Amitiza® (lubiprostone), Linzess® (linaclotide) Prior Authorization Criteria Program Summary OBJECTIVE The intent of the Prior Authorization (PA) program for Amitiza (lubiprostone) and Linzess (linaclotide) is to ensure appropriate selection of patients for treatment according to product labeling and/or clinical studies and/or guidelines. The PA defines appropriate use as use in patients with a Food and Drug Administration (FDA) approved indication of chronic idiopathic constipation (in adults), irritable bowel syndrome with constipation (for Amitiza, in women >18 years of age; for Linzess, in adults >18 years of age), or opioid-induced constipation in adults with chronic non-cancer pain (Amitiza only). The PA criteria require that the patient has had symptoms of chronic idiopathic constipation or irritable bowel syndrome with constipation > 3 months. The PA criteria also require that patients have tried at least two standard laxative therapy classes for constipation, including osmotic laxatives (polyethylene glycol, lactulose, magnesium hydroxide-based including milk of magnesia), fiber or bulking agents (psyllium, bran, methylcellulose), stool softeners (docusate), or over-the-counter stimulant laxatives containing senna or bisacodyl. Criteria do not allow coverage for lubiprostone or linaclotide in patients who have FDA labeled contraindication(s) to the requested product. Requests for lubiprostone and linaclotide will be reviewed when patient- specific documentation has been provided. TARGET DRUG Amitiza (lubiprostone) Linzess (linaclotide) PRIOR AUTHORIZATION CRITERIA FOR APPROVAL Amitiza or Linzess will be approved when BOTH of the following are met: 1. ONE of the following: a. The patient has a diagnosis of irritable bowel syndrome with constipation with documentation of symptoms for >3 months and ONE of the following: i. For Linzess, the patient is an adult >18 years of age OR ii. For Amitiza, the patient is a woman >18 years of age OR b. The patient is an adult >18 years of age with a diagnosis of chronic idiopathic constipation with documentation of symptoms for >3 months OR c. For Amitiza only, the patient is an adult >18 years of age with a diagnosis of opioid-induced constipation with chronic non-cancer pain and ALL of the following: i. The patient has chronic use of an opioid agent in the past 30 days AND ii. The patient is not receiving a diphenylheptane opioid (e.g. methadone) in the past 30 days AND 2. ONE of the following: a. The patient has tried at least 2 standard laxative therapy classes OR b. The patient has a documented intolerance, FDA labeled contraindication, or hypersensitivity to at least 2 standard laxative therapy classes AND 3. The patient does NOT have any FDA labeled contraindication(s) to the requested agent AL_PS_Amitiza_Linzess_PA_ProgSum_AR0715 Page 1 of 9 © Copyright Prime Therapeutics LLC. 07/2015 All Rights Reserved Length of approval: 12 months FDA Labeled Contraindication(s) Agent Contraindication(s) Amitiza (lubiprostone) Known or suspected mechanical gastrointestinal obstruction Linzess (linaclotide) Known or suspected mechanical gastrointestinal obstruction Pediatric patients up to 6 years of age AL_PS_Amitiza_Linzess_PA_ProgSum_AR0715 Page 2 of 9 © Copyright Prime Therapeutics LLC. 07/2015 All Rights Reserved FDA APPROVED INDICATIONS AND DOSAGE1,12 Product Indication(s) Dosage and Administration Amitiza Treatment of irritable bowel IBS- 8 mcg taken twice daily (lubiprostone) syndrome with constipation orally with food and water. (IBS-C) in women ≥ 18 years old. capsules (8 mcg, 24 mcg) Treatment of chronic idiopathic CIC, OIC - 24 mcg taken twice constipation (CIC) in adults daily orally with food and water. Treatment of opioid-induced constipation (OIC) in adults with For patients with moderately chronic, non-cancer pain impaired hepatic function Limitation of Use: Effectiveness (Child-Pugh Class B), of Amitiza in the treatment of recommended starting dose is OIC in patients taking 16 mcg twice daily; for patients diphenylheptane opioids with severely impaired hepatic (e.g. methadone) has not been function (Child-Pugh Class C), established. recommended starting dose is 8 mcg twice daily. If tolerated dose can be escalated if needed. Linzess Treatment of irritable bowel IBS- 290 mcg taken once daily (linaclotide) syndrome with constipation orally on an empty stomach, at (IBS-C) in adults. least 30 minutes prior to the first capsules meal of the day. (145 mcg, 290 mcg) Treatment of chronic idiopathic constipation (CIC) in adults. CIC- 145 mcg taken once daily orally on an empty stomach, at least 30 minutes prior to the first meal of the day Lubiprostone is a locally acting chloride channel activator that enhances a chloride-rich intestinal fluid secretion without altering sodium and potassium concentrations in the serum. Lubiprostone acts by specifically activating CIC-2 chloride channels, a normal constituent of the apical membrane of the human intestine. By increasing intestinal fluid secretion, lubiprostone increases motility in the intestine, alleviating symptoms associated with constipation.1 Linaclotide is a guanylate cyclase-C (GC-C) agonist. Both linaclotide and its active metabolite bind to GC-C and act locally on the luminal surface of the intestinal epithelium. Activation of GC-C results in an increase in both intracellular and extracellular concentrations of cyclic guanosine monophosphate (cGMP). Elevation in intracellular cGMP stimulates secretion of chloride and bicarbonate into the intestinal lumen, resulting in increased intestinal fluid and accelerated transit.12 CLINICAL RATIONALE Chronic Constipation: Chronic constipation is characterized by decreased frequency of bowel movements, persistent symptoms of straining, lumpy or hard stools, and feelings of blockade or incomplete bowel evacuation.2,11 In a position statement on the management of chronic constipation, the American College of Gastroenterology (ACG) Task Force advocates this definition: “Constipation is a symptom-based disorder and is characterized by infrequent defecation, difficult stool passage, or both,” with chronic constipation defined as the presence of these symptoms for at least three months.11 Chronic constipation is generally differentiated as primary or secondary in nature. Primary is classified as normal transit constipation (functional) or slow transit constipation. Secondary constipation may have several factors AL_PS_Amitiza_Linzess_PA_ProgSum_AR0715 Page 3 of 9 © Copyright Prime Therapeutics LLC. 07/2015 All Rights Reserved contributing to the condition.3,11 These include dietary causes, such as low fiber and fluid consumption, neurological disease, metabolic or endocrine disorders, psychological illness, or medications. Unknown causes of constipation are identified as chronic idiopathic constipation (CIC).3,11 The ACG Task Force review recommends the following for treatment of chronic constipation: bulking agents (psyllium), osmotic laxatives (polyethylene glycol [PEG], lactulose), and tegaserod. The task force found data insufficient to make a recommendation regarding stool softeners, stimulant laxatives, or herbal supplements.11 The efficacy of lubiprostone for CIC was demonstrated in two double-blind, placebo-controlled dose ranging study, phase III trials, a withdrawal study, and several open-label studies. The dose-ranging study evaluated the efficacy and safety of lubiprostone in 120 patients with symptoms of chronic constipation for ≥ 6 months of duration.6 Patients received either lubiprostone (24, 48, or 72 micrograms/day) or placebo for 3 weeks. Patients in the treatment groups had a significant increase in the average number of weekly spontaneous bowel movements (SBMs) during the first (p=0.006) and second week of the study (p=0.014) and over the entire study period (p=0.046) compared with placebo. Adverse effects increased with increasing dosage, especially nausea (occurring in up to 44% of patients on the 48 microgram dose). Data from the two other phase III trials reinforced the findings of the dose-ranging study.7-8 In the first study patients (N=242) with CIC were treated with lubiprostone (24 micrograms) or placebo twice daily for four weeks.8 Compared to placebo, the treatment group had more SBMs during week 1 (5.69 vs 3.46, p=0.0001), and the effect was sustained during each of the subsequent weeks of the study.8 The efficacy of linaclotide for the management of the signs and symptoms of CIC was assessed in two double-blind, placebo-controlled, randomized, multicenter studies in adult patients.13. A total of 642 patients in Trial 3 and 630 patients in Trial 4 received treatment with linaclotide 145 mcg or linaclotide 290 mcg or placebo. Patients with IBS were excluded from the studies. The primary efficacy end point was three or more complete spontaneous bowel movements (CSBMs) per week and an increase of ≥ CSBMs from baseline during ≥ 9 of the 12 weeks. The proportion of patients who were CSBM responders was statistically significantly greater in each of the 2 trials with each dose of linaclotide (145 mcg and 290 mcg) compared to placebo. Secondary endpoints included stool frequency, stool consistency, severity of straining, abdominal discomfort, bloating, and constipation severity.13 The primary end point was reached by 21.2% and 16.0% of the patients who received 145 mcg of linaclotide and by 19.4% and 21.3% of the patients who received 290 mcg of linaclotide, as compared with 3.3% and 6.0% of those who received placebo (P<0.01 for all comparisons of linaclotide