The Medical Letter ® on Drugs and Therapeutics Objective Drug Reviews Since 1959 Volume 57 ISSUE ISSUE No 1433 1465 Volume 56 March 30, 2015 IN THIS ISSUE Edoxaban (Savaysa): The Fourth New Oral Anticoagulant p 43 Secukinumab (Cosentyx) for Psoriasis p 45 Gardasil − A Broader HPV Vaccine p 47 OTC Fluticasone Nasal Spray for Allergic Rhinitis p 48 Spiriva Respimat − An Oral Inhalation Spray for COPD p 50 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 1465 Volume 56 ▶ March 30, 2015 Take CME Exams ALSO IN THIS ISSUE Secukinumab (Cosentyx) for Psoriasis p 45 Gardasil – A Broader HPV Vaccine p 47 OTC Fluticasone Nasal Spray for Allergic Rhinitis .p 48 Spiriva Respimat – An Oral Inhalation Spray for COPD .p 49 Edoxaban (Savaysa) – The Fourth New Oral Anticoagulant Related article(s) since publication The FDA has approved edoxaban (Savaysa – Daiichi Sankyo), a once-daily, oral, direct factor Xa inhibitor, for treatment of venous thromoboembolism (VTE) and for prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation It is the fourth new oral anticoagulant to be approved for VTE and nonvalvular atrial fibrillation Pronunciation Key Edoxaban: e dox' uh ban Savaysa: suh vay' suh STANDARD TREATMENT — Acute VTE (deep vein thrombosis or pulmonary embolism) is usually treated initially with a parenteral anticoagulant such as unfractionated heparin, low molecular weight heparin (LMWH), or fondaparinux (Arixtra, and generics) Warfarin (Coumadin, and others) is started on the same day as parenteral therapy and titrated to an INR of 2-3 After ≥5 days, the parenteral anticoagulant is stopped and warfarin is continued as monotherapy The new oral anticoagulants dabigatran etexilate (Pradaxa), rivaroxaban (Xarelto), and apixaban (Eliquis) all appear to be effective and safe alternatives to warfarin for treatment of acute VTE, but data in elderly patients and those with significant comorbidities are limited Treatment of acute VTE usually continues for at least months.1,2 In patients with nonvalvular atrial fibrillation, dabigatran, rivaroxaban, and apixaban all appear to be at least as effective as warfarin in preventing stroke, with significantly lower rates of intracranial bleeding and hemorrhagic stroke.3-5 Patients with Table Pharmacology Drug class Direct factor Xa inhibitor Formulation 15, 30, 60 mg tablets Route Oral Tmax 1-2 h Half-life (terminal) 10-14 h Metabolism Minimal; hydrolysis, conjugation, CYP3A4-mediated oxidation Excretion 50% unchanged in urine atrial fibrillation associated with a mechanical valve or moderate to severe mitral stenosis should take warfarin WARFARIN vs NEW ORAL ANTICOAGULANTS — Use of warfarin is complicated by the need for frequent monitoring of the INR, dietary restrictions, and concerns about its interactions with many other drugs The new oral anticoagulants not require routine INR-type monitoring, have no dietary restrictions, and may have fewer drug interactions than warfarin, but there is no fixed method for determining the extent of their anticoagulant effect, they have short half-lives that increase the risk of thrombosis with missed doses, and they are not recommended for use in patients with end-stage renal disease No established antidote is currently available for these new drugs, but their anticoagulant effect may be reversed by prothrombin complex concentrate, and clinical studies of more specific reversal agents are in progress.5-7 PHARMACOKINETICS — Because of its high renal clearance, blood levels of edoxaban are higher in patients with decreased renal function A pharmacokinetic study summarized in the package insert found that systemic exposure to edoxaban was >70% higher among patients with a CrCl ≤50 mL/min than among those with a CrCl ≥80 mL/min 43 Published by The Medical Letter, Inc • A Nonprofit Organization The Medical Letter March 30, 2015 Vol 57 (1465) ® Table Oral Anticoagulants for VTE and Atrial Fibrillation Drug Mechanism of Action Usual Dosage Cost1 Warfarin – generic Coumadin (BMS) Dabigatran etexilate – Pradaxa (Boehringer Ingelheim) Apixaban – Eliquis (BMS) Edoxaban – Savaysa (Daiichi Sankyo) Rivaroxaban – Xarelto (Janssen) Vitamin K antagonist 2-10 mg once/d $7.90 53.70 Direct thrombin inhibitor 150 mg bid3,4 Direct factor Xa inhibitor Direct factor Xa inhibitor Direct factor Xa inhibitor mg bid5 60 mg once/d3,6 20 mg once/d7 314.70 315.00 277.20 314.70 Approximate WAC for 30 days’ treatment at the lowest usual 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 March 5, 2015 Reprinted with permission by First Databank, Inc All rights reserved ©2015 www.fdbhealth.com/policies/drug-pricing-policy Coadministered with a parenteral coagulant for ≥5 days and until INR is in therapeutic range (2-3) for ≥24 hours After 5-10 days of parenteral anticoagulation for VTE Dosage is 75 mg bid for atrial fibrillation in patients with CrCl 15-30 mL/min, according to US labeling The American College of Chest Physicians and Health Canada not recommend use for atrial fibrillation in patients with CrCl 95 mL/min, the incidence of ischemic stroke was higher with edoxaban, and the drug should not be used in such patients How edoxaban compares in efficacy and safety with dabigatran (Pradaxa), rivaroxaban (Xarelto), or apixaban (Eliquis) remains to be determined ■ C Kearon et al Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines Chest 2012; 141 (2 suppl):e419S New oral anticoagulants for acute venous thromboembolism Med Lett Drugs Ther 2014; 56:3 CT January et al 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society Circulation 2014; 130:e199 AJ Camm et al 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation Developed with the special contribution of the European Heart Rhythm Association Eur Heart J 2012; 33:2719 Treatment of atrial fibrillation Med Lett Drugs Ther 2014; 56:53 Antithrombotic drugs Med Lett Drugs Ther 2014; 56:103 WI Gonsalves et al Management of bleeding complications in patients on new oral anticoagulants J Hematol Transfus 2014; 2:1015 Hokusai-VTE Investigators Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism N Engl J Med 2013; 369:1406 Vol 57 (1465) March 30, 2015 RP Giugliano et al Edoxaban versus warfarin in patients with atrial fibrillation N Engl J Med 2013; 369:2093 10 MJ Blank and T-Y McDowell Clinical review: edoxaban NDA 206316 Available at: http://www.accessdata.fda.gov/ drugsatfda_docs/nda/2015/206316Orig1Orig2s000MedR.pdf Accessed March 19, 2015 11 Inhibitors and inducers of CYP enzymes and P-glycoprotein Med Lett Drugs Ther 2013; 55:e44 ▶ Secukinumab (Cosentyx) for Psoriasis Secukinumab (Cosentyx – Novartis), an injectable human interleukin (IL)-17A antagonist, has been approved by the FDA for treatment of moderate to severe plaque psoriasis in adult patients who are candidates for systemic therapy or phototherapy It is the first IL-17 inhibitor to be approved for any indication in the US Pronunciation Key Secukinumab: sek" ue kin' ue mab Cosentyx: koh sen' tix STANDARD TREATMENT — Psoriasis is a chronic inflammatory, immune-mediated condition associated with multiple comorbidities.1 Topical preparations, including corticosteroids and vitamin D analogs, are usually tried first for treatment of mild disease UVB phototherapy can be used when the disease is more widespread or unresponsive to topical therapy For patients with moderate to severe disease, systemic options include methotrexate, cyclosporine, the oral retinoid acitretin, and biologic therapy Biologic agents approved to treat psoriasis include TNF inhibitors (etanercept, adalimumab, and infliximab) and ustekinumab, a human IL-12 and -23 antagonist.2 MECHANISM OF ACTION — IL-17A is a naturally occurring pro-inflammatory cytokine that plays an important role in the immunopathogenesis of plaque psoriasis and other immune-mediated diseases Secukinumab is a recombinant, fully human, highaffinity IgG1 monoclonal antibody that selectively binds and neutralizes IL-17A Table Pharmacology Drug class IL-17 inhibitor Route Subcutaneous injection Formulations 150 mg/mL preservative-free solution in single-use pen or prefilled syringe; 150 mg lyophilized powder in single-use vial Tmax ~6 days Half-life (terminal) 22-31 days Metabolism Not characterized Elimination Not characterized 45 The Medical Letter March 30, 2015 Vol 57 (1465) ® CLINICAL STUDIES — Four double-blind, placebocontrolled trials randomized a total of 2403 adults with moderate to severe plaque psoriasis to secukinumab 150 mg, secukinumab 300 mg, placebo, and, in one trial, etanercept as a biologic active control (Table 2) In all of the studies, patients taking secukinumab were significantly more likely than those taking placebo to achieve the co-primary endpoints of a ≥75% reduction in Psoriasis Area and Severity Index score (PASI 75) and a score of (clear) or (almost clear) on a 5-point Investigator’s Global Assessment (IGA) after 12 weeks of treatment Both doses of secukinumab were superior to etanercept in the FIXTURE trial Among responders at 12 weeks who continued treatment for 52 weeks in the ERASURE and FIXTURE trials, a PASI 75 response was maintained in 72% and 82% with secukinumab 150 mg and in 81% and 84% with secukinumab 300 mg An IGA response was maintained in 59% and 68% with secukinumab 150 mg and in 74% and 80% with secukinumab 300 mg.3-5 ADVERSE EFFECTS — The most common adverse effects of secukinumab in clinical trials were nasopharyngitis, diarrhea, and upper respiratory infection In general, infections occurred at a higher rate in secukinumab-treated patients than in those who received a placebo Patients should be screened for tuberculosis before starting therapy Exacerbations of Crohn’s disease were reported during clinical trials in patients taking secukinumab Urticaria and anaphylaxis have occurred PREGNANCY — Secukinumab is classified as category B (no evidence of toxicity in animals; no adequate studies in women) for use during pregnancy Table Secukinumab Clinical Trials Study PASI 751 IGA2 JUNCTURE (n=182) Secukinumab 150 mg Secukinumab 300 mg Placebo 71.7% 86.7% 3.3% 52.3% 73.3% 0% FEATURE4 (n=177) Secukinumab 150 mg Secukinumab 300 mg Placebo 69.5% 75.9% 0% 52.5% 69.0% 0% ERASURE5 (n=738) Secukinumab 150 mg Secukinumab 300 mg Placebo 71.6% 81.6% 4.5% 51.2% 65.3% 2.4% FIXTURE5 (n=1306) Secukinumab 150 mg Secukinumab 300 mg Etanercept 50 mg Placebo 67.0% 77.1% 44.0% 4.9% 51.1% 62.5% 27.2% 2.8% Proportion of subjects achieving a ≥75% reduction in Psoriasis Area and Severity Index (PASI) score from baseline to week 12, a primary endpoint Proportion of subjects achieving a score of (clear) or (almost clear) on the 5-point Investigators Global Assessment modified 2011 (IGA) scale from baseline to week 12, a primary endpoint C Paul et al J Eur Acad Dermatol Venereol 2014; Sept 22 (epub) A Blauvelt et al Br J Dermatol 2015; 172:484 RG Langley et al N Engl J Med 2014; 371:326 DRUG INTERACTIONS — Drug interaction studies have not been conducted with secukinumab Patients treated with the drug should not receive live vaccines DOSAGE AND ADMINISTRATION — The recommended dosage of secukinumab is 300 mg by subcutaneous injection at weeks 0, 1, 2, 3, and 4, followed by 300 mg every weeks Each 300-mg dose is given as two subcutaneous injections of 150 mg For some patients, a dose of 150 mg may be sufficient Cosentyx is supplied in cartons containing one or two singleuse 150-mg prefilled pens or syringes, or one 150-mg single-use vial of lyophilized powder for reconstitution Table Some Systemic Drugs for Psoriasis Drug Usual Adult Dosage Methotrexate – generic Cyclosporine – generic Neoral (Novartis) Acitretin – Soriatane (Stiefel) Apremilast – Otezla (Celgene) Biologics Adalimumab – Humira (Abbott) Etanercept – Enbrel (Amgen/Pfizer) Infliximab – Remicade (Janssen) Secukinumab – Cosentyx (Novartis) Ustekinumab – Stelara (Janssen) 7.5-25 mg/wk PO in a single dose or in divided doses over 36 hours 2.5-4 mg/kg/day PO in divided doses 10-50 mg/day PO in a single dose2 30 mg PO bid3 80 mg SC x 1, then 40 mg q2 wks 50 mg SC twice/wk x 12 wks, then once/wk mg/kg IV wks 0, 2, and 6, then q8 wks 300 mg4 SC wks 0, 1, 2, 3, and 4, then q4 wks 45 mg6 SC wks and 4, then q12 wks Cost1 $92.20 737.50 1090.30 2777.90 5250.00 8740.80 8920.80 5842.40 10,260.005 7661.20 Approximate WAC for 12 weeks’ treatment at the lowest maintenance dosage (cyclosporine and infliximab cost based on the lowest dose for a patient weighing 80 kg) 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 March 5, 2015 Reprinted with permission by First Databank, Inc All rights reserved ©2015 www.fdbhealth.com/policies/drug-pricing-policy Some expert clinicians recommend not exceeding 25 mg/day to avoid side effects The recommended starting dose is 10 mg, which should be titrated over days to 30 mg The maintenance dosage is 30 mg bid, which should be reduced to 30 mg once/day in patients with severe renal impairment (CrCl 100 kg is 90 mg 46 The Medical Letter Vol 57 (1465) ® Patients may use the pens or syringes to self-inject after receiving proper training CONCLUSION — Secukinumab (Cosentyx), an injectable IL-17A antagonist, has been highly effective in treating patients with moderate to severe plaque psoriasis It could be used either as initial therapy or for patients who have failed prior biologic treatments, but it is expensive Adverse effects of secukinumab have been tolerable in the short term; its long-term safety remains to be determined ■ ▶ Gardasil – A Broader HPV Vaccine The FDA has now approved a recombinant, 9-valent, human papillomavirus (HPV) vaccine (Gardasil – Merck) for use in girls and women 9-26 years old and boys 9-15 years old The new vaccine is indicated to prevent diseases associated with infection with HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58, which include genital warts and cervical, vulvar, vaginal, and anal precancerous lesions and cancer Two recombinant HPV vaccines are already available in the US: Gardasil prevents disease associated with HPV types 6, 11, 16, and 18,1 and Cervarix prevents disease associated with HPV types 16 and 18.2 HPV INFECTION — HPV is commonly acquired by young women soon after initiation of sexual activity, with a cumulative incidence of 40% within 16 months Although most HPV infections clear spontaneously without clinical sequelae, persistent infection can cause abnormalities in the cervical epithelium that may progress to cancer HPV types 16 and 18 are responsible for approximately 70% of cervical cancers The five HPV types added to the 9-valent vaccine – 31, 33, 45, 52, and 58 – are responsible for an additional 15-20% of cervical cancers.3 Types and 11 cause more than 90% of genital warts.4 March 30, 2015 MA Menter and CE Griffiths Psoriasis: the future Dermatol Clin 2015; 33:161 Drugs for psoriasis and psoriatic arthritis Med Lett Drugs Ther 2015; in press C Paul et al Efficacy, safety and usability of secukinumab administration by autoinjector/pen in psoriasis: a randomized, controlled trial (JUNCTURE) J Eur Acad Dermatol Venereol 2014; Sept 22 (epub) A Blauvelt et al Secukinumab administration by pre-filled syringe: efficacy, safety and usability results from a randomized controlled trial in psoriasis (FEATURE) Br J Dermatol 2015; 172:484 RG Langley et al Secukinumab in plaque psoriasis – results of two phase trials N Engl J Med 2014; 371:326 CLINICAL STUDIES — The efficacy and immunogenicity of Gardasil were evaluated in a randomized, double-blind trial in 14,215 previously unvaccinated females 16-26 years old who were given a dose of either the 9-valent or the quadrivalent HPV vaccine (Gardasil) on day and again at months and Compared to the quadrivalent vaccine, Gardasil reduced the risk of high-grade cervical, vulvar, or vaginal disease related to HPV types 31, 33, 45, 52, or 58 by 97% (0.1 vs 1.6 cases/1000 person-years) after a median of 40 months following the last vaccination Antibody responses to the HPV types found in both vaccines (HPV types 6, 11, 16, and 18) were similar with Gardasil and Gardasil 9, as was the incidence of disease or persistent infection related to those HPV types.5 The effectiveness of Gardasil for children 9-15 years old was inferred from an unpublished immunogenicity study (summarized in the package insert) that found antibody responses in girls and boys 9-15 years old to be noninferior to those in girls and women 16-26 years old An unpublished study in females 12-26 years old who were previously vaccinated with the quadrivalent vaccine found that administration of doses of Gardasil resulted in seropositivity to the five Table HPV Vaccines Brand Name HPV Types Formulations Dose/Schedule Cost1 Cervarix (GSK) 16 and 18 0.5 mL single dose syringes2 0.5 mL IM/3 doses (0, 1, and months) $384.00 Gardasil (Merck) 6, 11, 16, and 18 0.5 mL single dose vials3 0.5 mL single dose syringes3 0.5 mL IM/3 doses (0, 2, and months) 443.30 Gardasil (Merck) 6, 11, 16, 18, 31, 33, 45, 52, and 58 0.5 mL single dose vials4 0.5 mL single dose syringes4 0.5 mL IM/3 doses (0, 2, and months) 491.60 Approximate WAC for series (3 doses) 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 March 5, 2015 Reprinted with permission by First Databank, Inc All rights reserved ©2015 www.fdbhealth.com/policies/drug-pricing-policy Sold in packages of 10 single-dose prefilled syringes Sold in cartons of or 10 single-dose vials or or 10 single-dose prefilled syringes Sold in cartons of or 10 single-dose vials or 10 single-dose prefilled syringes 47 The Medical Letter ® additional HPV types in more than 98% of the subjects, but anti-HPV titers for those types were 25-63% of those reported in previously unvaccinated subjects given the new vaccine; the clinical significance of these differences is unknown ADVERSE EFFECTS — Injection-site reactions are common, slightly more so with Gardasil than with the quadrivalent vaccine (91% vs 85%).5 Syncope has occurred after administration of HPV vaccines; patients should be seated and observed for 15 minutes after the injection RECOMMENDATIONS — The US Advisory Committee on Immunization Practices (ACIP) has recommended routine vaccination with the bivalent or quadrivalent vaccine for girls 11-12 years old and with the quadrivalent vaccine for boys 11-12 years old Vaccination is also recommended for females 13-26 years old and males 13-21 years old who have not been vaccinated previously (immunocompromised men and men who have sex with men should be vaccinated through age 26).6 Specific recommendations regarding use of the 9-valent HPV vaccine have not been published yet, but the ACIP voted at a recent meeting to add Gardasil to its recommendations for HPV vaccination, which will probably include the possibility of using it to complete a vaccine series started with another HPV vaccine.7 CONCLUSION – The new HPV vaccine, Gardasil 9, should be more effective than Gardasil or Cervarix in preventing cervical and other genital cancers It will probably replace the currently marketed quadrivalent vaccine ■ A human papillomavirus vaccine Med Lett Drugs Ther 2006; 48:65 Cervarix – a second HPV vaccine Med Lett Drugs Ther 2010; 52:37 B Serrano et al Potential impact of a nine-valent vaccine in human papillomavirus related cervical disease Infect Agent Cancer 2012; 7:38 A Chatterjee The next generation of HPV vaccines: nonavalent vaccine V503 on the horizon Expert Rev Vaccines 2014; 13:1279 EA Joura et al A 9-valent HPV vaccine against infection and intraepithelial neoplasia in women N Engl J Med 2015; 372:711 LE Markowitz et al Human papillomavirus vaccination: recommendations of the Advisory Committee on Immunization Practices (ACIP) MMWR Recomm Rep 2014; 63(RR-05):1 LE Markowitz Proposed HPV vaccination recommendations ACIP presentation slides: February 26, 2015 meeting Available at: www.cdc.gov/vaccines/acip/meetings/slides-201502.html Accessed March 19, 2015 48 Vol 57 (1465) ▶ March 30, 2015 OTC Fluticasone Nasal Spray for Allergic Rhinitis The nasal spray formulation of the corticosteroid fluticasone propionate is now available over the counter (OTC) as Flonase Allergy Relief (GSK) in the same strength as the prescription product (Flonase, and generics) for patients ≥4 years old with seasonal or perennial allergic rhinitis It is the second corticosteroid nasal spray to become available OTC; triamcinolone acetonide (Nasacort Allergy 24HR) was the first.1 Unlike prescription Flonase, the OTC product is FDA-approved for reduction of ocular as well as nasal symptoms Brand-name prescription Flonase has been discontinued by the manufacturer CLINICAL USE — Intranasal corticosteroids are the most effective drugs available for prevention and relief of seasonal allergic rhinitis symptoms, including itching, sneezing, discharge, and congestion They are also effective in reducing ocular symptoms.2 The onset of action typically occurs within 12 hours, but maximal effects may not be achieved for 7-14 days For treatment of perennial allergic rhinitis, intranasal corticosteroids may be as effective as oral antihistamines, which are also available without a prescription.3 A CLINICAL STUDY — The efficacy of intranasal fluticasone for ocular allergy symptoms (a new indication for fluticasone OTC) was evaluated in a randomized, double-blind trial in 626 patients ≥12 years old with seasonal allergic rhinitis Patients were randomized to fluticasone propionate or to placebo nasal spray for 14 days; the mean decrease from baseline in ocular symptoms was significantly greater in the patients who received fluticasone.4 ADVERSE EFFECTS — Intranasal corticosteroids can cause dryness, irritation, burning or bleeding of the nasal mucosa, sore throat, epistaxis, and headache Ulceration, Candida albicans infection (thrush), mucosal atrophy, and septal perforation have been reported rarely Intranasal fungal infection with Alternaria has occurred with triamcinolone acetonide.5 Intranasal corticosteroids are absorbed systemically Older agents such as triamcinolone acetonide may be absorbed to a greater extent than newer (and more potent) intranasal corticosteroids such as fluticasone propionate.6 The effect of corticosteroid nasal sprays on growth in children has been a concern The effect of fluticasone The Medical Letter Vol 57 (1465) ® March 30, 2015 Table OTC Intranasal Corticosteroids for Allergic Rhinitis Drug FDA-approved Indication Available Formulations Dosage Cost1 Fluticasone propionate2 – Flonase Allergy Relief (GSK) Hayfever or other upper respiratory allergies (nasal congestion, runny nose, sneezing, itchy nose, and itchy, watery eyes) for patients ≥4 years old Metered-dose pump spray (50 mcg/actuation) 60, 120 sprays (9.9, 15.8 mL bottles) 4-11 years old: spray per nostril once/d3 ≥12 years old: sprays per nostril once/d x days, then 1-2 sprays per nostril once/d4 $11.80 Triamcinolone acetonide2 – Nasacort Allergy 24HR (Sanofi) Hayfever or other upper respiratory allergies (nasal congestion, runny nose, sneezing, itchy nose) for patients ≥2 years old Metered-dose pump spray (55 mcg/actuation) 60, 120 sprays (10.8, 16.9 mL bottles) 2-5 years old: spray per nostril once/d3 6-11 years old: 1-2 sprays per nostril once/d3,5 ≥12 years old: sprays per nostril once/d4 11.20 Approximate WAC for the smallest available bottle 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 March 5, 2015 Reprinted with permission by First Databank, Inc All rights reserved ©2015 www.fdbhealth.com/policies/drug-pricing-policy The brand-name products previously available by prescription have been discontinued Generic formulations are still available by prescription Many insurers no longer provide coverage for these products Corticosteroids are not recommended for more than months/year in children 6 months without the supervision of a physician A dose of two sprays per nostril should be used only until symptoms improve, then the dose should be reduced to spray per nostril propionate on growth was studied in a 1-year, placebo-controlled trial, summarized in the Flonase package insert, in about 100 children 3-9 years old Growth velocity in patients who received intranasal fluticasone propionate 200 mcg once daily (2 sprays per nostril once/d) was 0.14 cm/yr slower than with placebo (not statistically significant) No clinically significant changes in hypothalamic-pituitary-adrenal (HPA) axis function were detected In a similar study, treatment with triamcinolone acetonide 110 mcg (1 spray per nostril once/d) slowed growth velocity by 0.45 cm/yr compared to placebo, a statistically significant difference.7 Children requiring intranasal corticosteroids for allergic rhinitis often need to use an inhaled corticosteroid for asthma concomitantly, and sometimes a topical corticosteroid for atopic dermatitis as well Additive effects could occur DURATION OF USE — The manufacturer recommends that Flonase Allergy Relief not be used without physician supervision for more than months/year in children 4-11 years old or for more than months/ year in patients ≥12 years old CONCLUSION — Over-the-counter fluticasone propionate nasal spray (Flonase Allergy Relief) is the second intranasal corticosteroid to become available without a prescription for treatment of allergic rhinitis It might be safer than intranasal triamcinolone acetonide (Nasacort Allergy 24HR) for use in children, but long-term comparative data are lacking ■ An OTC corticosteroid nasal spray for allergic rhinitis Med Lett Drugs Ther 2013; 55:90 Drugs for allergic disorders Treat Guidel Med Lett 2013; 11:43 M Benninger et al Evaluating approved medications to treat allergic rhinitis in the United States: an evidence-based review of efficacy for nasal symptoms by class Ann Allergy Asthma Immunol 2010; 104:13 P Ratner et al Efficacy of daily intranasal fluticasone propionate on ocular symptoms associated with seasonal allergic rhinitis Ann Allergy Asthma Immunol 2015; 114:141 GH Chang and WH Wang Intranasal fungal (Alternaria) infection related to nasal steroid spray Am J Otolaryngol 2013; 34:743 J Sastre and R Mosges Local and systemic safety of intranasal corticosteroids J Investig Allergol Clin Immunol 2012; 22:1 DP Skoner et al Intranasal triamcinolone and growth velocity Pediatrics 2015; 135:e348 ▶ Spiriva Respimat – An Oral Inhalation Spray for COPD Tiotropium bromide, an inhaled long-acting anticholinergic available since 2004 as a dry powder inhaler (Spiriva Handihaler) for once-daily treatment of chronic obstructive pulmonary disease (COPD),1 has now also been approved in an inhalation spray formulation (Spiriva Respimat – Boehringer Ingelheim) According to the manufacturer, the Respimat device improves delivery of tiotropium to the lungs because, unlike with the Handihaler, it is not dependent on the strength of the patient’s breath intake MAINTENANCE TREATMENT – In patients with moderate to severe COPD, regular treatment with an inhaled long-acting bronchodilator (an anticholinergic or a 49 The Medical Letter ® beta2-agonist) can relieve symptoms, improve lung function, and reduce the frequency of exacerbations A combination of an anticholinergic and a beta2-agonist can be used for patients inadequately controlled with a single agent For patients with severe COPD who experience frequent exacerbations despite treatment with a long-acting beta2-agonist/anticholinergic combination, addition of an inhaled corticosteroid is recommended.2 CLINICAL STUDIES — Tiotropium inhalation spray, compared to placebo, significantly improved trough forced expiratory volume in second (FEV1), reduced the number of COPD exacerbations, and delayed the time to first exacerbation.3,4 A post-hoc pooled analysis of placebo-controlled trials of Spiriva Respimat, summarized in the package insert, showed an increased risk of death with use of the tiotropium inhalation spray compared to placebo (2.64 vs 1.98 deaths/100 patient-years) In an earlier randomized, doubleblind study (UPLIFT), there was no increase in risk of death with the Spiriva Handihaler compared to placebo.5 In response to this safety concern, the manufacturer sponsored a randomized, doubleblind trial comparing tiotropium 2.5 or mcg delivered via the Respimat inhaler with tiotropium 18 mcg delivered via the Handihaler device (TIOSPIR) The study, which enrolled 17,135 patients with COPD and followed them for a mean of 2.3 years, found that the risk of death and the risk of COPD exacerbation were similar with the devices.6 ADVERSE EFFECTS – In clinical trials of tiotropium inhalation spray, common adverse effects included pharyngitis, cough, dry mouth, and sinusitis Like other inhaled anticholinergic drugs, tiotropium may cause urinary retention and increased intraocular pressure All anticholinergics should be used with caution in patients with narrow-angle glaucoma, prostatic hyperplasia, or bladder-neck obstruction DOSAGE AND ADMINISTRATION — The recommended dosage of Spiriva Respimat is two 2.5-mcg inhalations once daily It is supplied in cartons containing one inhaler and one tiotropium cartridge Each cartridge contains enough tiotropium for 60 actuations, or one month’s treatment Before the inhaler can be used for the first time, it is necessary to insert the cartridge and prime the inhaler If the inhaler is not used for 21 days, it must be re-primed Some older patients may need assistance assembling and priming the inhaler 50 March 30, 2015 Vol 57 (1465) Table Tiotropium Inhalers for COPD Spiriva Handihaler1 Spiriva Respimat1 Manufacturer Boehringer Ingelheim Boehringer Ingelheim Formulation 18 mcg/capsule 2.5 mcg/inh Delivery Device DPI (5, 30, 90 inh/unit) MDI (28, 60 inh/unit) Usual Adult Dosage 18 mcg (2 inh of the mcg (2 inh) once/d contents of capsule) once/d Cost2 $297.80 $297.80 DPI = dry powder inhaler; MDI = metered dose inhaler; inh = inhalation FDA-approved for once-daily maintenance treatment of bronchospasm in patients with chronic obstructive pulmonary disease (COPD) and for reducing COPD exacerbations Approximate WAC for 30 days’ treatment (1 inhaler) WAC = wholesaler acquisition cost, or manufacturer’s published price to wholesalers; WAC represents published catalogue or list prices and may not represent actual transactional prices Source: AnalySource® Monthly March 5, 2015 Reprinted with permission by First Databank, Inc All rights reserved ©2015 www.fdbhealth.com/policies/drug-pricing-policy CONCLUSION — Tiotropium inhalation spray (Spiriva Respimat) improves lung function and reduces exacerbations in patients with chronic obstructive pulmonary disease (COPD) The new inhaler does not depend on the strength of the patient's breath intake to deliver the drug to the lungs, but assembly and priming of the device may be difficult for some patients Spiriva Handihaler will continue to be available ■ Tiotropium (Spiriva) for COPD Med Lett Drugs Ther 2004; 46:41 Drugs for asthma and COPD Treat Guidel Med Lett 2013; 11:75 E Bateman et al Efficacy and safety of tiotropium Respimat SMI in COPD in two 1-year randomized studies Int J Chron Obstruct Pulmon Dis 2010; 5:197 ED Bateman et al A one-year trial of tiotropium Respimat plus usual therapy in COPD patients Respir Med 2010; 104:1460 DP Tashkin et al A 4-year trial of tiotropium in chronic obstructive pulmonary disease N Engl J Med 2008; 359:1543 RA Wise et al Tiotropium Respimat inhaler and the risk of death in COPD N Engl J Med 2013; 369:1491 Coming Soon in The Medical Letter: Advice for Travelers Finafloxacin Otic Suspension (Xtoro) for Acute Otitis Externa Empagliflozin/Linagliptin (Glyxambi) for Diabetes Netupitant/Palonosetron (Akynzeo) for ChemotherapyInduced Nausea and Vomiting Drugs for Psoriasis and Psoriatic Arthritis Read Our Blog: More@MedLetter Each week or two we publish a 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efficacy and safety of OTC fluticasone propionate nasal spray (Flonase Allergy Relief) for treatment and prevention of allergic rhinitis Compare the new Spiriva Respimat inhaler to the Spiriva Handihaler for treatment of COPD Privacy and Confidentiality: The Medical Letter guarantees our firm commitment to your privacy We not sell any of your information Secure server software (SSL) is used for commerce transactions through VeriSign, Inc No credit card information is stored IT Requirements: Windows XP/Vista/7/8, Mac OS X+; current versions of Microsoft IE, Mozilla Firefox, Google Chrome, Safari, or any other compatible web browser Highspeed connection Have any questions? 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