The Medical Letter ® on Drugs and Therapeutics Objective Drug Reviews Since 1959 Volume 57 ISSUE ISSUE No 1433 1480 Volume 56 October 26, 2015 IN THIS ISSUE Cangrelor (Kengreal) — An IV Antiplatelet Drug for PCI .p 145 Drugs for Hypothyroidism p 147 In Brief: A New Albuterol Inhaler (ProAir RespiClick) for Asthma .p 150 Important Copyright Message FORWARDING OR COPYING IS A VIOLATION OF U.S AND INTERNATIONAL COPYRIGHT LAWS The Medical Letter, Inc publications are protected by U.S 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 U.S 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 Published by The Medical Letter, Inc • A Nonprofit Organization 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 Objective Drug Reviews Since 1959 Volume 57 ISSUE ISSUE No 1433 1480 Volume 56 ▶ October 26, 2015 Take CME Exams ALSO IN THIS ISSUE Drugs for Hypothyroidism p 147 In Brief: A New Albuterol Inhaler (ProAir RespiClick) for Asthma .p 150 Cangrelor (Kengreal) – An IV Antiplatelet Drug for PCI The FDA has approved cangrelor (Kengreal – The Medicines Company), an IV P2Y12 platelet inhibitor, as an adjunct to percutaneous coronary intervention (PCI) in patients who have not been pretreated with a P2Y12 inhibitor and are not being given a glycoprotein IIb/IIIa inhibitor Cangrelor : kan’ grel or Pronunciation Key Kengreal: ken’ gree al ANTIPLATELET DRUGS FOR PCI — Current guidelines recommend aspirin plus an oral P2Y12 inhibitor, either clopidogrel (Plavix, and generics), prasugrel (Effient), or ticagrelor (Brilinta), for all patients undergoing PCI.1,2 For prevention of myocardial infarction (MI) and stent thrombosis in patients with acute coronary syndrome, both prasugrel and ticagrelor have been more effective than clopidogrel, but with a higher incidence of bleeding.3-5 CLINICAL STUDIES — FDA approval of cangrelor was based on a double-blind, placebo-controlled trial (CHAMPION PHOENIX) in 11,145 patients undergoing PCI who were randomized to cangrelor or to a 300or 600-mg loading dose of clopidogrel Cangrelor was administered as a 30 mcg/kg bolus, followed by a mcg/kg/min infusion for the duration of the procedure or for hours, whichever was longer The primary endpoint (a composite of death, MI, ischemiadriven revascularization, or stent thrombosis at 48 hours) occurred in 4.7% of patients who received cangrelor and in 5.9% of those who took clopidogrel, a statistically significant difference that was mainly due to a reduction in acute periprocedural MI with cangrelor Stent thrombosis was also significantly less frequent with cangrelor than with clopidogrel (0.8% vs 1.4%).6 Cangrelor was not superior to clopidogrel in other studies (CHAMPION PCI and CHAMPION PLATFORM); these studies included fewer patients with stable angina, included patients who were intensively pretreated with antiplatelet agents, and used a less specific definition of periprocedural MI, all of which, according to an FDA summary review, made it more difficult to detect a beneficial effect of cangrelor.7-9 In both studies, the primary endpoint was a composite of death, MI, or ischemia-driven revascularization at Table Pharmacology of P2Y12 Inhibitors Cangrelor Clopidogrel Prasugrel Ticagrelor Structure Nonthienopyridine ATP analog Thienopyridine (prodrug) Thienopyridine (prodrug) Cyclopentyltriazolopyrimidine Mechanism Reversible binding to P2Y12 ADP receptors to prevent platelet activation Irreversible binding to P2Y12 ADP receptors to prevent platelet activation Irreversible binding to P2Y12 ADP receptors to prevent platelet activation Reversible binding to P2Y12 ADP receptors to prevent platelet activation Route Intravenous Oral Oral Oral Tmax minutes 30-60 minutes (active metabolite) 30 minutes (active metabolite) 1.5 hours (ticagrelor); 2.5 hours (active metabolite) Metabolism Non-hepatic; rapidly deactivated by dephosphorylation Hydrolysis to inactive metabolite; hepatic primarily by CYP2C19 to active metabolite Hydrolysis, then hepatic primarily by CYP3A4 and 2B6 to active metabolite Hepatic by CYP3A4 Elimination Urine (58%); feces (35%) Urine (50%); feces (46%) Urine (68%); feces (27%) Feces (58%); urine (26%) Half-life 3-6 minutes hours (clopidogrel); 30 minutes (active metabolite) hours (active metabolite) hours (ticagrelor); hours (active metabolite) 145 Published by The Medical Letter, Inc • A Nonprofit Organization The Medical Letter October 26, 2015 Vol 57 (1480) ® Table P2Y12 Inhibitors for PCI Drug Available Formulations Usual Loading Dose for PCI Cangrelor – Kengreal (The Medicines Company) 50 mg powder in 10 mL vial for reconstitution Clopidogrel – generic Plavix (BMS) Advantages Disadvantages Cost1 30 mcg/kg IV bolus, followed immediately by a mcg/kg/min IV infusion2 Rapid onset of action and rapid reversal of antiplatelet effect Must be given intravenously; not suitable for continuation therapy after PCI $749.00 75, 300 mg tabs 300-600 mg PO Standard of care; available generically Delayed onset of action; genetic polymorphisms and other drugs may interfere with activation; antiplatelet effect is irreversible 19.503 25.803 Prasugrel – Effient (Lilly) 5, 10 mg tabs 60 mg PO May be more effective than clopidogrel Higher risk of bleeding; contraindicated in patients with a history of stroke or transient ischemic attack (TIA); antiplatelet effect is irreversible; not recommended for most patients ≥75 years old4 64.70 Ticagrelor – Brilinta (AstraZeneca) 60, 90 mg tabs 180 mg PO Better platelet response and may be more effective than clopidogrel Higher risk of bleeding; should not be used with aspirin doses ˃100 mg/day; twice-daily dosing for continuation 9.50 Approximate WAC for a single loading dose or for a single vial of cangrelor WAC = wholesaler acquisition cost or manufacturer’s published price to wholesalers; WAC represents a published catalogue or list price and may not represent an actual transactional price Source: AnalySource® Monthly October 5, 2015 Reprinted with permission by First Databank, Inc All rights reserved ©2015 www.fdbhealth.com/policies/drug-pricing-policy Infusion is administered for the duration of the procedure or for hours, whichever is longer Cost for a 300-mg loading dose Use of prasugrel may be considered for patients ≥75 years old who are at high risk (diabetes or prior myocardial infarction) 48 hours Cangrelor did not significantly lower the rate of the primary endpoint compared to clopidogrel 600 mg given immediately before (CHAMPION PCI) or after (CHAMPION PLATFORM) PCI In the CHAMPION PLATFORM trial, rates of stent thrombosis and of death from any cause, both prespecified secondary endpoints, were significantly lower in patients who received cangrelor than in those who took clopidogrel (0.2% vs 0.6% and 0.2% vs 0.7%, respectively) ADVERSE EFFECTS — The most common adverse effect of cangrelor is bleeding In the CHAMPION PHOENIX trial, the rate of severe bleeding, the primary safety endpoint, was not significantly different with cangrelor than with clopidogrel (0.16% vs 0.11%) Transient dyspnea occurred significantly more often in cangrelor-treated patients (1.2% vs 0.3%) DRUG INTERACTIONS — When cangrelor was administered concurrently with a loading dose of clopidogrel or prasugrel, cangrelor blocked the antiplatelet effect of the oral drugs Treatment with clopidogrel or prasugrel should be started only after discontinuation of the cangrelor infusion.10 DOSAGE AND ADMINISTRATION — The recommended dosage of cangrelor is 30 mcg/kg given as an IV bolus before PCI, followed immediately by a mcg/kg/min IV infusion for the duration of the procedure or for hours, whichever is longer After stopping cangrelor, an oral P2Y12 inhibitor should be started to maintain platelet inhibition Ticagrelor does not interact with 146 cangrelor and can be given during or immediately after the cangrelor infusion CONCLUSION — Cangrelor (Kengreal) offers the option of IV administration of a P2Y12 platelet inhibitor in patients undergoing PCI Unlike clopidogrel (Plavix, and generics) and the other oral P2Y12 inhibitors, its antiplatelet effect occurs rapidly and is quickly reversed Three clinical trials comparing cangrelor with clopidogrel produced somewhat conflicting results, but taking into account differences in methodology, cangrelor appears to be more effective ■ Antithrombotic drugs Med Lett Drugs Ther 2014; 56:103 GN Levine et al 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions Circulation 2011; 124:e574 SD Wiviott et al Prasugrel versus clopidogrel in patients with acute coronary syndromes N Engl J Med 2007; 357:2001 L Wallentin et al Ticagrelor versus clopidogrel in patients with acute coronary syndromes N Engl J Med 2009; 361:1045 Ticagrelor (Brilinta) – better than clopidogrel (Plavix)? Med Lett Drugs Ther 2011; 53:69 DL Bhatt et al Effect of platelet inhibition with cangrelor during PCI on ischemic events N Engl J Med 2013; 368:1303 RA Harrington Platelet inhibition with cangrelor in patients undergoing PCI N Engl J Med 2009; 361:2318 DL Bhatt et al Intravenous platelet blockade with cangrelor during PCI N Engl J Med 2009; 361:2330 FDA Center for Drug Evaluation and Research: Summary Review Available at: www.accessdata.fda.gov/drugsatfda_docs/nda/2015/ 204958Orig1s000SumR.pdf Accessed October 15, 2015 10 HM Judge et al Cangrelor inhibits the binding of the active metabolites of clopidogrel and prasugrel to P2Y12 receptors in vitro Platelets 2015 Aug 13 (epub) The Medical Letter ▶ Vol 57 (1480) ® Drugs for Hypothyroidism Note: An addendum to this article has been published Primary hypothyroidism is usually the result of Hashimoto’s thyroiditis, thyroidectomy, or radioactive iodine therapy Treatment of hypothyroidism with replacement doses of thyroid hormone is usually lifelong Levothyroxine is the drug of choice LEVOTHYROXINE (LT4) — Pharmacokinetics – In healthy fasting adults, 70-80% of an oral dose of LT4 is absorbed in the jejunum and ileum LT4 has a halflife of about days, permitting once-daily dosing and maintenance of a steady state despite occasional missed doses Steady state is reached after about weeks of treatment Maintaining a steady-state level in the blood ensures sufficient tissue concentrations for peripheral deiodination of biologically inactive T4 into active triiodothyronine (T3) Dosage – LT4 has a narrow therapeutic index The usual replacement dose is about 1.6-1.8 mcg/kg/day Patients with thyroid cancer taking LT4 to suppress thyroid stimulating hormone (TSH) may require ≥2 mcg/kg/day The starting dose depends on age and whether cardiac risk factors, particularly coronary heart disease, are present October 26, 2015 In otherwise healthy patients under the age of 50, many clinicians begin with full replacement doses of LT4; some start with 50-100 mcg/day, especially if TSH values are only slightly elevated Signs and symptoms tend to improve at the same rate with either approach; patients treated with full replacement doses may achieve euthyroidism sooner, with little added risk.1 In older patients, who might have clinically silent coronary disease, some experts recommend an initial starting dose of 50 mcg/day In patients with coronary heart disease, LT4 replacement could begin at doses of 25 mcg/day The daily dose can be increased, as needed, by 25 mcg every 4-6 weeks In patients with severe hypothyroidism, the daily dose can be increased by 25 mcg every 2-4 weeks as needed Administration and Interactions – LT4 should be taken on an empty stomach with a full glass of water 30-60 minutes (60 is preferable) before breakfast Other drugs, including polyvalent cations such as iron or calcium, and foods (soy, fiber, coffee) may interfere with the absorption or metabolism of LT4 Some drugs that interact with LT4 listed in Table on page 148 Table Oral Drugs for Hypothyroidism Drug Levothyroxine (LT4) generic (Jerome Stevens/Lannett,3 Mylan, Sandoz) Levoxyl (Pfizer) Synthroid (Abbvie) Unithroid (Jerome Stevens/Gemini) Tirosint (Akrimax) Liothyronine (LT3)6 generic Cytomel (Pfizer) Available Formulations Usual Adult Daily Dose1 Cost2 25, 50, 75, 88, 100, 112, 125, 137, 150, 175, 200, 300 mcg tabs4 100-125 mcg $14.50 16.30 30.70 79.20 92.605 13, 25, 50, 75, 88, 100, 112, 125, 137, 150 mcg liquid-filled gel caps 5, 25, 50 mcg tabs 25-75 mcg 23.40 48.10 12.5/3.1, 25/6.25, 50/12.5, 100/25, 150/37.5 mcg tabs 50-100 mcg LT4/ 12.5-25 mcg LT3 19.00 0.25, 0.5, 1, 1.5, 2, 3, 4, gr tabs 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 4, gr tabs 0.5, 1, 1.5 gr tabs 0.5, 1, 1.5, 2, gr tabs 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, gr tabs 1-2 gr 16.90 2.80 Liotrix (LT4/LT3)6 Thyrolar (Forest) Thyroid USP6,7 Armour Thyroid (Forest) Nature-Throid (RLC Labs) NP Thyroid (Acella) Westhroid (RLC Labs)8 WP Thyroid (RLC Labs) 8.80 2.80 4.30 gr = grain Full replacement dose Approximate WAC for 30 days’ treatment with the lowest usual daily dosage WAC = wholesaler acquisition cost or manufacturer’s published price to wholesalers; WAC represents a published catalogue or list price and may not represent an actual transactional price Source: AnalySource® Monthly October 5, 2015 Reprinted with permission by First Databank, Inc All rights reserved ©2015 www.fdbhealth.com/policies/drug-pricing-policy Identical to Unithroid Levoxyl is not available in 300-mcg tabs Approximate WAC for 28 gel capsules Not recommended for first-line replacement therapy Each grain of desiccated thyroid contains mcg of T3 and 38 mcg of T4 Identical to Nature-Throid 147 The Medical Letter October 26, 2015 Vol 57 (1480) ® Table Some Drug Interactions with Levothyroxine (LT4)* Interacting Drug Effect Mechanism Management Amiodarone Decreased LT4 effect Monitor thyroid function Androgens Decreased LT4 requirements Antacids Decreased LT4 effect Bile acid sequestrants Calcium Decreased LT4 effect Amiodarone inhibits conversion of endogenous T4 and supplemental LT4 to T3 by decreasing D2 deiodinase activity Decreased TBG concentrations, leading to increased FT4 Decreased absorption due to increased stomach pH and/or chelation Decreased absorption (cholestyramine doubled fecal excretion of LT4) Decreased absorption due to binding of LT4 in the gut Artifact of commercially available free thyroid hormone assay kits Decreased LT4 effect Carbamazepine Decreased measured total and free T3 and T4 concentrations Ciprofloxacin2 Decreased LT4 effect Digoxin Decreased digoxin effect Estrogens3 Increased LT4 requirements Increased thyroxine-binding globulin concentrations, leading to decreased FT4 Iron Decreased LT4 effect Orlistat Decreased LT4 effect Phenobarbital Phenytoin Decreased LT4 effect Decreased measured total and free T3 and T4 concentrations Decreased absorption due to binding of LT4 in the gut Decreased absorption due to binding of LT4 in the gut Increased hepatic metabolism of T3 and T4 Artifact of commercially available free thyroid hormone assay kits Raloxifene Decreased LT4 effect Probably decreased absorption due to binding of LT4 in the gut Rifampin4 Sertraline Decreased LT4 effect Possible decreased serum FT4 concentrations Decreased LT4 effect Probably increased metabolism Increased hepatic metabolism with elevated TSH Decreased absorption due to binding of LT4 in the gut Probably decreased absorption due to binding of LT4 in the gut Sevelamer Sucralfate Possible decreased LT4 effect Tyrosine kinase inhibitors Decreased LT4 effect in post-thyroidectomy patients Warfarin Increased anticoagulant effect Possibly decreased absorption; possibly elevated TBG Probably increased digoxin metabolism Possibly increased conversion of T3 to rT3 due to increased D3 deiodinase and/or decreased thyroid hormone transport Increased clotting factor catabolism in hyperthyroidism LT4 doses may need to be adjusted if androgen therapy is started or stopped Take LT4 hours before or 4-6 hours after antacids; monitor thyroid function Take at least hours apart; monitor thyroid function Take LT4 hours before or 4-6 hours after calcium; monitor thyroid function Monitor thyroid function; patients may be euthyroid despite lower measured serum thyroid concentrations; serum TSH may be more reliable than FT4 Take at least hours apart; monitor thyroid function Digoxin dosage may need to be increased when LT4 is initiated LT4 doses may need to be adjusted if estrogen is started or stopped; monitor thyroid function Take at least hours apart; monitor thyroid function Take at least hours apart; monitor thyroid function Monitor thyroid function Monitor thyroid function; patients may be euthyroid despite lower measured serum thyroid concentrations; serum TSH may be more reliable than FT4 Take as far apart as possible; taking 12 hours apart avoided the interaction; monitor thyroid function Monitor thyroid function Clinical significance unclear; monitor thyroid function Take LT4 at least hour before or hours after sevelamer; monitor thyroid function Take LT4 at least hours before or hours after sucralfate; monitor thyroid function Monitor thyroid function; postthyroidectomy patients may request higher doses of LT4 Monitor INR5; no effect when patients are euthyroid on stable LT4 TBG = thyroxine-binding globulin; FT4 = free T4; rT3 = reverse triiodothyronine *Similar interactions may occur with other thyroid hormone preparations Cholestyramine, colesevelam, and colestipol Effect of other fluoroquinolones is not known Based on a study in postmenopausal women started on hormone replacement therapy; effect of oral contraceptives is unknown Rifabutin and rifapentine may also interact Only if iatrogenic hyperthyroidism occurs Thyroid Function Tests (TFTs) – Improvement in symptoms usually begins about 2-3 weeks after starting LT4, but steady-state free T4 (FT4) concentrations (typically 0.8-2.0 ng/dL) and optimal TSH levels (generally 0.4-4.5 mIU/L; may be higher in elderly patients) may not be achieved for ≥6 weeks TFTs should be assessed 4-6 weeks after 148 dosage adjustments are made After a biochemical euthyroid state is confirmed, follow-up TFTs can be performed at intervals of 6-12 months Additional testing is recommended when patients develop new symptoms or start or stop drugs that may interact with LT4 (see Table 2), and when women become or intend to become pregnant Patients requiring higher- The Medical Letter ® than-suggested doses to normalize TSH should be assessed for adherence to dosage instructions, concomitant use of interacting medications, and the presence of gastrointestinal disorders (e.g., celiac disease, Helicobacter pylori).2 In patients with central secondary hypothyroidism caused by hypothalamic or pituitary disease, the goal of therapy is to maintain FT4 concentrations at the mid- or upper-normal range; TSH values may be misleading and should not be used Generic Formulations – There is no evidence that any one brand or generic formulation of LT4 is better than any other Endocrine societies remain concerned, however, about prescribing generic LT4 because the FDA allows pharmacists to substitute one generic formulation for another In clinical practice, it is generally advisable to use the same brand or generic LT4 formulation for any given patient throughout treatment TSH levels should be checked about weeks after any change in LT4 formulation Adverse Effects – The adverse effects of LT4 are the same as the signs and symptoms of hyperthyroidism and are usually caused by overtreatment Palpitations, tremor, anxiety, weight loss, tachycardia, and increased bowel movement frequency can occur In patients with heart disease, LT4 can induce cardiac arrhythmias, angina pectoris, or myocardial infarction Iatrogenic hyperthyroidism can cause atrial fibrillation, particularly in older patients, and may cause bone loss Allergies to the inert compounds in LT4 tablets have been reported rarely A liquid-filled gel capsule formulation (Tirosint) that contains no dyes or excipients has shown bioequivalence in pharmacokinetic studies, but there is no convincing evidence that it does not cause allergic reactions, and it is expensive.3 LIOTHYRONINE (LT3) — LT3 is well absorbed (95-100% vs 70-80% absorption of LT4), has an onset of action of about 2-4 hours, and has a shorter half-life (~1 day) than LT4 (~7 days) Doses should be titrated at 1-2 week intervals rather than the 4-6 week intervals recommended for LT4 The rapid absorption of LT3 combined with its short half-life leads to marked fluctuations in T3 levels.4,5 LT4 is preferred for replacement therapy COMBINATION THERAPY — LT4 and LT3 are available in a fixed-dose combination as Thyrolar Multiple studies have found no significant differences in various quality-of-life measures (depression, fatigue, cognitive function, etc) with use of the LT4/LT3 Vol 57 (1480) October 26, 2015 combination compared to LT4 alone, and some patients prefer the combination.6 Whether genetic polymorphisms that reduce conversion of T4 to T3 explain why some patients on LT4 monotherapy feel symptomatic despite normal TSH or prefer LT4/LT3 combination therapy is unclear.7 THYROID USP — Several preparations of desiccated porcine thyroid tissue containing T3, T4, and iodine (primarily bound) are available Thyroid tissues from swine generally have higher T3:T4 ratios than those from humans; in thyroid USP, the ratio is 1:4.22 (9 mcg T3, 38 mcg T4 per grain), which can lead to supraphysiologic and fluctuating levels of T3 A 32-week randomized controlled trial in 70 patients found no symptom-related or neurocognitive benefit favoring desiccated thyroid over LT4 monotherapy; nevertheless, many patients preferred the desiccated thyroid.8 The starting dose is typically 0.25-0.5 gr/day, which is then titrated to achieve a normal TSH concentration One grain of desiccated thyroid should be equivalent to 74 mcg of T4, but many clinicians use a conversion ratio of grain:100 mcg LT4 is preferred for replacement therapy PREGNANCY — Because hypothyroidism during pregnancy can severely impair fetal brain development, thyroid function should be tested before and throughout pregnancy.9 The TSH goal is