• A Nonprofi t OrganizationISSUE No.1468 Peginterferon Beta-1a Plegridy for Multiple Sclerosis ...Concentrated Insulin Glargine Toujeo for Diabetes ...p 67p 69Extended-Release Hydrocodon
The Medical Letter ® on Drugs and Therapeutics Objective Drug Reviews Since 1959 Volume 57 ISSUE ISSUE No 1433 1468 Volume 56 May 11, 2015 IN THIS ISSUE Peginterferon Beta-1a (Plegridy) for Multiple Sclerosis p 67 Concentrated Insulin Glargine (Toujeo) for Diabetes p 69 Extended-Release Hydrocodone (Hysingla ER) for Pain p 71 Testosterone Nasal Gel (Natesto) for Hypogonadism p 73 Blinatumomab (Blincyto) for Acute Lymphoblastic Leukemia online only 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 1468 Volume 56 ▶ May 11, 2015 Take CME Exams ALSO IN THIS ISSUE Concentrated Insulin Glargine (Toujeo) for Diabetes p 69 Extended-Release Hydrocodone (Hysingla ER) for Pain p 71 Testosterone Nasal Gel (Natesto) for Hypogonadism p 73 Blinatumomab (Blincyto) for Acute Lymphoblastic Leukemia online only Peginterferon Beta-1a (Plegridy) for Multiple Sclerosis The FDA has approved a pegylated form of interferon beta-1a (Plegridy – Biogen) for biweekly treatment of patients with relapsing multiple sclerosis (MS) Pronunciation Key Peginterferon: peg" in ter feer' on Plegridy: pleh' gri dee STANDARD TREATMENT — FDA-approved drugs for treatment of relapsing-remitting MS are listed in Table (see p 68) Interferon beta (Avonex, and others) and glatiramer acetate (Copaxone, Glatopa), both of which must be injected, are generally used first They reduce clinical relapse rates by about 30% and decrease the number of brain lesions seen on MRI.1 Second-line drugs are usually reserved for patients with severe disease and for those who cannot take first-line drugs Natalizumab (Tysabri), an IV recombinant humanized monoclonal antibody, can decrease relapse frequency and slow progression of the disease Alemtuzumab, an IV anti-CD52 monoclonal antibody, is now approved as Lemtrada for treatment of MS; it has been more effective than interferon beta in preventing relapses in treatmentnaive patients, but because of its safety profile, the package insert recommends reserving Lemtrada for patients who have had an inadequate response to two or more anti-MS drugs Oral drugs have only been available since 2010 and have generally been used as second-line agents Fingolimod (Gilenya), the first oral drug approved for treatment of MS, has reduced relapse rates by >50% and delayed progression of disability Teriflunomide Table Pharmacology Class Route Interferon beta Subcutaneous injection Formulation 63 mcg/0.5 mL, 94 mcg/0.5 mL,1 125 mcg/0.5 mL preservative-free solution in single-use pen or prefilled syringe 1-1.5 days ~78 hrs Catabolic Primarily renal Tmax Half-life (terminal) Metabolism Excretion The 63 mcg/0.5 mL and 94 mcg/0.5 mL pens and syringes are only available in a 4-week starter pack (Aubagio), a pyrimidine synthesis inhibitor, appears to cause smaller reductions in relapse rates than fingolimod, but is better tolerated.2 Dimethyl fumarate (Tecfidera) is an antioxidant that appears to be more effective than teriflunomide and is also better tolerated than fingolimod.3 THE NEW FORMULATION — Interferon beta was the first drug to alter the course of MS, but its adverse effects and the need for every-other-day subcutaneous or weekly intramuscular injections have made it difficult to use.4 Plegridy is pegylated (attached to polyethylene glycol) to increase its duration of action A CLINICAL STUDY — FDA approval of peginterferon beta-1a was based on a 96-week, randomized, double-blind clinical trial (ADVANCE) comparing the new formulation given once every or weeks with placebo in 1512 patients with relapsing-remitting MS Annualized relapse rates after 48 weeks were significantly lower with peginterferon beta-1a every weeks (0.256) and every weeks (0.288) than with placebo (0.397).5 After 48 weeks, patients receiving placebo were re-randomized into one of the two active drug groups The annualized relapse rate during the second half of the trial was 0.178 among patients 67 Published by The Medical Letter, Inc • A Nonprofit Organization The Medical Letter May 11, 2015 Vol 57 (1468) ® Table FDA-Approved Drugs for Relapsing Multiple Sclerosis Frequent or Serious Adverse Effects Drug Reduction in Clinical Usual Maintenance Relapse Rate Dosage Cost1 $59,250.003 Parenteral Alemtuzumab – Lemtrada (Genzyme) Rash, headache, pyrexia, nasopharyngitis, nausea, autoimmune disorders, infusion reactions, malignancies, immune cytopenias (especially thrombocytopenia), glomerular nephropathies, thyroid disorder, infections, pneumonitis 50%-55%2 Glatiramer acetate – Copaxone (Teva) Injection-site reactions, transient post-injection systemic reactions, chest pain ~30%4 Injection-site reactions, flu-like symptoms, depression, transaminase elevations, possible cardiac toxicity, autoimmune disorders, allergic reactions, hepatotoxicity, seizures, suicidal ideation, lymphopenia with interferon beta-1b 30%-35%4 Glatopa (Sandoz) Interferon beta-1a – Avonex (Biogen) Rebif (EMD SeronoIdec) pegylated – Plegridy (Biogen) Interferon beta-1b – Betaseron (Bayer) Extavia (Novartis) Year 1: 12 mg IV once/d x 5d Year 2: 12 mg IV once/d x 3d 20 mg SC once/d or 40 mg 3x/wk 20 mg SC once/d 73,326.00 65,104.00 N.A 30 mcg IM once/wk 44 mcg SC 3x/wk 125 mcg SC q2 wks 65,442.00 70,638.10 65,442.00 250 mcg SC every other day 69,397.00 57,693.60 Mitoxantrone – generic Nausea, alopecia, amenorrhea, cardiotoxicity at cumulative doses >100 mg/m2, myelosuppression, secondary acute myeloid leukemia ~60%6 12 mg/m2 IV q3 mos Natalizumab – Tysabri (Biogen) Headache, fatigue, arthralgia, depression, infections, hypersensitivity reactions, hepatotoxicity, progressive multifocal leukoencephalopathy (PML) ~65% 300 mg IV q4 wks 64,480.00 Fingolimod – Gilenya (Novartis) Transaminase elevations, bradycardia, AV block, macular edema, mild hypertension, decreased pulmonary function, serious viral infections ~55%8 0.5 mg PO once/d 70,752.10 Teriflunomide – Aubagio (Genzyme) Diarrhea, nausea, alopecia, transaminase elevations, neutropenia, leukopenia, peripheral neuropathy, hyperkalemia, hypophosphatemia, hypertension, hepatic failure, acute renal failure ~30%4 or 14 mg PO once/d 66,017.00 Dimethyl fumarate – Tecfidera (Biogen) Flushing, abdominal pain, nausea, lymphopenia, progressive multifocal leukoencephalopathy (PML) ~50%9 240 mg PO bid 65,520.00 3167.407 Oral N.A = cost not yet available Approximate WAC for year’s treatment at the usual maintenance 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 April 5, 2015 Reprinted with permission by First Databank, Inc All rights reserved ©2015 www.fdbhealth.com/policies/drug-pricing-policy Compared to interferon beta-1a (JA Cohen et al Lancet 2012; 380:1819; AJ Coles et al Lancet 2012: 380:1829) Cost for first year’s treatment is $98,750 Med Lett Drugs Ther 2012; 54:89 Branded generic 20 mg/mL formulation approved April 16, 2015 Not commercially available at press time HP Hartung et al Lancet 2002; 360:9018 Cost for treatment of a patient with a body surface area of 1.7 m2 using 10-mL multi-dose vials containing mg/mL Med Lett Drugs Ther 2010; 52:98 Med Lett Drugs Ther 2013; 55:45 receiving peginterferon beta-1a every weeks and 0.291 among those receiving the drug every weeks.6 No studies directly comparing peginterferon beta-1a with other beta interferon formulations are available, but reductions in relapse rates have been similar ADVERSE EFFECTS — Injection-site reactions, influenza-like symptoms, fever, and headache were the most common adverse effects of peginterferon beta-1a in the ADVANCE trial 68 DOSAGE AND ADMINISTRATION — The recommended dosage of peginterferon beta-1a is 63 mcg by subcutaneous injection on day 1, followed by 94 mcg on day 15 and 125 mcg on day 29 and every 14 days thereafter Plegridy is supplied in cartons containing two single-use prefilled pens or syringes A starter pack contains the initial 63-mcg (orange) and 94mcg (blue) doses Most patients can self-inject after receiving proper training The Medical Letter ® CONCLUSION — Pegylated interferon beta-1a (Plegridy) injected subcutaneously every weeks appears to be similar in its efficacy and adverse effects to older interferon formulations that must be injected more frequently ■ Canadian Agency for Drugs and Technologies in Health CADTH therapeutic review Comparative clinical and cost-effectiveness of drug therapies for relapsing-remitting multiple sclerosis [Internet] Ottawa: The Agency; 2013 Oct (CADTH Therapeutic Review vol 1, no 26) [cited 2015 April 30] Available at: https:// www.cadth.ca/media/pdf/TR0004_RRMS_ScienceReport_e.pdf New drugs for multiple sclerosis Med Lett Drugs Ther 2012; 54:89 Dimethyl fumarate (Tecfidera) for multiple sclerosis Med Lett Drugs Ther 2013; 55:45 V Annibali et al IFN-β and multiple sclerosis: from etiology to therapy and back Cytokine Growth Factor Rev 2015; 26:221 PA Calabresi et al Pegylated interferon -1a for relapsing-remitting multiple sclerosis (ADVANCE): a randomised, phase 3, double-blind study Lancet Neurol 2014; 13:657 BC Kieseier et al Peginterferon beta-1a in multiple sclerosis: 2-year results from ADVANCE Mult Scler 2014 November 28 (epub) ▶ Concentrated Insulin Glargine (Toujeo) for Diabetes The FDA has approved Toujeo (Sanofi), a more concentrated form of insulin glargine containing 300 IU/mL compared to the 100 IU/mL in Lantus (Sanofi) Lantus is nearing the end of its patent protection in the US, and biosimilars are expected to become available Pronunciation Key Insulin glargine: in’ su lin glar’ jeen Toujeo: too jay’ oh INSULIN GLARGINE — A long-acting analog of human insulin synthesized by recombinant DNA technology, insulin glargine forms microprecipitates in subcutaneous tissue that prolong its duration of action, permitting once-daily injection in most patients Toujeo has a more gradual and prolonged release of insulin from the subcutaneous depot than Lantus, resulting in more even activity throughout the dosing period and a longer duration of action The prolonged time in subcutaneous tissue may reduce the bioavailability of Toujeo.1,2 CLINICAL STUDIES — FDA approval of Toujeo was based on one open-label trial in patients with type diabetes (available only as an abstract) and openlabel studies in patients with type diabetes.3-6 All of the studies compared Toujeo with Lantus; the primary endpoint was the change in HbA1c from baseline at 26 weeks, and the main secondary endpoint was the percentage of patients with at least one confirmed (≤70 mg/dL) or severe nocturnal hypoglycemic Vol 57 (1468) May 11, 2015 Table Some Toujeo Clinical Trials Study Design Regimen Type Diabetes EDITION 13 Mealtime insulin 26 weeks +/- metformin4 (n=807) + Glargine 300 IU/mL + Glargine 100 IU/mL HbA1c Nocturnal Change (%)1 Hypoglycemia2 -0.83 -0.83 36%† 46% EDITION 25 26 weeks (n=811) Oral antidiabetic drugs6 + Glargine 300 IU/mL + Glargine 100 IU/mL -0.57 -0.56 21.6%† 27.9% EDITION 37 26 weeks (n=878) Oral antidiabetic drugs8 + Glargine 300 IU/mL + Glargine 100 IU/mL -1.42 -1.46 16% 17% -0.40 -0.44 8.110 7.910 Type Diabetes EDITION 49 Mealtime insulin 26 weeks + Glargine 300 IU/mL (n=549) + Glargine 100 IU/mL †Statistically significant compared to insulin glargine 100 IU/mL Mean change from baseline Percent of patients with at least one confirmed (≤70 mg/dL) or severe nocturnal hypoglycemic event between week and month MC Riddle et al Diabetes Care 2014; 37:2755 In patients previously uncontrolled on ≥42 units/day of basal insulin and mealtime insulin with or without metformin H Yki-Järvinen et al Diabetes Care 2014; 37:3235 In patients previously taking ≥42 units/day of basal insulin and oral antidiabetic drugs (except sulfonylureas) GB Bolli et al Diabetes Obes Metab 2015; 17:386 In insulin-naive patients who were taking oral antidiabetic drugs Glinides, sulfonylureas, and oral antidiabetic drugs not approved for use with insulin were discontinued at baseline PD Home et al Diabetologia 2014; 57 (Suppl 1):S69 Abstract 148 10 Events per participant-year of confirmed (≤70 mg/dL) or severe nocturnal hypoglycemia between week and month event reported between week and month In all studies, the reduction in HbA1c with glargine 300 IU/mL was similar to that with the 100 IU/mL formulation In of the trials in patients with type diabetes, rates of nocturnal hypoglycemia were significantly lower in the glargine 300 IU/mL group compared to the glargine 100 IU/mL group Patients treated with glargine 300 IU/mL required about 1015% more basal insulin per day than those treated with glargine 100 IU/mL In a 6-month, open-label extension of one of the type diabetes trials, glycemic control at the end of 12 months was maintained in both the glargine 300 IU/ mL group and the glargine 100 IU/mL group Fewer patients treated with glargine 300 IU/mL experienced at least one confirmed or severe hypoglycemic event at night or at any time of the day compared to those treated with glargine 100 IU/mL Annualized rates of hypoglycemia were similar in both groups.8 A meta-analysis of the clinical trials in patients with type diabetes (available only as an abstract) found that the risk of a nocturnal hypoglycemic event or a hypoglycemic event at any time of day was lower in patients treated with glargine 300 IU/mL than in those treated with glargine 100 IU/mL (31.7% vs 41.3% and 67.8% vs 73.8%, respectively).7 69 The Medical Letter May 11, 2015 Vol 57 (1468) ® Table Intermediate- and Long-Acting Insulins Drug Concentration Some Formulations Intermediate-Acting Insulins NPH – Humulin N 2 (Lilly) Novolin N 2 (Novo Nordisk) ReliOn/Novolin N 2 (Novo Nordisk) Onset Duration 1-2 hrs 16-24+ hrs Cost1 100 IU/mL 100 IU/mL 100 IU/mL 3, 10 mL vials; mL KwikPen 10 mL vial 10 mL vial 100 IU/mL 10 mL vial; mL FlexTouch pen 1-4 hrs 12-20 hrs 298.20 100 IU/mL 300 IU/mL 10 mL vial; mL SoloStar pen 1.5 mL SoloStar pen 1-4 hrs 1-6 hrs 22-24 hrs 24-36 hrs 298.20 335.50 $278.303 219.103 49.803,4 Long-Acting Insulins Insulin detemir – Levemir (Novo Nordisk) Insulin glargine – Lantus (Sanofi) Toujeo (Sanofi) Approximate WAC for 30 days' treatment with 40 IU/day in prefilled pens (or vials if pen formulation not available) 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 April 5, 2015 Reprinted with permission by First Databank, Inc All rights reserved ©2015 www.fdbhealth.com/policies/drug-pricing-policy Available over the counter Cost of vials Cost from manufacturer Available at www.relion.com/products/relionnovolin-human-insulin-n-inj Accessed April 27, 2015 Available only at Walmart ADVERSE EFFECTS — In the published studies in patients with type diabetes, there were no differences in adverse effects other than nocturnal hypoglycemia between glargine 300 IU/mL and 100 IU/mL, except that in one study (EDITION 2), weight gain was less with glargine 300 IU/mL (0.08 kg vs 0.66 kg) PREGNANCY — There are no clinical studies of Toujeo in pregnant women According to the manufacturer, it should only be used if the potential benefit outweighs the potential risk Lantus is classified as category C (risk cannot be ruled out) for use during pregnancy DOSAGE AND ADMINISTRATION — Toujeo is injected subcutaneously once daily, at the same time each day The recommended starting dose for insulinnaive patients with type diabetes is about one-third to one-half of the total daily insulin dose (the usual total daily starting dose of insulin for patients with type diabetes is about 0.2-0.4 IU/kg); the remainder of the total daily insulin dose should be given as rapid-acting insulin In insulin-naive patients with type diabetes, the recommended starting dose is 0.2 IU/kg once daily In patients switching from a once-daily long-acting insulin, the starting dose of Toujeo should be the same as the once-daily long-acting insulin dose Patients previously controlled on Lantus may need a 10-15% higher daily dose of Toujeo to maintain glycemic control Patients switching from twice-daily NPH insulin should start Toujeo at a dose that is 80% of the total daily NPH dose The dose of Toujeo should not be titrated more frequently than every to days Toujeo is available in 1.5-mL disposable prefilled pens Unused pens should be refrigerated; pens that have 70 been opened should be stored at room temperature and discarded after 28 days CONCLUSION — Toujeo, the new 300 IU/mL formulation of insulin glargine, is as effective as insulin glargine 100 IU/mL (Lantus) in lowering HbA1c, and might cause less hypoglycemia ■ RH Becker et al New insulin glargine 300 units·mL-1 provides a more even activity profile and prolonged glycemic control at steady state compared with insulin glargine 100 units·mL-1 Diabetes Care 2015; 38:637 M Shiramoto et al Single-dose new insulin glargine 300 U/ml provides prolonged, stable glycaemic control in Japanese and European people with type diabetes Diabetes Obes Metab 2015; 17:254 PD Home et al Glycaemic control and hypoglycaemia with new insulin glargine 300 U/mL in people with type diabetes (EDITION 4) Diabetologia 2014; 57 (Suppl 1):S69 Abstract 148 MC Riddle et al New insulin glargine 300 units/mL versus glargine 100 units/mL in people with type diabetes using basal and mealtime insulin: glucose control and hypoglycemia in a 6-month randomized controlled trial (EDITION 1) Diabetes Care 2014; 37:2755 H Yki-Järvinen et al New insulin glargine 300 units/mL versus glargine 100 units/mL in people with type diabetes using oral agents and basal insulin: glucose control and hypoglycemia in a 6-month randomized controlled trial (EDITION 2) Diabetes Care 2014; 37:3235 GB Bolli et al New insulin glargine 300 U/ml compared with glargine 100 U/ml in insulin-naïve people with type diabetes on oral glucose-lowering drugs: a randomized controlled trial (EDITION 3) Diabetes Obes Metab 2015; 17:386 I Hramiak et al New insulin glargine 300 U/mL: glycemic control and hypoglycemia in a meta-analysis of phase 3a EDITION clinical trials in people with T2DM Can J Diabetes 2014; 38:s8 Abstract 16 MC Riddle et al One year sustained glycaemic control and less hypoglycaemia with new insulin glargine 300 U/mL compared with 100 U/mL in people with type diabetes using basal + meal-time insulin (EDITION 12-month randomized trial including 6-month extension) Diabetes Obes Metab 2015 April (epub) The Medical Letter ▶ ® Extended-Release Hydrocodone (Hysingla ER) for Pain The FDA has approved a second extended-release (ER) formulation of the oral opioid agonist hydrocodone (Hysingla ER – Purdue) for management of pain severe enough to require continuous long-term therapy and for which alternative treatment options are inadequate Hysingla ER tablets have abuse-deterrent properties to discourage their misuse Pronunciation Key Hydrocodone: hye droe koe' done Hysingla: hye sing' luh HYDROCODONE — Hydrocodone has been available for years in combination with acetaminophen (Vicodin, and others) or ibuprofen (Vicoprofen, and others) The first single-ingredient hydrocodone product to be marketed in the US was Zohydro ER,1 which is formulated as a capsule It was originally approved without abuse-deterrent properties, but a new formulation incorporating excipients that form a viscous gel when the capsules are crushed and dissolved has been approved and will be available soon Hydrocodone is a schedule II controlled substance Combination pain medications containing hydrocodone were previously classified as schedule III, but were reclassified as schedule II in October 2014 As part of a Risk Evaluation and Mitigation Strategy (REMS) program, the FDA has required that training in the use of extendedrelease or long-acting opioids such as Hysingla ER be made available to prescribers from the manufacturers Vol 57 (1468) May 11, 2015 POTENTIAL FOR ABUSE — The clinical abuse potential of Hysingla ER tablets by the intranasal or oral route was evaluated in double-blind, randomized trials (summarized in the package insert), each in about 30 nondependent opioid abusers In the intranasal administration trial, coarsely and finely ground Hysingla ER 60-mg tablets were compared to the same dose of powdered immediaterelease (IR) hydrocodone Incomplete dosing (due to the drug falling from the nostril) occurred in 23 patients (82%) taking Hysingla ER and in none of those taking hydrocodone powder Patients taking Hysingla ER had significantly lower scores for “drug liking” and desire to “take drug again” In the oral administration trial, scores for “drug liking” and desire to “take drug again” were also significantly lower with intact and chewed Hysingla ER 60-mg tablets compared to the same dose of an oral solution of IR hydrocodone If a Hysingla ER tablet is dissolved, it will form a viscous gel that is difficult to inject through a hypodermic needle PHARMACOLOGY — Plasma hydrocodone concentrations increase gradually with Hysingla ER and reach a peak (Tmax) after a median of 14-16 hours The area under the concentration time curve (AUC) and maximum concentration (Cmax) increase linearly with doses of 20-120 mg The mean terminal half-life for all doses ranges from 7-9 hours Table Some Extended-Release Oral Opioids Drug Hydrocodone – Hysingla ER (Purdue) Zohydro ER (Pernix) Hydromorphone – Exalgo (Mallinckrodt) generic Morphine – Kadian (Actavis) generic MS Contin (Purdue) generic Morphine/naltrexone – Embeda (Pfizer) Oxycodone – OxyContin (Purdue) generic Oxymorphone – Opana ER (Endo) generic Formulations Starting Dosage1 Duration of Action 20, 30, 40, 60, 80, 100, 120 mg ER tabs 10, 15, 20, 30, 40, 50 mg ER caps 8, 12, 16, 32 mg ER tabs 8, 12, 16 mg ER tabs 20 mg q24h 10 mg q12h Footnote 24 hrs 12 hrs 24 hrs 10, 20, 30, 40, 50, 60, 70, 80, 100, 130, 150, 200 mg ER caps 20, 30, 50, 60, 80, 100 mg ER caps 15, 30, 60, 100, 200 mg ER tabs 30 mg q24h 12-24 hrs 15 mg q12h 8-12 hrs 20/0.8 mg q24h 24 hrs 10 mg q12h 12 hrs mg q12h 12 hrs 20/0.8, 30/1.2, 50/2, 60/2.4, 80/3.2, 100/4 mg ER caps 10, 15, 20, 30, 40, 60, 80 mg ER tabs 10, 20, 40, 80 mg ER tabs 5, 7.5, 10, 15, 20, 30, 40 mg ER tabs Cost2 $197.10 368.40 380.304 333.504 242.20 136.50 156.30 41.60 166.80 161.50 129.80 139.50 87.00 ER = extended-release For patients who are not opioid tolerant For patients switching from another opioid, starting dosage is based on previous opioid dosage Approximate WAC for 30 days’ treatment at the starting dosage WAC = wholesaler acquisition cost, or manufacturer’s published price to wholesalers; WAC represents a published catalogue or list price and may not represent actual transactional prices Source: AnalySource® Monthly April 5, 2015 Reprinted with permission by First Databank, Inc All rights reserved ©2015 www.fdbhealth.com/policies/drug-pricing-policy Only recommended for patients who are opioid tolerant Starting dosage determined by previous opioid dosage Cost for 30 8-mg ER tablets 71 The Medical Letter ® CLINICAL STUDIES — FDA approval of Hysingla ER was based on one unpublished trial (summarized in the package insert) in patients with moderate to severe chronic lower back pain inadequately controlled by previous analgesic therapy Patients (n=905) discontinued their analgesic medications and took Hysingla ER once daily titrated every 3-5 days until an effective and tolerable dose was reached (maximum 120 mg) A total of 588 patients entered the doubleblind phase of the trial and were randomized to continue treatment with Hysingla ER or begin a gradual tapering of their dose to placebo At week 12, the hydrocodone group had significantly lower pain scores than the placebo group, and more patients treated with Hysingla ER experienced a ≥30% or a ≥50% improvement in their weekly average pain scores ADVERSE EFFECTS — Adverse effects that occurred in ≥5% of patients who took the active drug during clinical trials were constipation, nausea, vomiting, fatigue, upper respiratory tract infection, dizziness, headache, and somnolence Serious, sometimes fatal, respiratory depression can occur with modified-release opioids even when used as directed The risk of respiratory depression is greatest following initiation of therapy or after a dose increase Patients who are elderly or debilitated, have chronic obstructive pulmonary disease, have suffered a head injury or increased intracranial pressure, or are taking other CNS depressants concomitantly are at increased risk QTc prolongation has occurred in patients taking 160-mg doses of Hysingla ER Use of hydrocodone/acetaminophen, particularly with high doses of hydrocodone, has rarely been associated with sensorineural hearing loss2; audiologic assessments in 1207 patients treated with Hysingla ER for up to year found no evidence of drug-induced ototoxicity.3 PREGNANCY — Hysingla ER is classified as category C (teratogenic effects in animals; no adequate studies in women) for use during pregnancy Infants born to mothers who received opioid therapy while pregnant may need treatment for neonatal opioid withdrawal syndrome DRUG INTERACTIONS — Hydrocodone is metabolized primarily by CYP3A4 to norhydrocodone and partly by CYP2D6 to hydromorphone Coadministration of Hysingla ER with ketoconazole, a strong CYP3A4 inhibitor, significantly increased plasma concentrations of hydrocodone and hydromorphone 72 Vol 57 (1468) May 11, 2015 Taking the drug with a CYP3A4 inducer may lower plasma concentrations of hydrocodone, leading to decreased efficacy and possibly to withdrawal symptoms.4 Administration of Hysingla ER with the strong CYP2D6 inhibitor paroxetine (Paxil, Brisdelle, and others) did not result in significant changes in the AUC and Cmax of hydrocodone, but it did reduce the formation of hydromorphone, which might lead to reduced analgesia Taking hydrocodone with CNS depressants such as alcohol, sedatives, or other opioids can increase the risk of profound sedation, respiratory depression, coma, and death Mixed agonist/antagonist opioid analgesics such as pentazocine (Talwin) or butorphanol (Stadol, and generics) could decrease the analgesic effect of hydrocodone and cause withdrawal symptoms Urinary retention and severe constipation, possibly leading to paralytic ileus, could occur with concurrent use of an opioid and an anticholinergic drug Use of Hysingla ER within 14 days of a monoamine oxidase inhibitor is not recommended Taking a strong laxative such as lactulose concomitantly could decrease absorption of Hysingla ER DOSAGE AND ADMINISTRATION — Patients switching from another oral hydrocodone product can take the same amount of Hysingla ER as the total daily hydrocodone dose of their previous drug For patients switching from another opioid, the dosage depends on the previous drug and its dose; conversion factors for different opioids are listed in the package insert The recommended starting dosage of Hysingla ER in opioid-naive patients is 20 mg once daily CONCLUSION — Hysingla ER, the second singleingredient extended-release hydrocodone product to become available in the US, is formulated for oncedaily use Zohydro ER is dosed twice daily and costs more Both Hysingla ER and the new formulation of Zohydro ER have abuse-deterrent properties, but they will still be subject to misuse ■ Extended-release hydrocodone (Zohydro ER) for pain Med Lett Drugs Ther 2014; 56:45 D Krashin et al Extended-release hydrocodone – gift or curse? J Pain Res 2013; 6:53 JW Kutz, Jr et al No hearing impairment from once-daily, single-entity hydrocodone treatment (Hysingla ER): results of phase-3 studies Presented at PAINWeek National Conference, Sept 2-6, 2014, Las Vegas, NV Abstract 149 Available at http://conference.painweek.org/media/mediafile_ attachments/04/724-painweek2014acceptedabstracts.pdf Accessed April 28, 2015 Inhibitors and inducers of CYP enzymes and P-glycoprotein Med Lett Drugs Ther 2013; 55:e44 The Medical Letter ▶ ® Testosterone Nasal Gel (Natesto) for Hypogonadism The FDA has approved an intranasal gel formulation of testosterone (Natesto – Trimel/Endo) for replacement therapy in men with hypogonadism Packaged in a metered-dose pump, Natesto is the first intranasal testosterone to become available in the US Like other testosterone products, it is classified as a schedule III controlled substance The FDA recently cautioned against using testosterone to treat low testosterone levels solely due to aging because the benefits and safety of such use have not been established, and there is a possible increased risk of myocardial infarction (MI) and stroke.1 Pronunciation Key Testosterone: tes tos' ter one Natesto: na tes' toe HYPOGONADISM — Failure of the testes to produce adequate amounts of testosterone can lead to loss of energy, irritability, depression, decreased libido, erectile dysfunction, decreased axillary and pubic hair, loss of muscle mass, anemia, and osteoporosis Testosterone serum concentrations decrease by about Vol 57 (1468) May 11, 2015 1-2% per year after age 40 The normal range (usually 300-1000 ng/dL) is based on serum concentrations in younger men Older men with signs and symptoms of hypogonadism may have levels ≤200 ng/dL TESTOSTERONE REPLACEMENT — Testosterone is not effective when taken orally because of gut wall and first-pass hepatic metabolism, but injectable, transdermal, and buccal formulations can achieve normal serum concentrations The intranasal route offers a large surface area and avoidance of firstpass hepatic metabolism.2 Pharmacokinetic studies have shown that administration of testosterone intranasally or times daily in severely hypogonadal men can achieve serum concentrations in the normal physiological range.3 CLINICAL STUDIES — FDA approval of testosterone nasal gel was based on a single unpublished, 90-day, open-label trial (summarized in the package insert) in 306 hypogonadal men with a mean age of 54 years Patients self-administered 11 mg of the drug either or times daily At day 90, 69 of 73 men (90%) who used the drug three times daily had an average serum testosterone concentration within Table Some Testosterone Replacement Products Drugs Some Formulations Usual Adult Dosage Cost1 Testosterone enanthate – generic Delatestryl (Endo) mL vial (200 mg/mL) 50-400 mg IM every 2-4 wks $68.00 82.80 Testosterone cypionate – generic Depo-Testosterone (Pfizer) 1, 10 mL vial (100 mg/mL, 200 mg/mL)2 1, 10 mL vial (100 mg/mL, 200 mg/mL)2 50-400 mg IM every 2-4 wks 45.30 73.50 Testosterone undecanoate – Aveed (Endo) mL vial (250 mg/mL) Injectable 750 mg IM at and wks, then q10 wks 837.40 Transdermal Androderm (Actavis) 2, mg/d patch mg once nightly 404.00 Androgel 1% (Abbvie) 2.5 g gel packet (25 mg test.); g gel packet (50 mg test.); 75 g MDP (12.5 mg test in 1.25 g gel/act) 50 mg once/d 444.90 Androgel 1.62% (Abbvie) 1.25 g gel packet (20.25 mg test.); 2.5 g gel packet (40.5 mg test.); 75 g MDP (20.25 mg test in 1.25 g gel/act) 40.5 mg once/d 432.90 Axiron (Lilly) 90 mL MDP (30 mg test in 1.5 mL soln/act) 60 mg once/d3 432.00 Fortesta (Endo) 60 g MDP (10 mg test in 0.5 g gel/act) 40 mg once/d 383.50 Testim (Auxilium/Endo) g tube of gel (50 mg test.) 50 mg once/d 445.50 11 g MDP (5.5 mg test in 0.122 g gel/act) 11 mg tid4 597.00 30 mg buccal tablet 30 mg bid 496.00 Intranasal Natesto (Trimel/Endo) Buccal Striant (Auxilium/Endo) act = actuation; MDP = metered-dose pump; test = testosterone Approximate wholesale acquisition cost (WAC) for one 5-mL vial of testosterone enanthate, one 10-mL vial (100 mg/mL) of testosterone cypionate, one 3-mL vial of Aveed, or a 30-day supply of transdermal or buccal formulations at the 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 April 5, 2015 Reprinted with permission by First Databank, Inc All rights reserved ©2015 www.fdbhealth.com/policies/drug-pricing-policy Cost of administration is not included The 100-mg/mL formulation is only available in a 10-mL vial Should be administered as pump actuation (30 mg) to each axilla Should be administered as pump actuation (5.5 mg) in each nostril 73 The Medical Letter ® Table Pharmacology Class Androgen Formulation 11 g metered-dose pump (5.5 mg testosterone/actuation) Route Intranasal Tmax ~40 Half-life (terminal) 10-100 Metabolism Metabolized by 5α-reductase and aromatase to various 17-ketosteroids Excretion Not characterized the normal range (300-1050 ng/dL) No information is provided on the results with twice-daily dosing An NIH-sponsored trial of testosterone efficacy in elderly men is in progress.4 ADVERSE EFFECTS — The most common adverse effects in the clinical trial of intranasal testosterone were an increased prostate specific antigen (PSA) level, headache, rhinorrhea, epistaxis, nasal discomfort, nasopharyngitis, bronchitis, upper respiratory tract infection, sinusitis, and nasal scab Venous thromboembolism has been reported The concern about an increased risk of MI and stroke with testosterone is based on studies.5 The first examined the records of 8709 men who had undergone coronary angiography and incidentally were found to have low testosterone levels (