Crofelemer

1 INDICATIONS AND USAGE MYTESI is indicated for symptomatic relief of non-infectious diarrhea in adult patients with HIV/AIDS on anti-retroviral therapy. MYTESI is an anti-diarrheal indicated for the symptomatic relief of non-infectious diarrhea in adult patients with HIV/AIDS on anti-retroviral therapy. ( 1 )

12.1 Mechanism of Action Crofelemer is an inhibitor of both the cyclic adenosine monophosphate (cAMP)-stimulated cystic fibrosis transmembrane conductance regulator (CFTR) chloride ion (Cl¯) channel, and the calcium-activated Cl¯ channels (CaCC) at the luminal membrane of enterocytes. The CFTR Cl¯ channel and CaCC regulate Cl¯ and fluid secretion by intestinal epithelial cells. Crofelemer acts by blocking Cl¯ secretion and accompanying high volume water loss in diarrhea, normalizing the flow of Cl¯ and water in the gastrointestinal tract.

2 DOSAGE AND ADMINISTRATION Before starting MYTESI, rule out infectious etiologies of diarrhea [see Warnings and Precautions ( 5.1 )] . The recommended adult dosage of MYTESI is 125 mg taken orally two times a day, with or without food. Do not crush or chew MYTESI tablets. Swallow whole. Before starting MYTESI, rule out infectious etiologies of diarrhea. ( 2 , 5.1 ) The recommended adult dosage is 125 mg taken orally twice a day, with or without food. ( 2 ) Do not crush or chew the tablets. Swallow whole. ( 2 )

6 ADVERSE REACTIONS Most common adverse reactions (≥ 3%) are upper respiratory tract infection, bronchitis, cough, flatulence and increased bilirubin. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Napo Pharmaceuticals at 1-844-722-8256 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. A total of 696 HIV-positive patients in three placebo-controlled trials received MYTESI for a mean duration of 78 days. Of the total population across the three trials, 229 patients received a dosage of 125 mg twice a day for a mean duration of 141 days, and 171 patients received one of four higher than recommended dosages for a mean duration of 139 days (N=69) 14 days (N=102), 146 days (N=54), and 14 days (N=242), respectively. Adverse reactions in patients treated with MYTESI 125 mg twice daily that occurred in at least 2% of patients and at a higher incidence than placebo are provided in Table 1 . Table 1: Common Adverse Reactions occurring in at least 2% of patients and at a higher incidence than placebo in HIV-Positive Patients in Three Placebo-Controlled Trials Adverse Reaction MYTESI 125 mg Twice Daily N = 229 n (%) Placebo N = 274 n (%) Upper respiratory tract infection 13 (6) 4 (2) Bronchitis 9 (4) 0 Cough 8 (4) 3 (1) Flatulence 7 (3) 3 (1) Increased bilirubin 7 (3) 3 (1) Nausea 6 (3) 4 (2) Back pain 6 (3) 4 (2) Arthralgia 6 (3) 0 Urinary tract infection 5 (2) 2 (1) Nasopharyngitis 5 (2) 2 (1) Musculoskeletal pain 5 (2) 1 (<1) Hemorrhoids 5 (2) 0 Giardiasis 5 (2) 0 Anxiety 5 (2) 1 (<1) Increased alanine aminotransferase 5 (2) 3 (1) Abdominal distension 5 (2) 1 (<) Less common adverse reactions that occurred in between 1% and 2% of patients taking 125 mg twice daily of MYTESI were abdominal pain, acne, increased aspartate aminotransferase, increased conjugated bilirubin, increased unconjugated blood bilirubin, constipation, depression, dermatitis, dizziness, dry mouth, dyspepsia, gastroenteritis, herpes zoster, nephrolithiasis, pain in extremity, pollakiuria, sinusitis and decreased white blood cell count.

5 WARNINGS AND PRECAUTIONS Risks of Treatment in Patients with Infectious Diarrhea : Consider infectious etiologies of diarrhea before starting treatment to reduce the risk of inappropriate therapy and worsening disease. ( 2 , 5.1 ) 5. 1 Risks of Treatment in Patients with Infectious Diarrhea Before starting MYTESI, rule out infectious etiologies of diarrhea. If infectious etiologies are not considered, and MYTESI is initiated based on a presumptive diagnosis of non-infectious diarrhea, then there is a risk that patients with infectious etiologies will not receive the appropriate treatments, and their disease may worsen. MYTESI is not indicated for the treatment of infectious diarrhea.

4 CONTRAINDICATIONS None. None ( 4 )