tients with baseline CD4 cell counts greater than or equal to 404 cells/μL (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).
10 OVERDOSAGE
There has been no reported experience with overdosage of crofelemer.
11 DESCRIPTION
FULYZAQ (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: microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate.
Coating ingredients: ethylacrylate and methylacrylate copolymer dispersion, talc, triethyl citrate, and white dispersion which contains xanthan gum, titanium dioxide, propyl paraben, and methyl paraben.
12 CLINICAL PHARMACOLOGY
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 GI tract.
12.2 Pharmacodynamics
Consistent with the mechanism of action of crofelemer (i.e., inhibition of CFTR and CaCC in the GI lumen), data suggest stool chloride concentrations decreased in patients treated with FULYZAQ (500 mg four times daily) (n=25) for four days relative to placebo (n=24); stool chloride concentrations decreased in both African American patients treated with FULYZAQ (n=3) relative to placebo (n=5) and non-African American patients treated with FULYZAQ (n=22) relative to placebo (n=19).
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.
Distribution
The distribution of crofelemer has not been determined.
Metabolism
No metabolites of crofelemer have been identified in healthy subjects or patients in clinical trials.
Elimination
The elimination route has not been identified in humans.
Food Effect
Administration of crofelemer with a high-fat meal was not associated with an increase in systemic exposure of crofelemer in healthy volunteers. In the clinical trial, a single 500 mg dose of cr |
