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 )

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.

12.3 Pharmacokinetics Absorption The absorption of crofelemer is minimal following oral dosing in healthy adults and HIV–positive patients and concentrations of crofelemer in plasma are below the level of quantitation (50 ng/mL). Therefore, standard pharmacokinetic parameters such as area under the curve, maximum concentration, and half-life cannot be estimated. Effect of Food Administration of crofelemer with a high-fat meal was not associated with an increase in systemic exposure of crofelemer in healthy subjects. In the clinical trial, a single 500 mg dose of crofelemer (4-times the recommended dose) was administered one-half hour before the morning and evening meals [see Dosage and Administration ( 2 )] . Drug Interaction Studies In vitro studies have shown that crofelemer has the potential to inhibit transporters MRP2 and OATP1A2 but not P-gp and BCRP at concentrations expected in the gut. Due to the minimal absorption of crofelemer, crofelemer is unlikely to inhibit cytochrome P450 isoenzymes 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, and 2E1 systemically. Nelfinavir, Zidovudine, Lamivudine Results of a crossover study in healthy subjects showed crofelemer 500 mg administered four times daily (8- times the recommended daily dosage) for five days had no effect on the exposure of zidovudine and nelfinavir when administered as a single dose. A 20% decrease in lamivudine exposure was also observed in the same study but was not considered to be clinically important. Midazolam In vitro studies have shown that crofelemer has the potential to inhibit CYP3A4 enzymes at concentrations expected in the gut. The effects of crofelemer on the pharmacokinetics of a single oral dose of 2 mg midazolam, a sensitive CYP3A4 substrate, was evaluated in healthy subjects following crofelemer dosed orally at 500 mg twice daily (4-times the recommended dosage) for six consecutive days. No significant changes in the mean C max and AUC were observed for midazolam and its active metabolite, hydroxymidazolam after co- administration with crofelemer compared to that after administration of midazolam alone.