CROFELEMER: 177 Adverse Event Reports & Safety Profile

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.

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 )

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 )

None. None ( 4 )

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.

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.

INTERACTIONS

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 <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> .