Cigna Drug and Biologic Coverage Policy

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1 Cigna Drug and Biologic Coverage Policy Subject Transmucosal Fentanyl (Abstral, Actiq, Fentora, Lazanda, Subsys ) Effective Date... 4/15/2016 Next Review Date... 4/15/2017 Coverage Policy Number Table of Contents Coverage Policy... 1 General Background... 6 Coding/Billing Information... 8 References... 8 Related Coverage Resources INSTRUCTIONS FOR USE The following Coverage Policy applies to health benefit plans administered by Cigna companies. Coverage Policies are intended to provide guidance in interpreting certain standard Cigna benefit plans. Please note, the terms of a customer s particular benefit plan document [Group Service Agreement, Evidence of Coverage, Certificate of Coverage, Summary Plan Description (SPD) or similar plan document] may differ significantly from the standard benefit plans upon which these Coverage Policies are based. For example, a customer s benefit plan document may contain a specific exclusion related to a topic addressed in a Coverage Policy. In the event of a conflict, a customer s benefit plan document always supersedes the information in the Coverage Policies. In the absence of a controlling federal or state coverage mandate, benefits are ultimately determined by the terms of the applicable benefit plan document. Coverage determinations in each specific instance require consideration of 1) the terms of the applicable benefit plan document in effect on the date of service; 2) any applicable laws/regulations; 3) any relevant collateral source materials including Coverage Policies and; 4) the specific facts of the particular situation. Coverage Policies relate exclusively to the administration of health benefit plans. Coverage Policies are not recommendations for treatment and should never be used as treatment guidelines. In certain markets, delegated vendor guidelines may be used to support medical necessity and other coverage determinations. Proprietary information of Cigna. Copyright 2016 Cigna Coverage Policy Cigna covers generic transmucosal fentanyl lozenge as medically necessary for the treatment of breakthrough cancer pain in an individual 16 years of age and older who is currently receiving and tolerant to opioid therapy. Cigna covers transmucosal fentanyl (Actiq ) as medically necessary for the treatment of breakthrough cancer pain in an individual 16 years of age and older who is currently receiving and tolerant to opioid therapy AND ONE of the following: For Employer Group Benefit Plans, ONE of the following: o For Standard and Performance Prescription Drug Lists: documented prior use of generic transmucosal fentanyl lozenge AND documented inadequate response, intolerance, inability to use, or individual is not a candidate for the preferred brand transmucosal fentanyl product, Subsys. o For Value and Advantage Prescription Drug Lists: documented prior use of generic transmucosal fentanyl lozenge For Individual and Family Plans: documented prior use of transmucosal fentanyl lozenge Page 1 of 9

2 Cigna covers transmucosal fentanyl (Subsys ) as medically necessary when ONE of the following is met: For Employer Group Benefit Plans, ONE of the following: o Standard and Performance Prescription Drug Lists: Treatment of breakthrough cancer pain in an individual 18 years of age and older who is currently receiving and tolerant to o opioid therapy Value and Advantage Prescription Drug Lists: Treatment of breakthrough cancer pain in an individual 18 years of age and older who is currently receiving and tolerant to opioid therapy AND documented inadequate response, intolerance, inability to use or individual is not a candidate for the generic formulation of transmucosal fentanyl lozenge For Individual and Family Plans: Treatment of breakthrough cancer pain in an individual 18 years of age and older who is currently receiving and tolerant to opioid therapy AND documented inadequate response, intolerance, inability to use or individual is not a candidate for the generic formulation of transmucosal fentanyl lozenge Cigna covers transmucosal fentanyl (Abstral, Fentora, Lazanda ) as medically necessary for the treatment of breakthrough cancer pain in an individual 18 years of age and older who is currently receiving and tolerant to opioid therapy AND: For Employer Group Benefit Plans, ONE of the following: o For Standard and Performance Prescription Drug Lists: Documented inadequate response, intolerance, inability to use or individual is not a candidate for the generic formulation of transmucosal fentanyl lozenge AND the preferred brand transmucosal o fentanyl product, Subsys. For Value and Advantage Prescription Drug Lists: Documented inadequate response, intolerance, inability to use or individual is not a candidate for the generic formulation of transmucosal fentanyl lozenge For Individual and Family Plans: Documented inadequate response, intolerance, inability to use or individual is not a candidate for the generic formulation of transmucosal fentanyl lozenge FDA Approved Indications Product Abstral Actiq Indication Abstral sublingual tablets are indicated for the management of breakthrough pain in cancer patients 18 years of age and older who are already receiving, and who are tolerant to, opioid therapy for their underlying persistent cancer pain. Patients considered opioid tolerant are those who are taking around-the-clock medicine consisting of at least 60 mg of oral morphine daily, or at least 25 mcg of transdermal fentanyl/hour, or at least 30 mg of oral oxycodone daily, or at least 8 mg of oral hydromorphone daily or at least 25 mg oral oxymorphone daily, or an equianalgesic dose of another opioid medication daily for a week or longer.patients must remain on around-the-clock opioids when taking Abstral. Abstral is contraindicated for patients who are not already tolerant to opioids because life-threatening respiratory depression and death could result at any dose in patients not on a chronic regimen of opioids. For this reason, Abstral is contraindicated in the management of acute or postoperative pain, including headache/migraine, dental pain, or use in the emergency room. Actiq (oral transmucosal fentanyl citrate) (OTFC) is indicated for the management of breakthrough cancer pain in patients 16 and older with malignancies who are already receiving and who are tolerant to opioid therapy for their underlying persistent cancer pain. Patients considered opioid tolerant are those who are taking at least 60 mg morphine/day, at least 25 mcg transdermal fentanyl/hour, at least 30 mg of oxycodone daily, at least 8 mg oral hydromorphone daily or an equianalgesic dose of another opioid for a week or longer. This product must not be used in opioid non-tolerant patients because life-threatening respiratory depression could occur at any dose in patients not taking chronic opiates. For this reason, Actiq is contraindicated in the management of acute or postoperative pain. Actiq is intended to be used only in the care of opioid tolerant cancer patients and only by oncologists and pain specialists who are knowledgeable of and skilled in the use of Schedule II opioids to treat cancer pain. Page 2 of 9

3 Fentora Lazanda Subsys Limitations of Use: As a part of the TIRF REMS Access program, Actiq may be dispensed only to outpatients enrolled in the program [see Warnings and Precautions (5.10)]. For inpatient administration of Actiq (e.g., hospitals, hospices, and long-term care facilities that prescribe for inpatient use), patient and prescriber enrollment is not required. Fentora is indicated for the management of breakthrough pain in cancer patients 18 years of age and older who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain. Individuals considered opioid tolerant are those who are taking around-the-clock medicine consisting of at least 60 mg of oral morphine daily, at least 25 mcg of transdermal fentanyl/hour, at least 30 mg of oxycodone daily, at least 8 mg of oral hydromorphone daily, at least 25mg oral oxymorphone daily or an equianalgesic dose of another opioid daily for a week or longer. This product must not be used in opioid non-tolerant patients because life-threatening hypoventilation and death could occur at any dose in patients not on a chronic regimen of opioids. For this reason, Fentora is contraindicated in the management of acute or postoperative pain. Fentora is intended to be used only in the care of opioid tolerant cancer patients and only by healthcare professionals who are knowledgeable of and skilled in the use of Schedule II opioids to treat cancer pain. Limitations of Use: As a part of the TIRF REMS Access program, Fentora may be dispensed only to outpatients enrolled in the program. For inpatient administration of Fentora (e.g., hospitals, hospices, and long-term care facilities that prescribe for inpatient use), patient and prescriber enrollment is not required. Lazanda nasal spray is indicated for the management of breakthrough pain in cancer patients 18 years of age and older who are already receiving and who are tolerant to opioid therapy for their underlying persistent cancer pain. Patients considered opioid tolerant are those who are taking at least: 60 mg of oral morphine/day, 25 mcg of transdermal fentanyl/hour, 30 mg oral oxycodone/day, 8 mg oral hydromorphone/day, 25 mg oral oxymorphone/day, or an equianalgesic dose of another opioid for a week or longer. Patients must remain on around-theclock opioids when taking Lazanda. Lazanda is contraindicated for patients who are not already tolerant to opioids because life-threatening respiratory depression and death could occur in patients not taking chronic opioids. For this reason, Lazanda is contraindicated in the management of acute or postoperative pain, including headache/migraine or dental pain. Lazanda is intended to be prescribed only by healthcare professionals who are knowledgeable of and skilled in the use of Schedule II opioids to treat cancer pain. Limitations of use: As a part of the TIRF REMS Access program, Lazanda may be dispensed only to outpatients enrolled in the program. For inpatient administration of Lazanda (e.g. hospitals, hospices, and long-term care facilities that prescribe for inpatient use), patient enrollment is not required. Subsys is indicated for the management of breakthrough pain in adult cancer patients who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain. Patients considered opioid tolerant are those who are taking around-the-clock medicine consisting of at least 60 mg of oral morphine daily, at least 25 mcg of transdermal fentanyl/hour, at least 30 mg of oral oxycodone daily, at least 8 mg of oral hydromorphone daily or an equianalgesic dose of another opioid daily for a week or longer. Patients must remain on around-the-clock opioids when taking Subsys. This product must not be used in opioid non-tolerant patients because lifethreatening respiratory depression and death could occur at any dose in patients not on a chronic regimen of opioids. For this reason, Subsys is contraindicated in the management of acute or postoperative pain. Subsys is intended to be used only in the care of cancer patients and only by oncologists and pain specialists who are knowledgeable of and skilled in the use of Schedule II opioids to treat cancer pain. Limitations of Use: As part of the Transmucosal Immediate-Release Fentanyl (TIRF) REMS ACCESS Program, Subsys may be dispensed only to outpatiets enrolled in the program. For inpatient administration (e.g. hospitals, hospices, and long-term care facilities that prescribe for inpatient use) or Subsys, patient enrollment is not required. Page 3 of 9

4 FDA Recommended Dosing Product Abstral Actiq Fentora Dosing Begin titration of all patients with an initial dose of Abstral of 100 mcg. Due to differences in the pharmacokinetic properties and individual variability, even patients switching from other fentanyl containing products to Abstral must start with the 100 mcg dose. Abstral is not equivalent on a mcg per mcg basis with all other fentanyl products, therefore, do not switch patients on a mcg per mcg basis from any other fentanyl product. Abstral is NOT a generic version of any other fentanyl product. Start all patients with a single 100 mcg tablet. The appropriate dosing and safety of fentanyl citrate in opioid tolerant children with breakthrough cancer pain have not been established below the age of 16 years. The initial dose of oral transmucosal fentanyl citrate to treat episodes of breakthrough cancer pain is always 200 mcg. Patients should be prescribed an initial titration supply of six 200 mcg oral transmucosal fentanyl citrate units, thus limiting the number of units in the home during titration. Patients should use up all units before increasing to a higher dose. Because potent opioids can cause hypoventilation, fentanyl citrate should be titrated with caution in patients with chronic obstructive pulmonary disease or pre-existing medical conditions predisposing them to hypoventilation. Per FDA approved label, once a successful dose has been found, patients should limit consumption to four or fewer units per day. If consumption increases above four units per day, the dose of the long-acting opioid used for persistent cancer pain should be reevaluated. Fentora is not bioequivalent with other fentanyl products. Do not convert patients on a mcg per mcg basis from other fentanyl products. There are no conversion directions available for patients on any other fentanyl products other than Actiq. All patients should be titrated from the 100 mcg dose. Patients on Actiq - The initial dose of Fentora is always 100 mcg with the only exception being patients already using Actiq. For patients being converted from Actiq, prescribers must use the Initial Dosing Recommendations for Patients on Actiq table below. The doses of Fentora in this table are starting doses and not intended to represent equianalgesic doses to Actiq. Patients must be instructed to stop the use of Actiq and dispose of any remaining units. Current Actiq Dose (mcg) Initial Fentora Dose (mcg) x x 200 For patients converting from Actiq doses equal to or greater than 600 mcg, titration should be initiated with the 200 mcg Fentora tablet and should proceed using multiples of this tablet strength. Maintenance Dosing a. Once titrated to an effective dose, patients should generally use only ONE FENTORA tablet of the appropriate strength per breakthrough pain episode. b. On occasion when the breakthrough pain episode is not relieved after 30 minutes, patients may take ONLY ONE additional dose using the same strength for that episode. c. Patients MUST wait at least 4 hours before treating another episode of breakthrough pain with FENTORA. d. Dosage adjustment of FENTORA may be required in some patients. Generally, the FENTORA dose should be increased only when a single administration of the current dose fails to adequately treat the breakthrough pain episode for several consecutive episodes. e. If the patient experiences greater than four breakthrough pain episodes per day, the dose of the around-the-clock opioid used for persistent pain should be re-evaluated. f. Once an effective dose is determined using the titration scheme outlined above, an alternate route of administration is sublingual (placing the tablet under the tongue.) Lazanda The goal of dose titration is to find the individual patient s effective and tolerable dose. Individually titrate Lazanda to a dose that provides adequate analgesia with tolerable side effects. Begin Page 4 of 9

5 Subsys treatment of all patients (including those switching from another fentanyl product) using ONE 100 mcg spray of Lazanda (1 spray in one nostril). Due to differences in pharmacokinetic properties and individual variability, do not switch patients on a mcg per mcg basis from any other fentanyl product to Lazanda as Lazanda is not equivalent with any other fentanyl product, nor is Lazanda a generic version of any other fentanyl product. If adequate analgesia is obtained within 30 minutes of administration of the 100 mcg single spray, treat subsequent episodes of breakthrough pain with this dose. Titration steps: If adequate analgesia is not achieved with the first 100 mcg dose, dose escalate in a step-wise manner over consecutive episodes of breakthrough pain until adequate analgesia with tolerable side effects is achieved. Patients MUST wait at least 2 hours before treating another episode of breakthrough cancer pain with Lazanda. Subsys is not bioequivalent with other fentanyl products. Do not convert patients on a mcg per mcg basis from other fentanyl products. There are no conversion directions available for patients on any other fentanyl products other than Actiq. (Note: This includes oral, transdermal, or parenteral formulations of fentanyl.) The initial dose of Subsys is always 100 mcg with the only exception of patients already using Actiq (see table below). Prescribe an initial titration supply of 100 mcg Subsys units, which limits the number of units in the home during titration. Avoid prescribing a higher dose until patients have used up all units to prevent confusion and possible overdose. Current ACTIQ Dose (mcg) Initial SUBSYS Dose (mcg) mcg spray mcg spray mcg spray mcg spray mcg spray mcg spray TRANSMUCOSAL IMMEDIATE RELEASE FENTANYL (TIRF) RISK EVALUATION AND MITIGATION STRATEGY (REMS) In March, 2012, the FDA approved a single shared REMS for the TIRF products. This new shared system will replace the individual REMS and allow prescribers and pharmacies to enroll into just one system, easing the burden on the health care system. TIRF medicines, which include the brand-name drugs Abstral, Actiq, Fentora, Lazanda,and Subsys are narcotic pain medicines called opioids used to manage pain in adults with cancer who routinely take other opioid pain medicines around-the-clock. The goals of the TIRF REMS Access Program are to ensure patient access to important medications and mitigate the risk of misuse, abuse, addiction, overdose and serious complications due to medication errors by: prescribing and dispensing TIRF medicines only to appropriate patients, including use only in opioidtolerant patients preventing inappropriate conversion between fentanyl products preventing accidental exposure to children and others for whom TIRF medicines were not prescribed educating prescribers, pharmacists, and patients on the potential for misuse, abuse, addiction, and overdose. All TIRF products have an individual REMS in place. Prescribers and pharmacies enrolled in an individual REMS program for at least one TIRF medicine will automatically be transitioned to the shared TIRF REMS Access program. Health care professionals who prescribe TIRF medicines that will only be used in an inpatient setting (hospitals, hospices, or long-term care facilities) will not be required to enroll in the TIRF REMS Access program. Similarly, patients who receive TIRF medicines in an inpatient setting are not required to enroll in the program. Long term care and hospice patients who obtain their medications from outpatient pharmacies must still be enrolled. Page 5 of 9

6 General Background Pharmacology Opioids produce analgesia by interacting with opioid receptors at several sites within and outside of the central nervous system. Fentanyl, a synthetic opioid, is approximately 100 times more potent than morphine for analgesia. Opioids, including fentanyl, are central nervous system depressants and exert effects on the gastrointestinal tract. Guidelines National Comprehensive Cancer Network (NCCN) The NCCN 2016 guidelines suggest transmucosal fentanyl is a treatment option for incidents of breakthrough pain which is not the result of insufficient dosing of scheduled opioids. Patients should be started at a low dose and individualized for response. Clinical Efficacy Product Efficacy Abstral Fentanyl sublingual tablet has not been compared to other treatments for cancer breakthrough pain in published trials. Fentanyl was more effective than placebo in 2 randomized placebo-controlled trials in patients with breakthrough cancer pain. One fixed-dose crossover study comparing fentanyl sublingual tablet in 100, 200, and 400 mcg strengths to placebo reported the 400 mcg strength was better than placebo (p<0.0001) for reducing the overall mean PID (pain intensity difference before and after treatment). The 100 mcg and 200 mcg doses were not statistically superior to placebo for PID at any time point. The other controlled trial compared fentanyl sublingual tablet at a dose identified during titration (range: mcg) to placebo (7 doses of active drug and 3 doses of placebo in random order). Fentanyl sublingual tablet produced greater reduction in pain (endpoint: the sum of PID) at 30 minutes and at 60 minutes compared with placebo (p<0.0004). Improvement in PID was statistically significant starting at 10 minute and continued throughout the 60-minute assessment period (p< vs placebo). One open-label study evaluating fentanyl sublingual for up to 12-months duration reported patient satisfaction with pain medication was improved at the end-of-study visit compared to screening. Actiq Fentora The efficacy of OTFC for the management of breakthrough cancer pain has been studied in a double-blind, placebo-controlled, randomized study in cancer patients receiving the oral morphine sulfate daily or transdermal fentanyl per hour for the management of chronic cancer pain and who experienced at least one occurrence of breakthrough pain daily. Following titration to an effective dose of OTFC, patients experienced substantially more pain relief than placebo. Additionally, when OTFC was used for breakthrough cancer pain, rescue drug therapy was required less frequently than when placebo was used for such breakthrough pain. A randomized, double-blind crossover study evaluated the tolerability, efficacy, and formulation preference of two formulations of OTFC in 14 patients with grade 3 or 4 radiation-induced mucositis. Patients received an OTFC unit 45 minutes before radiation treatment on four separate days. Two units had a sweetened matrix formulation, two had a compressed powder formulation, with one unit of each formulation containing 200 mcg fentanyl, and one was placebo. Results showed that there were no changes in oral mucosa, and fentanyl 200 mcg did not yield analgesia greater than placebo. In addition, there were no significant differences between formulations in tolerability, patient preference, or visual analog scale (VAS) pain scores. A single-dose, randomized, open-label, three-period comparative study evaluated the relative bioavailability of FEBT1,080 mcg with OTFC 1,600 mcg and the dose proportionality of FEBT from 270 µg to 1300 µg in 39 healthy adults. In the first two periods, each participant randomly received 1080 mcg FEBT and 1600 mcg OTFC. Following the completion of the second period, subjects were re-randomized to receive 1300, 810, or 270 mcg FEBT. Total systemic exposure was statistically similar between FEBT 1,080 mcg and OTFC 1,600 mcg. However, the rate of absorption was faster for FEBT than for OTFC, leading to an approximate 23% higher peak exposure and an earlier T max (1 hr vs 2 hr, p<0.0001). Early systemic exposure [the area-under- the Page 6 of 9

7 curve (AUC) from time 0 to 1 hour) was significantly greater with FEBT compared with OTFC (p<0.001). Results showed that fentanyl AUC increased proportionally to dose from 270 mcg to 1300 mcg FEBT, and the doses above 810 mcg showed a less-than-dose-proportional increase in C(max). Based on the pharmacokinetic parameters (AUC, Cmax, and Tmax), fentanyl enters the systemic circulation to a significantly greater extent and significantly more rapidly with FEBT compared with OTFC. Lazanda Subsys A double-blind, randomized, placebo-controlled study evaluated the efficacy, safety, and tolerability of FEBT in opioid-treated Individuals with cancer-related breakthrough pain (BTP) in 123 Individuals. After a titration to identify fentanyl buccal dose to treat BTP episodes, 77 Individuals were randomly assigned to one of 18 prespecified dose sequences of 10 tablets including seven fentanyl buccal tablet and three placebo. Pain intensity, pain relief (PR), and global performance of the medication were recorded at regular time intervals between 15 and 60 minutes. Pain intensity differences (PID), the summed PID (SPID), and summed total PR were calculated. The primary endpoint was the SPID at 30 minutes (SPID30). A total of 80 out of 123 Individuals (65%) were titrated to an effective dose. The mean SPID30 for fentanyl buccal tablet was 3.0+/-0.12 versus 1.8+/-0.18 for placebo (p<0.0001). Compared to placebo, significant improvement with the measures of PR, PID, SPID, and summed total PR were observed with FEBT. Reported adverse events were similar to other types of opioid drugs. Poor oral tolerability was reported in two Individuals. The efficacy of Lazanda was evaluated in one clinical trial in opioid tolerant adult patients experiencing breakthrough cancer pain. All patients were on stable doses of either long-acting oral opioids or transdermal fentanyl for their persistent cancer pain. The clinical trial included an openlabel titration phase where a dose was identified that provided adequate analgesia with tolerable side effects, within the range of 100 to 800 mcg. In the double-blind, placebo-controlled portion of the study, patients who were titrated to an adequate dose were randomized to a blinded sequence of 10 treatments with 7 being the identified dose of Lazanda and 3 being placebo. Of the patients who enrolled in the study, 73% achieved an adequate dose during the titration phase, 6% withdrew for lack of effective pain relief, and 5% withdrew due to adverse events. The primary outcome measure, the mean sum of the pain intensity difference at 30 minutes (SPID30), was statistically significantly higher for Lazanda than for placebo The efficacy of Subsys was demonstrated in a double-blind, placebo-controlled, crossover study in opioid tolerant adult patients with cancer and breakthrough pain. The dose range studied was from 100 mcg per dose to 1600 mcg per dose. Patients entering the trial must have had on average 1-4 episodes of pain per day not controlled on stable, chronic maintenance doses of opioid medication of at least 60 mg/day of morphine, 25 mcg/hr of transdermal fentanyl, or an equianalgesic dose of another opioid for at least 7 days. The study began with an open-label dose titration period followed by a double-blind treatment period. The goal of titration was to find the dose of Subsys that provided adequate analgesia with acceptable side effects. Patients were titrated from a 100 mcg starting dose. Once a successful dose was established, patients were enrolled into the double-blind period and randomized to a sequence of 10 treatments; 7 with Subsys and 3 with placebo. Subsys produced a statistically significantly greater reduction in pain intensity compared to placebo as measured by the Summed Pain Intensity Differences scale (SPID) at 30 minutes. The primary outcome measure, the mean sum of the pain intensity difference at 30 minutes (SPID30), was statistically significantly higher for Subsys than for placebo. Experimental, Investigational, Unproven Uses Case series, randomized controlled trials and systematic reviews have investigated transmucosal fentanyl for various conditions/ indications, including the following: management of acute pain in children (intranasal fentanyl) outpatient treatment of acute refractory migraine headache pain in patients with history of opioid use refractory to conventional treatment pain relief during childbirth pediatric dental sedation Page 7 of 9

8 Coding/Billing Information Note: Transmucosal fentanyl is typically covered under pharmacy benefit plans. Certain prescription drugs require an authorization for coverage to ensure that appropriate treatment regimens are followed. Medical drug coding and diagnosis codes, however, are generally not required for pharmacy claims submissions, therefore, this section is not in use. References 1. Archimedes Pharma US Inc. Lazanda (fentanyl nasal spray) product information. Bedminster, NJ: Archimedes Pharma US Inc. Feb Caraceni A, Martini C, Zecca E, et al. Breakthrough pain characteristics and syndromes in patients with cancer pain. An international survey. Palliat Med. Apr 2004;18(3): Cephalon, Inc. Actiq (fentanyl citrate) oral transmucosal lozenge product information. Frazer, PA: Cephalon, Inc. Dec Cephalon, Inc. Fentora (fentanyl buccal tablet) product information. Frazer, PA: Cephalon, Inc. Feb Davies AN, Dickman A, Reid C, Stevens AM, Zeppetella G. The management of cancer-related breakthrough pain: recommendations of a task group of the Science Committee of the Association for Palliative Medicine of Great Britain and Ireland. Eur J Pain. Apr 2009;13(4): Fleet J, Belan I, Jones MJ, et al. A comparison of fentanyl with pethidine for pain relief during childbirth: a randomized controlled trial. BJOG. Jun 2015;122(7): Farrar JT, Cleary J, Rauck R: Oral transmucosal fentanyl citrate: randomized, double-blinded, placebocontrolled trial for treatment of breakthrough pain in cancer patients, J Natl Cancer Inst : Gutstein HB, Huda A. Opioid Analgesics. In: Brunton LL, Lazo JS, Parker KL, eds. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 11th ed. New York, NY: McGraw Hill Medical Publishing; 2006: Insys Therapeutics, Inc. Subsys fentanyl sublingual spray product information. Phoenix, AZ: Insys Therapeutics, Inc. Dec Landy SH. Oral transmucosal fentanyl citrate for the treatment of migraine headache pain in outpatients: a case series. Headache. 2004;44: Lennernas B, Frank-Lissbrant I, Lennernas H, Kalkner KM, Derrick R, Howell J. Sublingual administration of fentanyl to cancer patients is an effective treatment for breakthrough pain: results from a randomized phase II study. Palliat Med. Apr 2010;24(3): McEvoy GK, ed. AHFS 2013 Drug Information. Bethesda, MD: American Society of Health-Systems Pharmacists, Inc Miaskowski C, Cleary J, Burney R, et al. Guideline for the Management of Cancer Pain in Adults and Children, APS Clinical Practice Guidelines Series, No. 3. Glenview, IL: American Pain Society; Page 8 of 9

9 14. Murphy A, O Sullivan R, Wakai A, et al. Intranasal fentanyl for the management of acute pain in children. Cochrane Database Syst Rev Oct 10;10:CD DOI: / CD pub Nalamachu S, Hassman D, Wallace MS, Dumble S, Derrick R, Howell J. Long-term effectiveness and tolerability of sublingual fentanyl orally disintegrating tablet for the treatment of breakthrough cancer pain. Curr Med Res Opin. Mar 2011;27(3): NCCN Guidelines. Adult Cancer Pain. Feb National Comprehensive Cancer Network (NCCN). Available at Portenoy RK, Taylor D, Messina J, Tremmel L. A randomized, placebo-controlled study of fentanyl buccal tablet for breakthrough pain in opioid-treated Individuals with cancer. Clin J Pain. 2006,22(9): PROPOSED TRANSMUCOSAL IMMEDIATE RELEASE FENTANYL (TIRF) RISK EVALUATION AND MITIGATION STRATEGY (REMS). Initial REMS Approval: 12/2012. Updated 12/2015 Accessed 3/10/2015. Available at Prostrakan Inc. Abstral (fentanyl) sublingual tablets product information. Bedminster, NJ: Prostrakan Inc. Nov Rauck R, North J, Gever LN, Tagarro I, Finn AL. Fentanyl buccal soluble film (FBSF) for breakthrough pain in patients with cancer: a randomized, double-blind, placebo-controlled study. Ann Oncol. Nov Rauck RL, Tark M, Reyes E, et al. Efficacy and long-term tolerability of sublingual fentanyl orally disintegrating tablet in the treatment of breakthrough cancer pain. Curr Med Res Opin. Dec 2009;25(12): Shaiova L, Lapin J, Manco LS, et al. Tolerability and effects of two formulations of oral transmucosal fentanyl citrate (OTFC; ACTIQ) in patients with radiation-induced oral mucositis. Support Care Cancer April:12(4): Smith, H. et. al. A comparison of four sedation techniques for pediatric dental surgery. Paediatric Anaesthesia. 20(10):924-30, 2010 Oct. 24. Uberall MA, Muller-Schwefe GH. Sublingual fentanyl orally disintegrating tablet in daily practice: efficacy, safety and tolerability in patients with breakthrough cancer pain. Curr Med Res Opin. May Vasisht N, Gever LN, Tagarro I, Finn AL. Formulation selection and pharmacokinetic comparison of fentanyl buccal soluble film with oral transmucosal fentanyl citrate: a randomized, open-label, singledose, crossover study. Clin Drug Investig. 2009;29(10): William L, Macleod R. Management of breakthrough pain in patients with cancer. Drugs. 2008;68(7): Zeppetella G. Impact and management of breakthrough pain in cancer. Curr Opin Support Palliat Care. Mar 2009;3(1):1-6. The registered marks "Cigna" and the "Tree of Life" logo are owned by Cigna Intellectual Property, Inc., licensed for use by Cigna Corporation and its operating subsidiaries. All products and services are provided by or through such operating subsidiaries and not by Cigna Corporation. Such operating subsidiaries include Connecticut General Life Insurance Company, Cigna Health and Life Insurance Company, Cigna Behavioral Health, Inc., Cigna Health Management, Inc., and HMO or service company subsidiaries of Cigna Health Corporation. Page 9 of 9