controlled study Osteoporos Int 2012; 23:351 Inhibitors and inducers of CYP enzymes and P-glycoprotein Med Lett Drugs Ther 2013; 55:e44 10 Approximate wholesale acquisition cost (WAC) Source: Analy$ource® Monthly (Selected from FDB MedKnowledge™) April 5, 2014 Reprinted with permission by FDB, Inc All rights reserved ©2014 www.fdbhealth.com/policies/drug-pricing-policy Actual retail prices may be higher Tasimelteon (Hetlioz) for Non-24-Hour Sleep-Wake Disorder The FDA has approved the melatonin receptor agonist tasimelteon (Hetlioz – Vanda) for treatment of non-24hour sleep-wake disorder (non-24), which is common in totally blind persons Tasimelteon is the first drug approved for this indication and the second melatonin receptor agonist approved for use in the US; ramelteon (Rozerem) was approved earlier for treatment of insomnia.1 Melatonin itself has not been approved by the FDA for any indication; it is available in the US as a dietary supplement and is promoted as a sleep aid.2 The Medical Letter • Volume 56 • Issue 1441 • April 28, 2014 NON-24 — The intrinsic period of circadian rhythms is typically slightly longer than 24 hours In sighted persons, the light-dark cycle is the main signal that resets the circadian timing system every 24 hours In totally blind persons, the absence of light permits the circadian cycle to run longer than 24 hours, causing disruption of nighttime sleep and increased daytime sleepiness Administration of exogenous melatonin has been tried in the treatment of non-24, with some success.3 MECHANISM OF ACTION — Melatonin acts on two receptors in the suprachiasmatic nucleus of the hypothalamus (MT1 and MT2) to affect both sleep and circadian rhythms.4 How it does so is not fully understood, but it may act as a physiological signal of darkness; in sighted persons, melatonin is secreted into the bloodstream during the night, and its secretion is suppressed by light The MT1 receptor appears to be more important in sleep-related effects, and the MT2 receptor may mediate the phase-shifting effects of melatonin Melatonin receptor agonists may have higher binding affinities for these receptors than melatonin itself Ramelteon has a stronger affinity for MT1 and tasimelteon has a stronger affinity for MT2 CLINICAL STUDIES — According to the manufacturer, it can take weeks or months of daily use of tasimelteon before the patient experiences any benefit FDA approval of the drug was based on unpublished, randomized, double-masked, placebo-controlled clinical trials in totally blind adults with non-24 Tasimelteon 20 mg was administered one hour before bedtime at the same time each night The SET (Safety and Efficacy of Tasimelteon) trial in 84 patients with non-24 compared tasimelteon and placebo for months Significantly more tasimelteontreated patients (20% vs 3%) achieved entrainment (synchronization) of the circadian rhythm as measured by urine levels of a melatonin metabolite Mean total nighttime sleep was 28 minutes longer and daytime nap time was 27 minutes shorter in patients taking tasimelteon than in patients taking placebo.5 In the RESET (Randomized Withdrawal Study of the Efficacy and Safety of Tasimelteon) trial, 20 patients who were entrained after a 3-month open-label run-in phase were randomized to tasimelteon or placebo for months Entrainment was maintained in 90% of tasimelteontreated patients compared to 20% of those in the placebo group Mean total nighttime sleep was 67 minutes longer and daytime nap time was 59 minutes shorter in patients taking tasimelteon than in patients taking placebo.6 In a double-blind, placebo-controlled trial in 411 healthy persons with transient insomnia induced by shifting their sleep-wake schedule, tasimelteon given 30 minutes before bedtime improved sleep.7 ADVERSE EFFECTS — In the 6-month clinical trial, the most common adverse effects of tasimelteon were headache (17%), elevated aminotransferases (10%), and nightmares or unusual dreams (10%) Serum concentrations of tasimelteon are 2-fold higher in patients >65 years old, which might increase the risk of adverse effects DRUG INTERACTIONS — Strong CYP1A2 and CYP3A4 inhibitors can increase serum concentrations of tasimelteon, and strong inducers such as rifampin can reduce them.8 Tasimelteon should not be used with strong CYP1A2 inhibitors or strong CYP3A4 inducers Smoking moderately induces CYP1A2, which may reduce the efficacy of tasimelteon DOSAGE, ADMINISTRATION AND COST — The recommended dosage of tasimelteon is one 20-mg capsule taken without food before bedtime at the same time each night Tasimelteon should not be used in patients with severe hepatic impairment The cost of 30 capsules of Hetlioz is $7020.9 CONCLUSION — The melatonin receptor agonist tasimelteon (Hetlioz) taken once each night, at the cost of more than $200 per capsule, can improve non-24-hour sleep-wake disorder (non-24) in totally blind patients How it compares with ramelteon (Rozerem), which costs much less, or melatonin itself in treating non-24 or other sleep disorders remains to be established □ Ramelteon (Rozerem) for insomnia Med Lett Drugs Ther 2005; 47:89 Drugs for insomnia Treat Guidel Med Lett 2012; 10:57 RL Sack et al Circadian rhythm sleep disorders: part II, advanced sleep phase disorder, delayed sleep phase disorder, free-running disorder, and irregular sleep-wake rhythm An American Academy of Sleep Medicine review Sleep 2007; 30:1484 SA Ferguson et al Melatonin agonists and insomnia Expert Rev Neurother 2010; 10:305 SW Lockley et al Tasimelteon treatment entrains the circadian clock and demonstrates a clinically meaningful benefit in totally blind individuals with non-24-hour circadian rhythms The Endocrine Society 95th annual meeting (ENDO), San Francisco, June 15-18, 2013 Poster SUN-134 SW Lockley et al RESET study demonstrates that tasimelteon maintains entrainment of melatonin and cortisol in totally blind individuals with non-24-hour circadian rhythms The Endocrine Society 95th annual meeting (ENDO), San Francisco, June 15-18, 2013 Poster SUN-137 SM Rajaratnam et al Melatonin agonist tasimelteon (VEC-162) for transient insomnia after sleep-time shift: two randomized controlled multicentre trials Lancet 2009; 373:482 Inhibitors and inducers of CYP enzymes and P-glycoprotein Med Lett Drugs Ther 2013; 55:e44 Approximate wholesale acquisition cost (WAC) Source: Analy$ource® Monthly (Selected from FDB MedKnowledge™) April 5, 2014 Reprinted with permission by FDB, Inc All rights reserved ©2014 www.fdbhealth com/policies/drug-pricing-policy Actual retail prices may be higher The Medical Letter • Volume 56 • Issue 1441 • April 28, 2014 35 IN BRIEF Enteric-Coated Aspirin as an Antiplatelet Drug One of our readers has suggested that more attention should have been paid to a study comparing the antiplatelet effects of immediate-release and entericcoated aspirin that appeared in Circulation last year.1 The safety benefits of enteric-coated aspirin are unclear It may protect against dyspepsia, but not against major gastrointestinal bleeding, which is thought to be mainly a systemic effect of prostaglandin inhibition ANTIPLATELET EFFECTS OF ASPIRIN — Aspirin irreversibly acetylates cyclooxygenase-1, blocking thromboxane synthesis and inhibiting platelet activation and aggregation for the life of the platelet (5-7 days) Aspirin prophylaxis reduces the incidence of myocardial infarction and/or death by 15-25% in patients with coronary heart disease or ischemic stroke, and in those undergoing angioplasty or a coronary artery bypass graft Aspirin can also prevent myocardial infarction in asymptomatic men and ischemic stroke in asymptomatic women, but the riskbenefit ratio is less favorable because the thrombotic risk is lower and the benefit in preventing thrombosis is offset by a small risk of gastrointestinal bleeding or hemorrhagic stroke.2 THE STUDY — The effects of a single 325-mg dose of immediate-release or enteric-coated aspirin on platelet aggregation were assessed or hours postdose in 400 healthy volunteers The rate of platelet nonresponse (