Crofelemer

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 )

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 )

Delayed-Release Tablets: 125 mg of crofelemer as a white, oval, delayed-release tablet printed on one side with 125SLXP. Delayed-Release Tablets: 125 mg ( 3 )

None. None ( 4 )

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.

7.1 Nelfinavir, Zidovudine, and Lamivudine MYTESI administration did not have a clinically relevant interaction with nelfinavir, zidovudine, or lamivudine in a drug-drug interaction trial [see Clinical Pharmacology ( 12.3 )] .

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.

Lactation : Women infected with HIV-1 should be instructed not to breastfeed due to the potential for HIV transmission. ( 8.2 )

8.1 Pregnancy Risk Summary Crofelemer is minimally absorbed systemically by the oral route of administration and maternal use is not expected to result in fetal exposure to the drug [see Clinical Pharmacology ( 12.3 )] . In pregnant rats, no adverse fetal effects were observed with oral administration of crofelemer at doses up to 177 times the recommended clinical dose during the period of organogenesis. In pregnant rabbits, an increase in fetal resorptions and abortions compared to controls were observed with crofelemer at a dose of 96 times the recommended clinical dose. However, it is not clear whether these effects in rabbits are related to the maternal toxicity (decreased body weight and decreased food consumption) observed at this dose (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data Crofelemer was not teratogenic and did not produce embryofetal toxicity in pregnant rats following oral administration at doses up to 738 mg/kg/day during the period of organogenesis. The 738 mg/kg/day dose is 177 times the recommended daily human dose of 4.2 mg/kg/day. Crofelemer was not teratogenic in pregnant rabbits following oral administration at doses up to 400 mg/kg/day during the period of organogenesis. At a dose level of 400 mg/kg/day, which is 96 times the recommended daily human dose of 4.2 mg/kg/day, crofelemer produced an increase in fetal resorptions and abortions compared to controls. However, it is not clear whether these effects are related to the maternal toxicity (decreased body weight and decreased food consumption) observed.

8.2 Lactation Risk Summary The Centers for Disease Control and Prevention recommend that HIV-1 infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1. There are no data on the presence of crofelemer in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for HIV transmission and adverse effects on a breastfed infant, instruct mothers not to breastfeed if they are taking MYTESI.

8.4 Pediatric Use The safety and effectiveness of MYTESI have not been established in pediatric patients.

8.5 Geriatric Use Clinical studies with MYTESI did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger patients.

8.6 Use in Patients with Low CD4 Counts and High Viral Loads No dose modifications are recommended with respect to CD4 cell count and HIV viral load, based on the findings in subgroups of patients defined by CD4 cell count and HIV viral load. The safety profile of MYTESI was similar in patients with baseline CD4 cell count less than 404 cells/microL (lower limit of normal range) (N=388) and patients with baseline CD4 cell counts greater than or equal to 404 cells/microL (N=289). The safety profile of crofelemer was similar in patients with baseline HIV viral loads less than 400 copies/mL (N = 412) and patients with baseline HIV viral loads greater than or equal to 400 copies/mL (N = 278).

Risk Summary Crofelemer is minimally absorbed systemically by the oral route of administration and maternal use is not expected to result in fetal exposure to the drug [see Clinical Pharmacology ( 12.3 )] . In pregnant rats, no adverse fetal effects were observed with oral administration of crofelemer at doses up to 177 times the recommended clinical dose during the period of organogenesis. In pregnant rabbits, an increase in fetal resorptions and abortions compared to controls were observed with crofelemer at a dose of 96 times the recommended clinical dose. However, it is not clear whether these effects in rabbits are related to the maternal toxicity (decreased body weight and decreased food consumption) observed at this dose (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data Crofelemer was not teratogenic and did not produce embryofetal toxicity in pregnant rats following oral administration at doses up to 738 mg/kg/day during the period of organogenesis. The 738 mg/kg/day dose is 177 times the recommended daily human dose of 4.2 mg/kg/day. Crofelemer was not teratogenic in pregnant rabbits following oral administration at doses up to 400 mg/kg/day during the period of organogenesis. At a dose level of 400 mg/kg/day, which is 96 times the recommended daily human dose of 4.2 mg/kg/day, crofelemer produced an increase in fetal resorptions and abortions compared to controls. However, it is not clear whether these effects are related to the maternal toxicity (decreased body weight and decreased food consumption) observed.

The safety and effectiveness of MYTESI have not been established in pediatric patients.

Clinical studies with MYTESI did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger patients.

MYTESI (crofelemer) delayed-release tablets is an anti-diarrheal, enteric-coated drug product for oral administration. It contains 125 mg of crofelemer, a botanical drug substance that is derived from the red latex of Croton lechleri Müll. Arg. Crofelemer is an oligomeric proanthocyanidin mixture primarily composed of (+)–catechin, (–)–epicatechin, (+)–gallocatechin, and (–)–epigallocatechin monomer units linked in random sequence, as represented below. The average degree of polymerization for the oligomers ranges between 5 and 7.5, as determined by phloroglucinol degradation. R = H or OH range n = 3 to 5.5 Inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, and microcrystalline cellulose. Coating ingredients: ethylacrylate and methylacrylate copolymer dispersion, talc, triethyl citrate, and white dispersion which contains xanthan gum, titanium dioxide, propyl paraben, and methyl paraben. The following chemical structure for MYTESI (crofelemer) is delayed-release tablets is an anti-diarrheal, enteric-coated drug product for oral administration. It contains 125 mg of crofelemer, a botanical drug substance that is derived from the red latex of Croton lechleri Müll. Arg. Crofelemer is an oligomeric proanthocyanidin mixture primarily composed of (+)–catechin, (–)–epicatechin, (+)–gallocatechin, and (–)–epigallocatechin monomer units linked in random sequence, as represented below. The average degree of polymerization for the oligomers ranges between 5 and 7.5, as determined by phloroglucinol degradation.

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.

12.2 Pharmacodynamics Consistent with the mechanism of action of crofelemer (i.e., inhibition of CFTR and CaCC in the gastrointestinal lumen), data suggest stool chloride concentrations decreased in patients treated with crofelemer 500 mg four times daily (8-times the recommended daily dosage) (n=25) for four days relative to placebo (n=24); stool chloride concentrations decreased in both African American patients treated with crofelemer (n=3) relative to placebo (n=5) and non-African American patients treated with Mytesi (n=22) relative to placebo (n=19). Cardiac Electrophysiology At a dose 10 times the maximum recommended dose, crofelemer does not prolong the QTc interval to any clinically relevant extent.

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.

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.

Consistent with the mechanism of action of crofelemer (i.e., inhibition of CFTR and CaCC in the gastrointestinal lumen), data suggest stool chloride concentrations decreased in patients treated with crofelemer 500 mg four times daily (8-times the recommended daily dosage) (n=25) for four days relative to placebo (n=24); stool chloride concentrations decreased in both African American patients treated with crofelemer (n=3) relative to placebo (n=5) and non-African American patients treated with Mytesi (n=22) relative to placebo (n=19). Cardiac Electrophysiology At a dose 10 times the maximum recommended dose, crofelemer does not prolong the QTc interval to any clinically relevant extent.

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.

, Mutagenesis, Impairment of Fertility Carcinogenesis In a 6-month carcinogenicity study in Tg.rasH2 transgenic mice, crofelemer at oral doses up to 125 mg/kg twice a day (250 mg/kg/day) did not produce any drug-related neoplasms in male and female animals. The 250 mg/kg/day dose is about 60 times the recommended clinical dose of 4.2 mg/kg/day (125 mg twice daily). In a 2-year oral carcinogenicity study in rats, crofelemer at doses up to 100/50 mg/kg twice a day (200/100 mg/kg/day), which is 47.6/23.8 times the recommended clinical dose, did not produce any drug-related neoplastic findings in male and female rats (due to drug-related decreased survival in male rats, 37.5 mg/kg twice daily and 100 mg/kg twice daily doses were reduced to 25 mg/kg twice daily and 50 mg/kg twice daily, respectively, at week 67). Mutagenesis Crofelemer was negative in the bacterial reverse mutation assay, chromosomal aberration assay, and rat bone marrow micronucleus assay. Impairment of Fertility Crofelemer, at oral doses of up to 738 mg/kg/day (177 times the recommended human daily dose of 125 mg twice daily), had no effects on fertility or reproductive performance of male and female rats.

17 PATIENT COUNSELING INFORMATION Instruct patients that MYTESI tablets may be taken with or without food. Instruct patients to swallow MYTESI tablets whole and not to crush or chew the tablets. Manufactured by Patheon, Inc. for Napo Pharmaceuticals, Inc., San Francisco, CA 94105 Copyright © Napo Pharmaceuticals, Inc. US Patent Nos. 7,341,744 and 7,323,195. NP-367-1 11/2020 70033046 The botanical drug substance of MYTESI is extracted from Croton lechleri (the botanical raw material) that is harvested from the wild in South America.