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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 calciumactivated 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.
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.
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.
The distribution of crofelemer has not been determined.
No metabolites of crofelemer have been identified in healthy subjects or patients in clinical trials.
The elimination route has not been identified in humans.
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 crofelemer was administered one-half hour before the morning and evening meals. Therefore, crofelemer may be administered with or without a meal.
Results of a crossover study in healthy volunteers showed crofelemer 500 mg administered four times daily 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.
The efficacy of FULYZAQ 125 mg delayed-release tablets twice daily was evaluated in a randomized, double-blind, placebo-controlled (one month) and placebo-free (five month), multi-center study. The study enrolled 374 HIV-positive patients on stable anti-retroviral therapy (ART) with a history of diarrhea for one month or more. Diarrhea was defined as either persistently loose stools despite regular use of anti-diarrheal medication (ADM) (e.g., loperamide, diphenoxylate, and bismuth subsalicylate) or one or more watery bowel movements per day without regular ADM use.
Patients were excluded if they had a positive gastrointestinal (GI) biopsy, GI culture, or stool test for multiple bacteria (Salmonella, Shigella, Campylobacter, Yersinia, Mycobacterium), bacterial toxin (Clostridium difficile), ova and parasites (Giardia, Entamoeba, Isospora, Cyclospora, Cryptosporidium, Microsporidium), or viruses (Cytomegalovirus). Patients were also excluded if they had a history of ulcerative colitis, Crohn's disease, celiac sprue (gluten-enteropathy), chronic pancreatitis, malabsorption, or any other GI disease associated with diarrhea.
The study had a two-stage adaptive design. In both stages, patients received placebo for 10 days (screening period) followed by randomization to crofelemer or placebo for 31 days of treatment (doubleblind period). Only patients with 1 or more watery bowel movements per day on at least 5 of the last 7 days in the screening period were randomized to the double-blind period. Each stage enrolled patients separately; the dose for the second stage was selected based on an interim analysis of data from the first stage. In the first stage, patients were randomized 1:1:1:1 to one of three crofelemer dose regimens (125, 250, or 500 mg twice daily) or placebo. In the second stage, patients were randomized 1:1 to crofelemer 125 mg twice daily or placebo. The efficacy analysis was based on results from the double-blind portion of both stages.
Each study stage also had a five month period (placebo-free period) that followed the double-blind period. Patients treated with crofelemer continued the same dose in the placebo-free period. In the first stage, patients that received placebo were re-randomized 1:1:1 to one of the three crofelemer dose regimens (125, 250, or 500 mg twice daily) in the placebo-free period. In the second stage, patients that received placebo were treated with crofelemer 125 mg twice daily in the placebo-free period.
The median time since diagnosis of HIV was 12 years. The percentage of patients with a CD4 cell count of less than 404 was 39%. The percentage of patients with a HIV viral load greater than or equal to 1000, 400 to 999, and less than 400 HIV copies/mL was 7%, 3%, and 9%, respectively; the remainder had a viral load that was not detectable. The median time since diarrhea started was 4 years. The median number of daily watery bowel movements was 2.5 per day.
Most patients were male (85%). The percentage of patients that were Caucasian was 46%; the percentage of patients that were African- American was 32%. The median age was 45 years with a range of 21 to 68 years.
In the double-blind period of the study, 136 patients received crofelemer 125 mg twice daily, 54 patients received 250 mg twice daily, 47 patients received 500 mg twice daily, and 138 patients received placebo. The percentages of patients that completed the double-blind period were 92%, 100%, 85%, and 94% in the 125 mg, 250 mg, 500 mg, and placebo arms, respectively.
Most patients received concomitant protease inhibitors (PI) during the double-blind period (Table 2). The most frequently used ARTs in each group were tenofovir/emtricitabine, ritonavir, and lopinavir/ritonavir.
Table 2: Concomitant ART Use in the Double-Blind
|125 mg BID
(N = 136) n (%)
|250 mg BID
(N = 54) n (%)
|500 mg BID
(N = 46) n (%)
N = 138 n (%)
|Any ART||135 (99)||53 (98)||45 (98)||134 (97)|
|Any PI||87 (64)||41 (76)||33 (72)||97 (70)|
|Tenofovir/ Emtricitabine||45 (33)||22 (41)||16 (35)||52 (38)|
|Ritonavir||46 (34)||18 (33)||15 (33)||49 (36)|
|Lopinavir/ Ritonavir||30 (22)||21 (39)||15 (33)||40 (29)|
|Efavirenz/ Tenofovir/ Emtricitabine||30 (22)||7 (13)||7 (15)||21 (15)|
|Tenofovir disoproxil fumarate||18 (13)||8 (15)||5 (11)||14 (10)|
|Atazanavir sulfate||19 (14)||3 (6)||6 (13)||22 (16)|
|Abacavir w/ lamivudine||17 (13)||5 (9)||5 (11)||18 (13)|
|Darunavir||19 (14)||4 (7)||4 (9)||14 (10)|
|Raltegravir||16 (12)||4 (7)||5 (11)||11 (8)|
|Valaciclovir hydrochloride||12 (9)||8 (15)||5 (11)||16 (12)|
|Fosamprenavir||12 (9)||6 (11)||4 (9)||13 (9)|
|Zidovudine w/ lamivudine||12 (9)||3 (6)||3 (7)||15 (11)|
|Lamivudine||7 (5)||6 (11)||4 (9)||6 (4)|
|Nevirapine||8 (6)||6 (11)||3 (7)||9 (7)|
|Atazanavir||5 (4)||6 (11)||2 (4)||2 (1)|
|Abbreviations: ART = antiretroviral therapy; PI = Protease Inhibitor; BID = twice daily.|
The primary efficacy endpoint was the proportion of patients with a clinical response, defined as less than or equal to 2 watery bowel movements per week during at least 2 of the 4 weeks of the placebo-controlled phase. Patients who received concomitant ADMs or opiates were counted as clinical non-responders.
A significantly larger proportion of patients in the crofelemer 125 mg twice daily group experienced clinical response compared with patients in the placebo group (17.6% vs. 8.0%, 1–sided p < 0.01).
In the randomized clinical study, examination of duration of diarrhea, baseline number of daily watery bowel movements, use of protease inhibitors, CD4 cell count and age subgroups did not identify differences in the consistency of the crofelemer treatment effect among these subgroups. There were too few female subjects and subjects with an HIV viral load > 400 copies/mL to adequately assess differences in effects in these populations. Among race subgroups, there were no differences in the consistency of the crofelemer treatment effect except for the subgroup of African-Americans; crofelemer was less effective in African-Americans than non-African-Americans.
Although the CD4 cell count and HIV viral load did not appear to change over the one month placebo-controlled period, the clinical significance of this finding is unknown because of the short duration of the placebo-controlled period.
Of the 24 clinical responders to crofelemer (125 mg twice daily), 22 entered the placebo-free period; 16 were responding at the end of month 3, and 14 were responding at the end of month 5.
Last reviewed on RxList: 4/14/2016
This monograph has been modified to include the generic and brand name in many instances.
Additional Fulyzaq Information
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