The medical letter on drugs and therapeutics august 31 2015

The Medical Letter ® on Drugs and Therapeutics Objective Drug Reviews Since 1959 Volume 57 ISSUE ISSUE No 1433 1476 Volume 56 August 31, 2015 IN THIS ISSUE Abuse-Deterrent Opioid Formulations p 119 A New Subcutaneous Immune Globulin (HyQvia) for Primary Immunodeficiency p 121 Reshape and Orbera — Two Gastric Balloon Devices for Weight Loss .p 122 Onexton Gel for Acne p 124 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 1476 Volume 56 ▶ August 31, 2015 Take CME Exams ALSO IN THIS ISSUE A New Subcutaneous Immune Globulin (HyQvia) for Primary Immunodeficiency p 121 ReShape and Orbera — Two Gastric Balloon Devices for Weight Loss .p 122 Onexton Gel for Acne p 124 Abuse-Deterrent Opioid Formulations Development of abuse-deterrent opioid products, including reformulation of existing products, has become a priority for drug manufacturers and public health advocates Three available opioid formulations, OxyContin (Purdue), Embeda (Pfizer), and Hysingla ER (Purdue), now include claims of abuse deterrence in their package inserts DETERRENCE MECHANISMS — No opioid formulation prevents consumption of a large number of intact dosage units, the most common method of abuse Abuse-deterrent formulations have one or more properties that make their intentional nontherapeutic use more difficult, less attractive, or less rewarding; examples of such properties are listed in the table.1 Table Some Mechanisms that Deter Opioid Abuse ▶ Controlled release of drug ▶ Sequestered opioid antagonist ▶ Tablets that resist crushing or grinding ▶ Gelling agents that make injection via hypodermic needle difficult ▶ Reduced amount of intact drug produced by vaporization ▶ Increased difficulty extracting pure opioid after dissolution ▶ Increased crushed particle size that resists absorption through nasal mucosa ▶ Substances that burn/irritate nasal mucosa if drug is crushed and snorted ▶ Depot/subcutaneous delivery system LABELING REQUIREMENTS — For claims of abuse deterrence to be included in the labeling of an opioid formulation, the FDA requires that laboratory tests first be performed to assess how easily the abusedeterrent properties of the formulation can be compromised In vivo studies should then compare the pharmacokinetic profiles of the formulation before and after manipulation Based on these results, a randomized, double-blind, placebo- and activecontrolled study should evaluate subjective effects of the formulation, such as differences in "drug liking" in recreational drug users Postmarketing epidemiological studies are required for all opioid formulations that have claims of abuse deterrence in their labeling These studies assess whether a formulation has been associated with meaningful reductions in adverse clinical outcomes related to abuse and misuse ABUSE-DETERRENT FORMULATIONS — OxyContin, an ER oxycodone tablet formulation, was reformulated in 2010 to deter abuse; the current product is more difficult to crush, break, or dissolve than the original, and when dissolved forms a viscous gel that is difficult to inject through a hypodermic needle In an intranasal administration trial in nondependent opioid abusers, scores for “drug liking” and desire to “take drug again” were significantly lower with the newer formulation than with original OxyContin or with oxycodone HCl powder.2 Embeda is formulated as capsules of ER morphine pellets that contain a sequestered core of the opioid antagonist naltrexone If the pellets are swallowed, the morphine is gradually released and absorbed, while the naltrexone core passes through the gut intact If the pellets are crushed, chewed, or dissolved, naltrexone is released, blocking morphine-induced euphoria.3 In oral, intranasal, and IV administration trials in nondependent opioid abusers (one published; three summarized in the package insert), Embeda had significantly lower “drug liking” and “drug high” scores than morphine without naltrexone.4 Hysingla ER is an ER hydrocodone tablet formulation; when dissolved it forms a viscous gel that is difficult 119 Published by The Medical Letter, Inc • A Nonprofit Organization The Medical Letter ® to inject through a hypodermic needle In oral and intranasal administration trials in nondependent opioid abusers (summarized in the package insert), Hysingla ER had significantly lower scores for “drug liking” and desire to “take drug again” than immediaterelease hydrocodone.5 Zohydro ER (Zogenix), an ER hydrocodone capsule formulation, was originally approved without abusedeterrent properties,6 but now incorporates excipients that form a viscous gel when the capsules are crushed and dissolved The manufacturer is expected to submit clinical data supporting claims of abuse deterrence in the labeling later this year.7 Targiniq ER (Purdue), an opioid agonist/antagonist combination containing ER oxycodone and naloxone, has been approved by the FDA with claims of abuse deterrence in the labeling, but is not yet commercially available If the formulation is crushed and administered intravenously or intranasally, high naloxone concentrations block opiate-induced euphoria and can induce withdrawal symptoms The FDA has not provided guidance for developing generic equivalents of abuse-deterrent opioid products EFFECTIVENESS — FDA-mandated postmarketing epidemiological studies evaluating changes in drug abuse patterns after reformulation of OxyContin have been completed One study found that reformulation was associated with a 32% reduction in the rate of ER oxycodone-related poison control abuse cases and a 15% reduction in the rate of poisonings related to therapeutic use of ER oxycodone The rate of ER oxycodone diversion declined by 50%, and the street price of ER oxycodone declined by 22%.8 Another study in 140,496 people assessed for substance abuse problems found that the ER oxycodone abuse rate declined by 33% after reformulation of OxyContin; non-oral abuse of ER oxycodone declined by 66% and frequency of abuse by 30%.9 In other studies, reformulation of OxyContin was associated with similar declines in ER oxycodone abuse and its complications,10-14 but some reported increases in abuse rates of other opioids, including heroin.13-15 One study found that the estimated prescription opioid overdose rate was 20% lower years after introduction of the new OxyContin formulation, but the estimated heroin overdose rate increased by 23%.16 Another found that the annual rate of change in ER oxycodone prescription sales declined 120 Vol 57 (1476) August 31, 2015 from +4.9% to -23.8% in the year after reformulation, with no significant differences in the sales of other prescription opioids.17 Postmarketing studies of Hysingla ER and Embeda are scheduled for completion in 2018 and 2019, respectively No studies comparing the relative safety of different formulations of abuse-deterrent opioids are available REMS — As part of a Risk Evaluation and Mitigation Strategy (REMS) program, the FDA has required the manufacturers of long-acting opioids to make training in their use available to prescribers CONCLUSION — Whether the availability of single-source, abuse-deterrent opioid products such as OxyContin, Embeda, and Hysingla ER will result in a reduction in overall opioid abuse remains to be determined There are no generic equivalents to these products ■ FDA Abuse-deterrent opioids – evaluation and labeling: guidance for industry April 2015 Available at: www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm334743.pdf Accessed August 20, 2015 SC Harris et al Abuse potential, pharmacokinetics, pharmacodynamics, and safety of intranasally administered crushed oxycodone HCl abuse-deterrent controlled-release tablets in recreational opioid users J Clin Pharmacol 2014; 54:468 A morphine/naltrexone combination (Embeda) for pain Med Lett Drugs Ther 2010; 52:22 J Stauffer et al Subjective effects and safety of whole and tampered morphine sulfate and naltrexone hydrochloride (ALO-01) extended-release capsules versus morphine solution and placebo in experienced non-dependent opioid users: a randomized, double-blind, placebo-controlled, crossover study Clin Drug Investig 2009; 29:777 Extended-release hydrocodone (Hysingla ER) for pain Med Lett Drugs Ther 2015; 57:71 Extended-release hydrocodone (Zohydro ER) for pain Med Lett Drugs Ther 2014; 56:45 Press release Zogenix receives FDA approval of new formulation of Zohydro® ER January 30, 2015 Available at: www.zogenix.com/content/news/press-releases.php Accessed August 20, 2015 SG Severtson et al Reduced abuse, therapeutic errors, and diversion following reformulation of extended-release oxycodone in 2010 J Pain 2013; 14:1122 SF Butler et al Abuse rates and routes of administration of reformulated extended-release oxycodone: initial findings from a sentinel surveillance sample of individuals assessed for substance abuse treatment J Pain 2013; 14:351 10 NE Sessler et al Reductions in reported deaths following the introduction of extended-release oxycodone (OxyContin) with an abuse-deterrent formulation Pharmacoepidemiol Drug Saf 2014; 23:1238 11 JR Havens et al The impact of a reformulation of extendedrelease oxycodone designed to deter abuse in a sample of prescription opioid abusers Drug Alcohol Depend 2014; 139:9 12 L Degenhardt et al The introduction of a potentially abuse deterrent oxycodone formulation: early findings from the Australian National Opioid Medications Abuse Deterrence (NOMAD) study Drug Alcohol Depend 2015; 151:56 The Medical Letter ® 13 PM Coplan et al Changes in oxycodone and heroin exposures in the National Poison Data System after introduction of extended-release oxycodone with abuse-deterrent characteristics Pharmacoepidemiol Drug Saf 2013; 22:1274 14 TJ Cicero et al Effect of abuse-deterrent formulation of OxyContin N Engl J Med 2012; 367:187 15 TA Cassidy et al Changes in prevalence of prescription opioid abuse after introduction of an abuse-deterrent opioid formulation Pain Med 2014; 15:440 16 MR Larochelle et al Rates of opioid dispensing and overdose after introduction of abuse-deterrent extended-release oxycodone and withdrawal of propoxyphene JAMA Intern Med 2015; 175:978 17 CS Hwang et al Impact of abuse-deterrent OxyContin on prescription opioid utilization Pharmacoepidemiol Drug Saf 2015; 24:197 ▶ A New Subcutaneous Immune Globulin (HyQvia) for Primary Immunodeficiency Immune globulin (IgG) has been available for administration intravenously once every 3-4 weeks or subcutaneously once daily, once weekly, or every weeks for treatment of primary immunodeficiencies Now the FDA has approved human immune globulin 10% with recombinant human hyaluronidase (HyQvia – Baxter) for subcutaneous administration only every 3-4 weeks in adults with these disorders The IgG component of HyQvia is identical to Gammagard Liquid, which was approved in 2005 for IV administration and in 2011 for SC administration Pronunciation Key HyQvia: hi kyu' vee a PRIMARY IMMUNODEFICIENCY — Primary immunodeficiencies include common variable immunodeficiency (CVID), X-linked or congenital agammaglobulinemia, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies.1 These disorders are usually congenital or develop in early childhood, but may also develop later in life TREATMENT — Immunoglobulin replacement is the standard treatment for many primary immunodeficiencies Immune globulin subcutaneous (IGSC) is as effective as immune globulin intravenous (IGIV), but its use has been limited by the need for more frequent infusions Table Pharmacology Class Human immunoglobulin Route Subcutaneous infusion Formulations Immune globulin infusion 10% (human)/ recombinant human hyaluronidase solution in dual vial units containing 2.5 g/200 U, g/400 U, 10 g/800 U, 20 g/1600 U, 30 g/2400 U Tmax (mean) days Terminal half-life (mean) 59.3 days Vol 57 (1476) August 31, 2015 and multiple infusion sites to deliver large volumes of solution.2 Addition of recombinant human hyaluronidase increases the permeability of subcutaneous tissue, enabling large volumes of immune globulin to be infused at one site.3 CLINICAL STUDIES — Approval of HyQvia was based on an open-label trial in 87 patients ≥2 years old with primary immunodeficiencies All patients had been treated with IGIV 10% for months before receiving HyQvia.The systemic serum IgG exposure (AUC) with HyQvia was 93.3% of that with IGIV, and trough levels of IgG were similar with both routes After 14-18 months of treatment with HyQvia, the rate of acute serious bacterial infection, the primary endpoint, was 0.025 infections/patient/year, significantly less than 1.0, the threshold for demonstrating evidence of efficacy.4 Table Comparison of HyQvia and Other IGSC Infusions in a Clinical Study1 Parameter Median monthly number of infusion sites Median monthly infusion time (hrs) HyQvia Other IGSC 1.1 21.4 2.6 5.4 IGSC = Immune globulin subcutaneous Data summarized in the FDA Summary Basis for Regulatory Action September 2014 Available at www.fda.gov/BiologicsBloodVaccines/ default.htm Accessed August 20, 2015 ADVERSE EFFECTS — Most patients receiving IGSC, including HyQvia, experience infusion-site reactions such as discomfort/pain, erythema, swelling, and pruritus, which are seldom severe but can take a few days to resolve; they diminish over time Headache, thrombosis, hemolysis, transfusion-related acute lung injury, and aseptic meningitis syndrome have been reported with immune globulin products In the clinical trial, systemic reactions occurred less frequently with HyQvia than with IGIV (8.3% vs 25.0% of infusions) Non-neutralizing antibodies to recombinant human hyaluronidase developed in 18% of patients who received HyQvia Endogenous hyaluronidase is highly expressed in adult male testes, epididymides, and sperm; whether long-term exposure to recombinant human hyaluronidase could elicit antibodies that interfere with fertilization or have other adverse effects is not known PREGNANCY — HyQvia is classified as category C (adverse effects on the fetus with high doses of hyaluronidase in animals; no adequate studies in women) for use during pregnancy IMMUNIZATION — Like other human immune globulins, HyQvia may impair the immune response to live attenuated virus vaccines, which are 121 The Medical Letter ® August 31, 2015 Vol 57 (1476) Table Some Immune Globulin Subcutaneous Products for Primary Immunodeficiencies Drug Volume Usual Dosage Maximum Infusion Rate HyQvia (Baxter)2 25/1.25, 50/2.5, 100/5, 200/10, 300/15 mL dual vial units for single use (100 mg IgG/ 160 U hyaluronidase/mL) 10, 25, 50, 100, 200, 300 mL single-use vials (100 mg IgG/mL) 10, 25, 50, 100, 400 mL single-use bottles (100 mg IgG/mL) 5, 10, 20, 50 mL single-use vials (200 mg IgG/mL) 300-600 mg/kg q3-4 wks SC3