The Medical Letter ® on Drugs and Therapeutics Volume 58 ISSUE ISSUE No 1433 1485 Volume 56 January 4, 2016 IN THIS ISSUE Naloxone (Narcan) Nasal Spray for Opioid Overdose p Ambrisentan (Letairis) and Tadalafil (Adcirca) for Pulmonary Arterial Hypertension p Eluxadoline (Viberzi) for Irritable Bowel Syndrome with Diarrhea p ColciGel – A Homeopathic Colchicine Gel for Gout p In Brief: New Indications for Harvoni p 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 Volume 58 ISSUE ISSUE No 1433 1485 Volume 56 ▶ January 4, 2016 ALSO IN THIS ISSUE Ambrisentan (Letairis) and Tadalafil (Adcirca) for Pulmonary Arterial Hypertension p Eluxadoline (Viberzi) for Irritable Bowel Syndrome with Diarrhea p ColciGel – A Homeopathic Colchicine Gel for Gout p In Brief: New Indications for Harvoni p Naloxone (Narcan) Nasal Spray for Opioid Overdose Note: A clarification to this article has been published The recent increase in deaths due to overdose of heroin and prescription opioids in the US has renewed interest in the opioid antagonist naloxone, particularly in making it available to first responders and to relatives and close friends of persons using heroin or taking prescription opioids IV or IM administration by healthcare professionals is preferred, but peripheral venous access may be difficult to obtain in IV drug abusers, and exposure to their blood may be hazardous Pronunciation Key Naloxone: nal ox’ one Narcan: nar' kan The FDA has now approved an intranasal formulation of naloxone (Narcan nasal spray – Adapt) for emergency treatment of opioid overdose It is the first nasal spray to be approved for this indication, but naloxone solution has been administered intranasally off-label, using a mucosal atomizer device.1 The drug also recently became available in an auto-injector formulation (Evzio) for IM or SC administration.2 PHARMACOLOGY — Naloxone is a competitive muopioid receptor antagonist in the brain and has no opioid agonist effects In opioid overdose, naloxone begins to reverse sedation, respiratory depression, and hypotension within 1-2 minutes after IV administration, 2-5 minutes after IM or SC administration, and 8-13 minutes after intranasal administration Table Pharmacology Class Opioid antagonist Formulation mg in 0.1 mL nasal spray Route Intranasal Tmax 20-30 minutes Half-life ~2 hours Table Some Naloxone Formulations Drug Formulation Usual Dosage Cost1 Parenteral generic 0.4 mg/mL vials 0.4-2 mg IV, and syringes; IM, or SC2 mg/mL syringes $17.403 Evzio (Kaleo) 0.4 mg/0.4 mL prefilled autoinjector 375.005 0.4 mg IM or SC4 Intranasal Narcan nasal mg/0.1 mL spray (Adapt) nasal spray mg intranasally4 62.506,7 Approximate WAC for a single dose 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 December 5, 2015 Reprinted with permission by First Databank, Inc All rights reserved ©2015 www.fdbhealth.com/ policies/drug-pricing-policy Dose can be repeated every 2-3 minutes up to a total of 10 mg Cost for a 1-mL vial Dose can be repeated every 2-3 minutes until the patient responds or emergency medical personnel arrive Cost for one auto-injector, but supplied in packages containing autoinjectors Cost for one nasal spray device, but supplied in cartons containing nasal spray devices Available from the manufacturer at a discounted price of $37.50 per mg nasal spray device to law enforcement, firefighters, first responders, departments of health, local school districts, colleges and universities, and community-based organizations The half-life of naloxone is much shorter than that of most opioids and repeated administration may be necessary, especially for overdose with a long-acting opioid agonist such as methadone or a sustainedrelease formulation of a short-acting agonist such as oxycodone.3 Pure heroin is an exception, with a halflife of only 2-6 minutes, but other drugs used to "cut" heroin may have longer half-lives CLINICAL STUDIES — No new clinical trials were required for FDA approval of Narcan nasal spray An unpublished pharmacokinetic study (summarized in the package insert) in 30 healthy adults compared intranasal naloxone mg (one dose) and mg (two doses) with 0.4 mg of naloxone given Published by The Medical Letter, Inc • A Nonprofit Organization The Medical Letter ® intramuscularly Intranasal administration of either or doses resulted in serum concentrations higher than those achieved with a single dose of the IM formulation The time to reach peak serum concentrations was similar with intranasal administration and IM injection (20 minutes with doses of the intranasal formulation, 23 minutes with IM administration, and 30 minutes with a single intranasal dose) ADVERSE EFFECTS — Whether naloxone itself has any toxicity is unclear, but it can precipitate acute withdrawal symptoms in opioid-dependent patients Acute opioid withdrawal is associated with anxiety, piloerection, yawning, sneezing, rhinorrhea, nausea, vomiting, diarrhea, and abdominal or muscle cramps, which are uncomfortable but generally not lifethreatening, except in neonates In the pharmacokinetic study, the most common adverse effects of intranasal naloxone were increased blood pressure, musculoskeletal pain, headache, and intranasal effects including dryness, edema, congestion, and inflammation PREGNANCY — No embryotoxic or teratogenic effects were observed in mice and rats treated with large doses of naloxone Naloxone does cross the placenta, however, and may cause fetal opioid withdrawal DOSAGE AND ADMINISTRATION — Narcan nasal spray is supplied in cartons containing two mg/0.1 mL single-use nasal spray devices The recommended dosage for adults and children is mg administered as a single spray into one nostril Additional doses can be given every to minutes in alternating nostrils using a new nasal spray device for each dose No assembly or priming of the device is required Caregivers should be instructed to call emergency medical personnel immediately after the first dose of Narcan nasal spray is given CONCLUSION — Naloxone (Narcan) nasal spray is a needle-free alternative to injectable formulations of the drug that can be administered by first responders or family members for emergency treatment of lifethreatening opioid overdose ■ Intranasal naloxone for treatment of opioid overdose Med Lett Drugs Ther 2014; 56:21 In brief: a naloxone auto-injector (Evzio) Med Lett Drugs Ther 2014; 56:45 EW Boyer Management of opioid analgesic overdose N Engl J Med 2012; 367:146 January 4, 2016 Vol 58 (1485) ▶ Ambrisentan (Letairis) and Tadalafil (Adcirca) for Pulmonary Arterial Hypertension The FDA has approved the use of ambrisentan (Letairis) and tadalafil (Adcirca) together for treatment of pulmonary arterial hypertension (PAH) It is the first 2-drug regimen to be approved for this indication Pronunciation Key Ambrisentan: am" bri sen' tan Letairis: le tair' is Tadalafil: ta da' la fil Adcirca: ad sur' kuh TREATMENT OF PAH — Monotherapy with an oral drug is usually recommended for initial treatment of PAH Drugs approved by the FDA for this indication include phosphodiesterase-5 (PDE5) inhibitors, endothelin receptor antagonists, and a guanylate cyclase stimulator.1 Patients with more advanced disease may be treated with a prostacyclin (see Table 2) The FDA recently approved the oral selective IP prostacyclin receptor agonist selexipag (Uptravi) for treatment of PAH; it will be reviewed in a future issue Combination Therapy – Limited data are available on the effectiveness of combination therapy for initial treatment of PAH.2 Current US guidelines recommend treatment with two or more classes of PAH drugs only when the response is inadequate or the patient deteriorates on monotherapy, but recently published European guidelines include recommendations for initial combination therapy.3,4 CLINICAL STUDY — In a randomized, double-blind trial (AMBITION), treatment-naive patients with WHO functional class II or III symptoms of PAH were treated with ambrisentan plus tadalafil (n=253), ambrisentan alone (n=126), or tadalafil alone (n=121) Doses were titrated to a target of 10 mg once daily for ambrisentan and 40 mg once daily for tadalafil The mean duration of study medication use was 517 days Table AMBITION Trial Results1 Efficacy Endpoint Ambrisentan/ Tadalafil Ambrisentan Tadalafil Clinical failure2 18% Change in 6-minute +49 meters walk distance3 Satisfactory clinical 39% response4 34% +27 meters 28% +23 meters 31% (NS) 27% NS = Difference not significant vs combination therapy N Galiè et al N Engl J Med 2015; 373:834 First occurrence of death, hospitalization for worsening PAH, disease progression, or unsatisfactory long-term clinical response (the composite primary endpoint) Median change from baseline to week 24 in 6-minute walk distance (a secondary endpoint) Increase of 10% from baseline in 6-minute walk distance, reduction of symptoms to, or maintenance of, WHO functional class I or II, and no worsening of clinical condition at week 24 (a secondary endpoint) The Medical Letter Vol 58 (1485) ® January 4, 2016 Table Some Drugs for Treatment of Pulmonary Arterial Hypertension Drug Route Some Formulations Usual Adult Dosage Cost1 Soluble Guanylate Cyclase (sGC) Stimulator Oral Riociguat – Adempas (Bayer) 0.5, 1, 1.5, 2, 2.5 mg tabs 1-2.5 mg tid $8188.50 Endothelin Receptor Antagonists Ambrisentan – Letairis (Gilead) Bosentan – Tracleer (Actelion) 5, 10 mg tabs 62.5, 125 mg tabs 5-10 mg once/d 62.5 mg bid for wks, then 125 mg bid2 7368.90 8220.00 10 mg tabs 10 mg once/d 7185.00 20 mg tabs 20 mg tid 20 mg tabs 40 mg once/d 117.80 2734.20 2749.80 0.5, 1.5 mg in 10 mL single-dose vials 0.5, 1.5 mg in 17 mL single-dose vials 10, 20 mcg/mL ampules 0.125, 0.25, 1, 2.5 mg ER tabs 1, 2.5, 5, 10 mg/mL multidose vials 1.74 mg/2.9 mL ampules 20-40 ng/kg/min continuous infusion4 Oral Oral Macitentan – Opsumit (Actelion) Oral Phosphodiesterase-5 (PDE5) Inhibitors Sildenafil – generic Oral Revatio3 (Pfizer) Tadalafil – Adcirca (Lilly) Oral Prostacyclins Epoprostenol – generic IV Veletri (Actelion) Flolan (GSK) Iloprost – Ventavis (Actelion) Treprostinil – Orenitram (United Therapeutics) Remodulin (United Therapeutics) Tyvaso (United Therapeutics) Inhalation Oral SC or IV Inhalation 2.5-5 mcg/inhalation 6-9 times/d 0.25-21 mg bid7 40-160 ng/kg/min continuous infusion9 breaths (54 mcg) qid10 1603.905 1849.905 1850.705 19,260.006 11,700.008 7130.605 13,650.0011 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 December 5, 2015 Reprinted with permission by First Databank, Inc All rights reserved ©2015 www.fdbhealth.com/policies/drug-pricing-policy Initial and maintenance dosage for patients 12 years old is 62.5 mg bid Also available in an IV formulation for patients on oral sildenafil who are temporarily unable to take oral medication, and in a powder for oral suspension Initial dosage is ng/kg/min with subsequent increases of 1-2 ng/kg/min every 15 minutes or longer as tolerated Average dosage after months is about 20-40 ng/kg/min Approximate WAC for a 70-kg patient Approximate WAC for 180 ampules of either strength The initial dosage is 0.25 mg bid or 0.125 tid with food, with subsequent increases of 0.25 or 0.5 mg bid or 0.125 mg tid every 3-4 days if tolerated Average dose after 12 weeks in a clinical trial was 3.4 mg bid Maximum doses studied have been 12 mg bid (in a 12-week blinded study) and 21 mg bid (in a long-term openlabel study) Approximate WAC for a dose of mg bid for 30 days Initial dosage is 1.25 ng/kg/min, or half if poorly tolerated, with subsequent increases of 1.25 ng/kg/min weekly for the first weeks, then 2.5 ng/kg/min weekly thereafter Average dosage after months is about 60 ng/kg/min 10 Initial dosage is breaths (18 mcg) times daily, or 1-2 breaths if poorly tolerated then increasing to breaths The dosage should be increased by an additional breaths at 1-2 week intervals as tolerated The target and maximum dosage is breaths (54 mcg) times daily 11 Approximate WAC for foil pouches containing ampules each Dual therapy significantly reduced the risk of a first event of clinical failure, the primary endpoint, compared to either drug alone (see Table 1) The reduced risk was primarily due to a lower rate of hospitalization for worsening PAH in patients treated with both ambrisentan and tadalafil (4% vs 14% with ambrisentan alone and 10% with tadalafil alone) Decreases in levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), a biomarker of right-sided heart failure and death, were significantly greater with dual therapy than with the monotherapies from baseline to week 24 There were no significant differences between groups in change in WHO functional class.5 ADVERSE EFFECTS — Adverse effects reported with the two drugs together were similar to those with the individual drugs Peripheral edema, headache, nasal congestion, cough, anemia, dyspepsia, and bronchitis occurred more often with the two drugs together than with either drug alone PREGNANCY — Ambrisentan can cause fetal harm and is contraindicated for use during pregnancy It is only available for women through a Risk Evaluation and Mitigation Strategy (REMS) program Tadalafil is classified as category B (no evidence of fetal harm) for use during pregnancy DOSAGE — The starting dosages of the two drugs when they are used together are ambrisentan mg and tadalafil 20 mg once daily The doses can be increased at 4-week intervals as needed and tolerated to 10 mg for ambrisentan and 40 mg for tadalafil CONCLUSION — Use of the endothelin receptor antagonist ambrisentan (Letairis) and the phosphodiesterase-5 (PDE5) inhibitor tadalafil (Adcirca) together in treatment-naive patients with symptomatic pulmonary arterial hypertension (PAH) improved clinical outcomes and exercise capacity compared to monotherapy with either drug Data are limited on the effectiveness of using other drug combinations for initial treatment of PAH ■ The Medical Letter ® Riociguat (Adempas) for pulmonary hypertension Med Lett Drugs Ther 2014; 56:17 G Ruiz et al Combination therapy in pulmonary arterial hypertension: is this the new standard of care? Am J Manag Care 2015; 21:s151 DB Taichman et al Pharmacologic therapy for pulmonary arterial hypertension in adults: CHEST guideline and expert panel report Chest 2014; 146:449 N Galiè et al 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS) endorsed by: Assoication for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT) Eur Heart J 2015 Aug 29 (epub) N Galiè et al Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension N Engl J Med 2015; 373:834 ▶ Eluxadoline (Viberzi) for Irritable Bowel Syndrome with Diarrhea The FDA has approved eluxadoline (Viberzi – Actavis), a mu-opioid receptor agonist and delta-opioid receptor antagonist, for oral treatment of adults with irritable bowel syndrome with diarrhea (IBS-D) Pronunciation Key Eluxadoline: el ux ad' oh leen Viberzi: vye ber' zee IBS — Symptoms of IBS can include abdominal pain, bloating, flatulence, diarrhea, and constipation IBS is subtyped, according to the predominant bowel symptom, as IBS-D, IBS with constipation (IBS-C), mixed-type (IBS-M), or unclassified (IBS-U) SOME DRUGS FOR IBS-D — The goal of IBS treatment is symptom control; dietary modifications may help improve symptoms of all subtypes of the disorder For patients with IBS-D, antidiarrheals such as loperamide (Imodium A-D, and others) taken as needed may reduce stool urgency and frequency In short-term clinical trials, the minimally absorbed antibiotic rifaximin (Xifaxan) was modestly more effective than placebo in relieving symptoms of IBS-D, but relapse was common Alosetron (Lotronex, and generics), a serotonin (5-HT3) receptor antagonist that decreases intestinal motility and pain signals, is FDA-approved for treatment of women with severe IBS-D that has not responded to conventional therapy, but its use has been limited by serious GI adverse effects such as ischemic colitis.1 MECHANISM OF ACTION — Eluxadoline stimulates mu-opioid receptors in the GI tract, leading to decreased muscle contractility, inhibition of water and electrolyte secretion, and increased rectal sphincter January 4, 2016 Vol 58 (1485) Table Pharmacology Class Mu-opioid agonist, delta-opioid antagonist Route Oral Formulation 75, 100 mg tablets Metabolism Not established Excretion Feces (82.2%); urine (