The Medical Letter ® on Drugs and Therapeutics Objective Drug Reviews Since 1959 Volume 57 ISSUE ISSUE No 1433 1481 Volume 56 November 9, 2015 IN THIS ISSUE Sumatriptan Patch (Zecuity) for Migraine p 151 Two Long-Acting Injectable Antipsychotics for Schizophrenia p 152 Budesonide Rectal Foam (Uceris) for Ulcerative Colitis p 154 Transdermal Fentanyl (Ionsys) for Postoperative Pain .p 155 In Brief: Hepatic Injury with Hepatitis C Drugs p 156 Addendum: Flibanserin (Addyi) for Hypoactive Sexual Desire Disorder p 156 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 Revised 11/24/2015: In the Zecuity introductory paragraph "serotonin receptor antagonists" has been changed to "serotonin 1B/1D-receptor agonists" 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 1481 Volume 56 ▶ November 9, 2015 Take CME Exams ALSO IN THIS ISSUE Two Long-Acting Injectable Antipsychotics for Schizophrenia p 152 Budesonide Rectal Foam (Uceris) for Ulcerative Colitis p 154 Transdermal Fentanyl (Ionsys) for Postoperative Pain .p 155 In Brief: Hepatic Injury with Hepatitis C Drugs p 156 Addendum: Flibanserin (Addyi) for Hypoactive Sexual Desire Disorder p 156 A Sumatriptan Patch (Zecuity) for Migraine The FDA has approved a sumatriptan iontophoretic transdermal system (Zecuity – Teva) for acute treatment of migraine in adults Sumatriptan, the first of seven serotonin 1B/1D-receptor agonists (triptans) approved for this indication, is the most frequently prescribed migraine treatment in the US It is also available in oral, intranasal, and injectable formulations THE PATCH — Zecuity is a disposable, single-use transdermal patch composed of a battery-operated iontophoretic device and a drug reservoir card Activation of a low-intensity electrical current moves sumatriptan through the skin and subcutaneous tissue into the systemic circulation Pronunciation Key Sumatriptan : soo" ma trip' tan Zecuity: zeh cue' eh tee PHARMACOKINETICS — Serum concentrations of sumatriptan peak at a median of 1.1 hours after application of the Zecuity patch Cmax and AUC values are 37% and 45%, respectively, of those with 100-mg sumatriptan tablets, but are higher than those achieved with the nasal spray.3 RATIONALE FOR A PATCH — Patients with migraine who also have nausea, vomiting, or gastroparesis may not be able to take or absorb an oral triptan Nasal sprays have a more rapid onset of action than oral formulations (1015 vs 30-60 minutes), but they can have an unpleasant taste and they also depend on gastrointestinal absorption of the significant portion of the dose that is swallowed Subcutaneously administered sumatriptan is the fastest acting (about 10 minutes) and most effective triptan formulation, but it causes more adverse effects than other formulations and some patients are reluctant to use it.1,2 CLINICAL STUDY — A randomized, double-blind trial in 469 patients with a moderate to severe acute migraine attack compared the sumatriptan patch with a placebo patch that delivered sodium chloride Significantly greater pain relief was reported with the active patch than with placebo at hour after patch activation The percentage of patients who were free of headache pain hours after beginning treatment, the primary endpoint, was 18% with the active patch and 9% with placebo The percentage reporting relief of headache pain at hours was 53% with the active patch and 29% with placebo.4 Table Some Sumatriptan Products for Acute Treatment of Migraine Drug Some Available Formulations Usual Adult Dosage generic 25, 50, 100 mg tabs mg/0.5 mL vial, prefilled syringe, auto-injector 50 or 100 mg PO; can be repeated after hrs (max 200 mg/d) mg SC; can be repeated once after hr (max 12 mg/d) $2.10 25.502 Imitrex (GSK) 25, 50, 100 mg tabs 5, 20 mg/0.1 mL nasal spray 50 or 100 mg PO; can be repeated after hrs (max 200 mg/d) 5, 10 or 20 mg intranasally; can be repeated once after hrs (max 40 mg/d) mg SC; can be repeated once after hr (max 12 mg/d) 48.20 60.10 mg/0.5 mL vial; 4, mg/0.5 mL cartridges, auto-injectors Cost1 140.502 Alsuma (Pfizer) mg/0.5 mL auto-injector mg SC; can be repeated once after hr (max 12 mg/d) 98.90 Sumavel DosePro (Endo) 4, mg/0.5 mL needle-free injector mg SC; can be repeated once after hr (max 12 mg/d) 150.60 Zecuity (Teva) 6.5 mg transdermal patch 6.5 mg transdermally; a second patch can be applied after hrs (max patches/d) 289.00 Approximate WAC for one 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 October 5, 2015 Reprinted with permission by First Databank, Inc All rights reserved ©2015 www.fdbhealth.com/policies/drug-pricing-policy Cost of vial 151 Published by The Medical Letter, Inc • A Nonprofit Organization The Medical Letter ® ADVERSE EFFECTS — Most patients treated with the patch experience erythema at the application site, which may take or days to resolve In an open-label study, 45% of 183 patients with migraine who used the patch for up to 12 months (maximum patches in any 30-day period) reported other applicationsite reactions, including pruritus, pain, exfoliation, vesicles, and bruising Nausea was reported in 3% of patients and 1.6% experienced typical triptanassociated adverse events such as tingling, flushing, and chest tightness.5 DOSAGE AND ADMINISTRATION — Before application, patients must assemble the patch by attaching the medication pads in the drug reservoir card to the iontophoretic device The patch must then be applied to the upper arm or thigh, and activated within 15 minutes of initiating assembly by pressing a button The button will light up and remain on as the patch delivers 6.5 mg of sumatriptan over about hours When the light turns off, the patient should remove and discard the patch If the headache persists, a second patch can be applied at a different site at least hours after activation of the first patch No more than patches should be applied in a 24-hour period Zecuity should not be applied near or over other electrically-active medical devices and it must be removed before an MRI procedure CONCLUSION — The iontophoretic patch formulation of sumatriptan (Zecuity) for acute treatment of migraine provides relief of headache pain in about 50% of patients after hours, but it requires some assembly by the patient, has a slower onset of action than injectable or intranasal formulations, and frequently causes application-site reactions It is much more expensive than other sumatriptan formulations, but causes few triptan-associated adverse events It might be worth trying in patients who are unable to tolerate or unwilling to use other triptan formulations ■ Drugs for migraine Treat Guidel Med Lett 2013; 11:107 M Vikelis et al Sumatriptan transdermal iontophoretic patch (NP101-Zelrix™): review of pharmacology, clinical efficacy, and safety in the acute treatment of migraine Neuropsychiatr Dis Treat 2012; 8:429 MW Pierce Transdermal delivery of sumatriptan for the treatment of acute migraine Neurotherapeutics 2010; 7:159 J Goldstein et al A sumatriptan iontophoretic transdermal system for the acute treatment of migraine Headache 2012; 52:1402 TR Smith et al Twelve-month tolerability and efficacy study of NP101, the sumatriptan iontophoretic transdermal system Headache 2012; 52:612 152 Vol 57 (1481) ▶ November 9, 2015 Two Long-Acting Injectable Antipsychotics for Schizophrenia The FDA has approved two new long-acting injectable formulations of second-generation antipsychotics for treatment of schizophrenia: aripiprazole lauroxil (Aristada – Alkermes), which is given once every 4-6 weeks, and paliperidone palmitate (Invega Trinza – Janssen), which is given once every months Once-monthly injectable formulations of aripiprazole (Abilify Maintena) and paliperidone palmitate (Invega Sustenna) were approved earlier.1,2 Pronunciation Key Aripiprazole lauroxil: ar” i pip’ zole lawr ox’ il Aristada: air is tah’ dah Paliperidone palmitate: pal’’ ee per’ i done pawl’ mi tate Invega Trinza: in vay’ guh trin’ za SECOND-GENERATION ANTIPSYCHOTICS — Secondgeneration antipsychotics are used more commonly than first-generation drugs, even though controlled trials have failed to demonstrate a clear advantage in efficacy with the newer drugs, except for clozapine (Clozaril, and others) and possibly olanzapine (Zyprexa, and others) Because of its potential for serious toxicity, clozapine, the most effective antipsychotic drug, is usually reserved for patients whose symptoms have failed to respond adequately to other antipsychotics Olanzapine may have slight advantages over some other drugs in efficacy, but its metabolic adverse effects can make it unacceptable for long-term use Patients who not respond to one antipsychotic may respond to another Adverse effects such as movement disorders and metabolic effects, cost, and lack of access to nonpharmacological services can interfere with adherence to antipsychotics Long-acting injectable antipsychotics may be useful when adherence is a problem CLINICAL STUDIES — Approval of aripiprazole lauroxil was based on a 12-week, double-blind trial in which 622 patients with schizophrenia who were experiencing an acute exacerbation or relapse were randomized to receive a monthly injection of aripiprazole lauroxil (441 mg or 882 mg) or placebo The Positive and Negative Syndrome Scale (PANSS) total score improved significantly more from baseline to day 85 in patients who received aripiprazole lauroxil, compared to those who received placebo.3 Approval of the new formulation of paliperidone palmitate was based on a trial in 305 patients with The Medical Letter Vol 57 (1481) ® November 9, 2015 Table Long-Acting Injectable Antipsychotics Drug First-Generation Fluphenazine decanoate – generic Haloperidol decanoate – generic Haldol Decanoate (Janssen) Second-Generation Aripiprazole – Abilify Maintena (Otsuka/Lundbeck) Aripiprazole lauroxil – Aristada (Alkermes) Olanzapine pamoate – Zyprexa Relprevv (Lilly) Paliperidone palmitate – Invega Sustenna (Janssen) Invega Trinza (Janssen) Risperidone – Risperdal Consta (Janssen) Some Available Formulations Usual Adult Dosage1 Cost2 25 mg/mL vial 50 mg/mL, 100 mg/mL vials 12.5-25 mg IM or SC q2-3 weeks 10-15 times previous daily oral dose IM q4 weeks $144.903 33.804 151.004 300, 400 mg vials, prefilled syringes 400 mg IM once/month 1646.30 441, 662, 882 mg prefilled syringes 441-882 mg IM once/month or 882 mg IM q6 weeks 150-300 mg IM q2 weeks or 300-405 mg IM once/month 210, 300, 405 mg vials 39, 78, 117, 156, 234 mg prefilled syringes 273, 410, 546, 819 mg prefilled syringes 12.5, 25, 37.5, 50 mg vials 117 mg IM once/month 410 mg IM q3 months 25 mg IM q2 weeks N.A 842.40 1004.70 3014.20 723.70 IM = intramuscular; SC = subcutaneous; N.A = Cost not yet available Dosage for schizophrenia Dosage is usually based on patient’s stable oral maintenance dosage Approximate WAC for weeks’ or month’s treatment (3 months' treatment with Invega Trinza) with the lowest usual adult dosage WAC = wholesaler acquisition cost or manufacturer’s published price to wholesalers; WAC represents a published catalogue or list price and may not represent an actual transactional price Source: AnalySource® Monthly October 5, 2015 Reprinted with permission by First Databank, Inc All rights reserved ©2015 www.fdbhealth.com/policies/drug-pricing-policy Cost of one 5-mL vial Cost of one 100-mg dose schizophrenia who were first treated with oncemonthly paliperidone palmitate for 17 weeks, followed by a single dose of 3-month paliperidone palmitate Patients were then randomized to receive paliperidone palmitate once every months or to placebo The trial was terminated early after an interim analysis found that the median time to relapse was 274 days with placebo, and was not estimable for 3-month paliperidone palmitate.4 ADVERSE EFFECTS — The most common adverse effects of aripiprazole lauroxil in the clinical trial were akathisia, insomnia, and headache.3 Adverse effects of the new formulation of paliperidone palmitate, including injection-site reactions, weight gain, akathisia, and parkinsonism, were similar to those with the once-monthly formulation DOSAGE AND ADMINISTRATION — Aripiprazole lauroxil is a prodrug of aripiprazole It is administered once monthly by intramuscular injection; the 882-mg dose can also be given every weeks The dose is based on the current daily oral aripiprazole dose (10 mg of oral aripiprazole = 441 mg of Aristada, 15 mg = 662 mg, and ≥20 mg = 882 mg) Oral aripiprazole should be continued for 21 days after the first injection of Aristada Patients who are aripiprazole naive should take oral aripiprazole for weeks before starting aripiprazole lauroxil to establish tolerability Dosage adjustments (described in the package insert) are recommended if aripiprazole lauroxil is taken concurrently with a strong inhibitor or inducer of CYP3A4 or a strong inhibitor of CYP2D6 for ≥2 weeks.5 The new formulation of paliperidone palmitate is injected intramuscularly once every months It is only approved for use in patients who have been adequately treated with the once-monthly formulation of paliperidone palmitate for at least months The dose of Invega Trinza is based on the previous dose of the once-monthly formulation (78 mg of Invega Sustenna = 273 mg Invega Trinza, 117 mg = 410 mg, 156 mg = 546 mg, and 234 mg = 819 mg) Paliperidone palmitate is not recommended for patients with moderate or severe renal impairment CONCLUSION — The long-acting injectable antipsychotics aripiprazole lauroxil (Aristada) and paliperidone palmitate (Invega Trinza) both appear to be effective for maintenance treatment of schizophrenia Like other long-acting injectable antipsychotics, they may improve adherence, but their effects cannot be reversed if toxicity or pregnancy occur, which may be especially problematic with Invega Trinza since its effects last for months There are no trials directly comparing either of these products with other available long-acting injectable antipsychotics ■ Drugs for psychiatric disorders Treat Guidel Med Lett 2013; 11:53 Long-acting injectable aripiprazole (Abilify Maintena) for schizophrenia Med Lett Drugs Ther 2013; 55:34 HY Meltzer et al A randomized, double-blind, placebo-controlled trial of aripiprazole lauroxil in acute exacerbation of schizophrenia J Clin Psychiatry 2015; 76:1085 J Berwaerts et al Efficacy and safety of the 3-month formulation of paliperidone palmitate vs placebo for relapse prevention of schizophrenia: a randomized clinical trial JAMA Psychiatry 2015; 72:830 Inhibitors and inducers of CYP enzymes and P-glycoprotein Med Lett Drugs Ther 2013; 55:e44 153 The Medical Letter ▶ ® Budesonide Rectal Foam (Uceris) for Ulcerative Colitis The FDA has approved a rectal foam formulation of the corticosteroid budesonide (Uceris - Salix/Valeant) for induction of remission in patients with active mild to moderate distal ulcerative colitis (UC) extending up to 40 cm from the anal verge Budesonide is also available as oral extended-release tablets (also branded as Uceris) for use in patients with UC and as oral enteric-coated tablets (Entocort EC, and generics) for treatment of Crohn’s disease.1,2 Pronunciation Key Budesonide : bue des' oh nide Uceris: ue sair' us TOPICAL TREATMENT OF DISTAL UC – Rectally instilled aminosalicylates and corticosteroids can induce remission in mild to moderate distal UC Enemas reach the splenic flexure, but may be difficult for patients to tolerate Hydrocortisone rectal foam (Cortifoam) and mesalamine rectal suppositories (Canasa) are better tolerated, but their activity is generally limited to the 15 cm and 10 cm, respectively, nearest the anal verge Combination treatment with orally and rectally administered aminosalicylates is often used for distal UC that does not respond to rectal therapy alone.3,4 CLINICAL STUDIES – FDA approval of budesonide rectal foam was based on two 6-week, double-blind, placebo-controlled trials in a total of 546 patients with active distal UC extending 5-40 cm from the anal verge.5 Patients were randomized to receive budesonide rectal foam mg or placebo twice daily for weeks, then once daily for weeks Use of oral aminosalicylates was allowed; 51.0% and 59.8% of patients in the two trials were taking mesalamine at baseline In both trials, the remission rate (the primary endpoint) was significantly greater with budesonide than with placebo (38.3% vs 25.8% and 44.0% vs 22.4%) The active drug was also more likely than placebo to reduce the rectal bleeding score to (46.6% vs 28.0% and 50.0% vs 28.3%), a secondary endpoint ADVERSE EFFECTS – In the two clinical trials, morning blood cortisol levels declined in some patients during the weeks of twice-daily budesonide treatment and gradually normalized during the subsequent weeks of once-daily treatment; all patients with decreased morning blood cortisol levels responded to ACTH challenge After weeks of treatment, the rates of glucocorticoid adverse effects were similar with Uceris and placebo 154 Vol 57 (1481) November 9, 2015 Table Some Topical Drugs for Distal Ulcerative Colitis Drug Aminosalicylates Mesalamine - generic Rowasa (Meda) sfRowasa (Meda) Canasa (Actavis) Corticosteroids Budesonide Uceris (Salix/Valeant) Hydrocortisone - generic Colocort (Perrigo) Cortenema (Ani) Cortifoam (Meda) Available Formulations Cost1 g/60 mL enema $561.50 2189.40 2171.40 1141.80 1000 mg rectal suppository mg/application rectal foam 1024.00 100 mg/60 mL enema 256.00 291.10 327.60 10% rectal foam 980.302 Approximate WAC for weeks’ treatment WAC = wholesaler acquisition cost or manufacturer’s published price to wholesalers; WAC represents a published catalogue or list price and may not represent an actual transactional price Source: AnalySource® Monthly October 5, 2015 Reprinted with permission by First Databank, Inc All rights reserved ©2015 www.fdbhealth com/policies/drug-pricing-policy Approximate WAC for 45 applications PREGNANCY – Budesonide is classified as category C (teratogenic and embryocidal in animals; no adequate studies in women) for use during pregnancy DRUG INTERACTIONS – Budesonide is a substrate of CYP3A4 Concurrent use of CYP3A4 inhibitors, such as clarithromycin, may increase systemic exposure to budesonide and should be avoided.6 DOSAGE AND ADMINISTRATION – The recommended dosage of budesonide rectal foam is mg in the morning and at bedtime for weeks, then mg once daily at bedtime for weeks The drug is supplied in a kit containing two 14-dose canisters that release mg of budesonide per metered dose After attaching an applicator, the canister should be warmed in the hands while being shaken vigorously for 10-15 seconds before administration CONCLUSION – The rectal foam formulation of budesonide (Uceris) appears to be well tolerated and modestly effective in inducing remission in patients with mild to moderate distal ulcerative colitis extending up to 40 cm from the anal verge How it compares to other topical drugs for this indication remains to be determined ■ Budesonide (Uceris) for ulcerative colitis Med Lett Drugs Ther 2013; 55:23 Budesonide (Entocort EC) for Crohn’s disease Med Lett Drugs Ther 2002; 44:6 Drugs for inflammatory bowel disease Med Lett Drugs Ther 2014; 56:65 A Kornbluth et al Ulcerative colitis practice guidelines in adults: American College of Gastroenterology, Practice Parameters Committee Am J Gastroenterol 2010; 105:501 WJ Sandborn et al Budesonide foam induces remission in patients with mild to moderate ulcerative proctitis and ulcerative proctosigmoiditis Gastroenterology 2015; 148:740 Inhibitors and inducers of CYP enzymes and P-glycoprotein Med Lett Drugs Ther 2013; 55:e44 The Medical Letter ▶ ® Transdermal Fentanyl (Ionsys) for Postoperative Pain A patient-controlled fentanyl iontophoretic transdermal system (Ionsys – The Medicines Company) is now available for short-term management of acute postoperative pain in adults requiring opioid analgesia in the hospital Before using Ionsys, patients must be titrated to a comfortable level of analgesia with another opioid formulation Fentanyl : fen' ta nil Pronunciation Key Ionsys: eye on' sis THE DEVICE — The fentanyl iontophoretic transdermal system (ITS) has two parts: a drug unit and a controller containing the battery and electronics The single-use, disposable device, which is about the size of a credit card, is attached to the patient’s skin by an adhesive strip A button on the controller activates a low-intensity electric current that drives a fixed dose of fentanyl ions from a hydrogel reservoir through the skin and into the systemic circulation PHARMACOKINETICS – The pharmacokinetic profile of transdermal fentanyl is similar to that of IV fentanyl, but serum concentrations of the drug rise more slowly, peak at a lower level, and fluctuate less with the ITS.1 CLINICAL STUDIES — The efficacy of the fentanyl ITS was established in three randomized, doubleblind, placebo-controlled trials, two of which have been published, in patients with postoperative pain following major surgery.2,3 In each of the trials, pain was treated immediately after surgery with IV fentanyl or morphine until the patient was comfortable Patients were then randomized to the fentanyl ITS or placebo for 24 hours Rescue IV fentanyl was permitted during the first hours after randomization The results are summarized in Table In a meta-analysis of four randomized, activecontrolled trials comparing the fentanyl ITS to IV patient-controlled analgesia with morphine in ˃2500 postoperative patients, patient-rated pain control scores and the number of patients who required supplemental opioids were similar with both treatments.4 In ease-of-use studies, patients, nurses, and physical therapists rated transdermal Ionsys more efficient and convenient to use than IV patientcontrolled analgesia with morphine.5-7 ADVERSE EFFECTS — In clinical trials, the most common adverse effects reported with the fentanyl Vol 57 (1481) November 9, 2015 Table Ionsys Clinical Trials Withdrew due to Inadequate Pain Control1 Required Supplemental Fentanyl2 Mean Pain Intensity Score3 Study 14 Fentanyl (n=244) Placebo (n=240) 29% 60% 46% 58% 3.5 5.4 25% 40% 48% 55% 31 41 8% 41% 34% 36% 21 37 Study 25 Fentanyl (n=142) Placebo (n=47) Study 36 Fentanyl (n=77) Placebo (n=22) After the first hours (the primary endpoint) All of these differences were statistically significant Supplemental IV fentanyl could be administered as needed for up to hours after randomization At 24 hours or withdrawal (a secondary endpoint) Study used a verbal numerical rating scale that ranged from 0-10 Studies and used a visual analogue scale that ranged from 0-100 mm All of these differences were statistically significant ER Viscusi et al Anesth Analg 2006; 102:188 JE Chelly et al Anesth Analg 2004; 98:427 Results summarized in the package insert ITS were nausea, application-site erythema, pruritus, vomiting, headache, anemia, dizziness, urinary retention, and hypotension Fentanyl is classified as a schedule II controlled substance Due to the risk of fatal respiratory depression with accidental exposure to fentanyl, Ionsys is only available through a Risk Evaluation and Mitigation Strategy (REMS) program The fentanyl ITS is contraindicated in patients with paralytic ileus, gastrointestinal obstruction, significant respiratory depression, or acute or severe bronchial asthma Patients using the fentanyl ITS who have biliary tract disease, seizure disorders, or bradyarrhythmias should be monitored for worsening symptoms PREGNANCY — Ionsys has not been studied in pregnant women Embryonic death and developmental delays have occurred in pregnant animals given fentanyl DRUG INTERACTIONS — Fentanyl is metabolized primarily by CYP3A4 Taking a CYP3A4 inducer concurrently could decrease serum concentrations of fentanyl and lead to loss of efficacy and opioid withdrawal Concomitant use of a CYP3A4 inhibitor could result in increased fentanyl concentrations and toxicity.8 Use of fentanyl with CNS depressants such as alcohol, sedatives, and other opioids can result in additive CNS depressant effects Concomitant use of muscle relaxants can increase the degree of respiratory depression Ionsys should not be used with or within 14 days of a monamine oxidase (MAO) inhibitor or with mixed agonist/antagonist or partial agonist opioid analgesics 155 The Medical Letter ® DOSAGE, ADMINISTRATION, AND COST — Ionsys should only be used after the patient has been titrated to an acceptable level of analgesia with another opioid formulation The device should be assembled by a healthcare provider and applied to healthy, intact skin on the upper outer arm or chest The Ionsys transdermal system contains 9.7 mg of fentanyl The device is programmed to deliver a 40mcg dose of fentanyl over 10 minutes To administer a dose, the patient pushes the dosing button twice within seconds A digital counter displays the total number of doses given A maximum of doses can be administered per hour Ionsys will deactivate after 80 doses of the drug have been delivered or after 24 hours, whichever occurs first A patient can receive up to 72 hours of treatment with the fentanyl ITS Each new device should be applied to a different area of skin One fentanyl ITS costs $200.9 The Ionsys device must be removed before magnetic resonance imaging (MRI) It can also interfere with x-ray imaging and CT scans The device can be damaged by exposure to electromagnetic fields such as those created during cardioversion or defibrillation procedures, and by using it near electronic security systems, communications equipment, or Radio Frequency Identification (RFID) transmitters Use of Ionsys does not interfere with electromechanical devices such as pacemakers and electrical monitoring equipment CONCLUSION — Transdermal iontophoretic fentanyl (Ionsys) is an expensive option for patient-controlled, in-hospital treatment of postsurgical pain after the patient has been titrated to comfort using another form of opioid analgesia It may be more convenient to use than IV patient-controlled analgesia, but lacks dosing flexibility Some patients will require supplemental analgesia during the first hours after application of the device ■ JB Phipps et al Pharmacokinetic characteristics of fentanyl iontophoretic transdermal system over a range of applied current Expert Opin Drug Metab Toxicol 2015; 11:481 ER Viscusi et al An iontophoretic fentanyl patient-activated analgesic delivery system for postoperative pain: a double-blind, placebo-controlled trial Anesth Analg 2006; 102:188 JE Chelly et al The safety and efficacy of a fentanyl patient-controlled transdermal system for acute postoperative analgesia: a multicenter, placebo-controlled trial Anesth Analg 2004; 98:427 RS Sinatra et al Meta-analysis of the efficacy of the fentanyl iontophoretic transdermal system versus intravenous patientcontrolled analgesia in postoperative pain management Expert Opin Pharmacother 2015; 16:1607 P Pennington et al Patients’ assessment of the convenience of fentanyl HCl iontophoretic transdermal system (ITS) versus morphine intravenous patient-controlled analgesia (IV PCA) in the management of postoperative pain after major surgery Pain Manag Nurs 2009; 10:124 156 Vol 57 (1481) November 9, 2015 P Lindley et al Comparison of postoperative pain management using two patient-controlled analgesia methods: nursing perspective J Adv Nurs 2009; 65:1370 MH Bourne et al Physical therapists’ perceptions of ease of care in patients receiving forms of analgesia after total hip arthroplasty Phys Ther 2010; 90:707 Inhibitors and inducers of CYP enzymes and P-glycoprotein Med Lett Drugs Ther 2013; 55:e44 Approximate WAC WAC = wholesaler acquisition cost or manufacturer’s published price to wholesalers; WAC represents a published catalogue or list price and may not represent an actual transactional price Source: AnalySource® Monthly October 5, 2015 Reprinted with permission by First Databank, Inc All rights reserved ©2015 www.fdbhealth.com/policies/drug-pricing-policy IN BRIEF Hepatic Injury with Hepatitis C Drugs The FDA recently announced labeling changes for the combination antiviral products Viekira Pak (ombitasvir/ paritaprevir/ritonavir with dasabuvir)1 and Technivie (ombitasvir/paritaprevir/ritonavir)2 warning of a risk of serious, potentially fatal liver injury.3 Viekira Pak, approved in December 2014 for treatment of hepatitis C virus (HCV) genotype infection, including patients with compensated cirrhosis, and Technivie, approved in July 2015 for treatment of HCV genotype infection without cirrhosis, have been identified as “possible” or “probable” causes in 26 postmarketing cases of hepatic decompensation, including 10 cases (mostly in patients with preexisting advanced cirrhosis) that resulted in death or liver transplant Hepatic injury generally occurred within 1-4 weeks of treatment initiation All therapies for chronic HCV infection have been associated with cases of hepatic decompensation in patients with advanced fibrosis or cirrhosis, but cause and effect are difficult to determine Viekira Pak and Technivie are now contraindicated in patients with moderate to severe (Child-Pugh B/C) hepatic impairment Ledipasvir/sofosbuvir (Harvoni), another recently approved treatment for HCV genotype infection,4 is still indicated for treatment of patients with any degree of compensated hepatic impairment (Child-Pugh A/B/C) The efficacy and safety of all three combinations in patients with decompensated cirrhosis have not been established ■ A 4-drug combination (Viekira Pak) for hepatitis C Med Lett Drugs Ther 2015; 57:15 In brief: Technivie for HCV genotype infection Med Lett Drugs Ther 2015; in press FDA Drug Safety Communication: FDA warns of serious liver injury risk with hepatitis C treatments Viekira Pak and Technivie Available at: www.fda.gov/Drugs/DrugSafety/ucm468634.htm Accessed October 29, 2015 A combination of ledipasvir and sofosbuvir (Harvoni) for hepatitis C Med Lett Drugs Ther 2014; 56:111 Addendum: Flibanserin (Addyi) for Hypoactive Sexual Desire Disorder When our article on flibanserin (Addyi) was published (Med Lett Drugs Ther 2015; 57:133), the drug had not yet been marketed Flibanserin became available on October 17, 2015 at a cost of $800 for a 30-day supply The Medical Letter ® Continuing Medical Education Program medicalletter.org/cme-program Earn Up To 52 Credits Per Year Choose CME from The Medical Letter in the format that’s right for you! ▶ Comprehensive Exam – Available online or in print to Medical Letter subscribers, this 130 question exam enables you to earn 26 credits immediately upon successful completion of the test A score of 70% or greater is required to pass the exam Our comprehensive exams allow you to test at your own 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acute migraine Review the efficacy and safety of aripiprazole lauroxil (Aristada) and paliperidone palmitate (Invega Trinza) for treatment of schizophrenia Review the efficacy and safety of budesonide rectal foam (Uceris) for treatment of distal ulcerative colitis Review the efficacy and safety of fentanyl iontophoretic transdermal system (Ionsys) for treatment of postoperative pain 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 7/8/10, Mac OS X+; current versions of Microsoft IE/Edge, Mozilla Firefox, Google Chrome, Safari or any other compatible Web browser High-speed connection Have any questions? Call us at 800-211-2769 or 914-235-0500 or e-mail us at: custserv@medicalletter.org Questions start on next page The Medical Letter ® Online Continuing Medical Education DO NOT FAX OR MAIL THIS EXAM To take CME exams and earn credit, go to: medicalletter.org/CMEstatus Issue 1481 Questions (Correspond to questions #91-100 in Comprehensive Exam #73, available January 2016) A Sumatriptan Patch (Zecuity) for Migraine Sumatriptan is available for acute treatment of migraine in which of the following formulations? a subcutaneous injection b iontophoretic transdermal patch c intranasal d all of the above Which of the following statements is true regarding the Zecuity patch? a The maximum mean sumatriptan serum concentration (Cmax) achieved with the patch was higher than those achieved with oral sumatriptan tablets b The Cmax achieved with the patch was higher than those achieved with nasal spray formulations of sumatriptan c The Cmax achieved with the patch was lower than those achieved with nasal spray and injectable formulations of sumatriptan d all of the above A 35-year-old woman with frequent debilitating migraine headaches recently saw an advertisement for Zecuity on television and asks if she should use the new patch instead of Imitrex nasal spray You could tell her that: a most patients who use the patch have redness at the application site which may take to days to resolve b the patch is more expensive than the nasal spray formulation c she can only use patches in a 24-hour period d all of the above Two Long-Acting Injectable Antipsychotics for Schizophrenia The new extended-release formulation of paliperidone palmitate (Invega Trinza) should be injected intramuscularly: a once every weeks b once every month c once every months d once every 4-6 weeks Aripiprazole lauroxil (Aristada): a should be injected intramuscularly once every weeks b dosage is based on the current daily oral aripiprazole dose c should not be used in patients with moderate renal impairment d all of the above A 30-year-old woman with schizophrenia who has been adequately treated with Invega Sustenna for month says that she would like to receive a medication that lasts longer because it is difficult to get to the clinic each month She also states that she just got married and would like to have a baby within the next year and doesn’t want to take an antipsychotic while pregnant You should tell her that: a the effects of Invega Trinza last for months b the once-monthly formulation of paliperidone palmitate is more effective than the 3-month formulation c she can switch to the new formulation after receiving another month of Invega Sustenna d all of the above Budesonide Rectal Foam (Uceris) for Ulcerative Colitis Budesonide: a is available in a rectal foam and oral extended-release tablets for use in ulcerative colitis b rectal foam was more effective than placebo in inducing remission in patients with active distal ulcerative colitis c rectal foam should be administered twice daily for weeks, then once daily at bedtime for weeks d all of the above Transdermal Fentanyl (Ionsys) for Postoperative Pain Compared to IV fentanyl, iontophoretic transdermal fentanyl produces serum concentrations that: a rise more slowly b peak at a lower level c fluctuate less d all of the above Iontophoretic transdermal fentanyl has been shown to control pain better than: a placebo b oral fentanyl c subcutaneous fentanyl d all of the above 10 The percentage of postoperative patients treated with iontophoretic transdermal fentanyl in clinical trials who required supplemental fentanyl to control their pain during the first hours after randomization was about: a 10-20% b 20-30% c 35-50% d 50-65% ACPE UPN: Per Issue Exam: 0379-0000-15-481-H01-P; Release: November 9, 2015, Expire: November 9, 2016 Comprehensive Exam 73: 0379-0000-16-073-H01-P; Release: January 2016, Expire: January 2017 EDITOR IN CHIEF: Mark Abramowicz, M.D.; EXECUTIVE EDITOR: Gianna Zuccotti, M.D., M.P.H., F.A.C.P., Harvard Medical School; EDITOR: Jean-Marie Pflomm, Pharm.D.; ASSISTANT EDITORS, DRUG INFORMATION: Susan M Daron, Pharm.D., Corinne Z Morrison, Pharm.D., Michael P Viscusi, Pharm.D.; CONSULTING EDITORS: Brinda M Shah, Pharm.D., F Peter Swanson, M.D; SENIOR ASSOCIATE EDITOR: Amy Faucard CONTRIBUTING EDITORS: Carl W Bazil, M.D., Ph.D., Columbia University College of Physicians and Surgeons; Vanessa K Dalton, M.D., M.P.H., University of Michigan Medical School; Eric J Epstein, M.D., Albert Einstein College of Medicine; Jane P Gagliardi, M.D., M.H.S., F.A.C.P., Duke University School of Medicine; David N Juurlink, BPhm, M.D., Ph.D., Sunnybrook Health Sciences Centre; Richard B Kim, M.D., University of Western Ontario; Franco M Muggia, M.D., New York University Medical Center; Sandip K Mukherjee, M.D., F.A.C.C., Yale School of Medicine; Dan M Roden, M.D., Vanderbilt University School of Medicine; Esperance A.K Schaefer, M.D., M.P.H., Harvard Medical School; F Estelle R Simons, M.D., University of Manitoba; Neal H Steigbigel, M.D., New York University School of Medicine; Arthur M F Yee, M.D., Ph.D., F.A.C.R., Weill Medical College of Cornell University MANAGING EDITOR: Susie Wong; ASSISTANT MANAGING EDITOR: Liz Donohue; EDITORIAL ASSISTANT: Cheryl Brown EXECUTIVE DIRECTOR OF SALES: Gene Carbona; FULFILLMENT & SYSTEMS MANAGER: Cristine Romatowski; DIRECTOR OF MARKETING COMMUNICATIONS: Joanne F Valentino; VICE PRESIDENT AND PUBLISHER: Yosef Wissner-Levy Founded in 1959 by Arthur Kallet and Harold Aaron, M.D Copyright and Disclaimer: The Medical Letter, Inc is an independent nonprofit organization that provides healthcare professionals with unbiased drug prescribing recommendations The editorial process used for its publications relies on a review of published and unpublished literature, with an emphasis on controlled clinical trials, and on the opinions of its consultants The Medical Letter, Inc is supported solely by subscription fees and accepts no advertising, grants, or donations No part of the material may be reproduced or transmitted by any process in whole or in part without prior permission in writing The editors not warrant that all the material in this publication is accurate and complete in every respect The editors shall not be held responsible for any damage resulting from any error, inaccuracy, or omission Subscription Services Address: The Medical Letter, Inc 145 Huguenot St Ste 312 New Rochelle, NY 10801-7537 www.medicalletter.org Customer Service: Call: 800-211-2769 or 914-235-0500 Fax: 914-632-1733 E-mail: custserv@medicalletter.org Permissions: To reproduce any portion of this issue, please e-mail your request to: permissions@medicalletter.org Copyright 2015 ISSN 1523-2859 Subscriptions (US): year - $129; 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