1.1 Travelers' Diarrhea

AEMCOLO is indicated for the treatment of travelers' diarrhea (TD) caused by non-invasive strains of Escherichia coliin adults.

1.2 Usage

To reduce the development of drug-resistant bacteria and maintain the effectiveness of AEMCOLO and other antibacterial drugs, AEMCOLO should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

2.1 Basic Dosing Information

The recommended dose of AEMCOLO is 388 mg (two tablets) orally twice daily (in the morning and evening) for three days. Take each dose with a glass of liquid (6-8 ounces). Do NOTtake AEMCOLO concomitantly with alcohol. AEMCOLO can be taken with or without food.

2.2 Important Administration Instructions

AEMCOLO must be taken orally. Swallow the tablets whole. Do NOTcrush, break or chew the delayed-release tablets.

5.1 Risk of Persistent or Worsening of Diarrhea Complicated by Fever and/or Bloody Stool

AEMCOLO was not shown to be effective in patients with diarrhea complicated by fever and/or bloody stool. Patients with these conditions treated with AEMCOLO had prolonged time to last unformed stool (TLUS). The effectiveness of AEMCOLO in travelers' diarrhea caused by pathogens other than E. colihas not been demonstrated. AEMCOLO is not recommended for use in patients with diarrhea accompanied by fever or bloody stools or due to pathogens other than noninvasive strains of E. coli [see Indications and Usage (1), Clinical Studies (14)].

Discontinue AEMCOLO if diarrhea gets worse or persists more than 48 hours and consider alternative antibacterial therapy.

5.2 Clostridium difficile-Associated Diarrhea

Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon which may lead to overgrowth of C. difficile.

C. difficileproduces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficilemay cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial drug use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, antibacterial drug use not directed against C. difficilemay need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, specific antibacterial treatment of C. difficile, and/or surgical evaluation should be instituted as clinically indicated.

5.3 Development of Drug-Resistant Bacteria

Prescribing AEMCOLO in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

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.

The safety of oral AEMCOLO 388 mg twice daily was assessed in 619 adults with travelers' diarrhea in two controlled clinical trials (Trial 1 and Trial 2) with 96% of patients receiving three or four days of treatment. These patients had a mean age of 36.2 years (range 18 to 87 years) with 7% ≥ 65 years old; 49% were male, 84% were White, and 4% were Hispanic.

Discontinuation of AEMCOLO due to adverse reactions occurred in 1% of patients. The most frequent adverse reactions leading to discontinuation of AEMCOLO were abdominal pain (0.5%) and pyrexia (0.3%).

In Trial 1 (placebo-controlled), the adverse reaction that occurred in at least 2% of AEMCOLO-treated patients (n = 199) and with an incidence higher than in the placebo group was constipation (3.5% AEMCOLO, 1.5% placebo)

In Trial 2 (active comparator), the adverse reaction that occurred in at least 2% of AEMCOLO-treated patients (n = 420) and with an incidence higher than in the ciprofloxacin group was headache (3.3% AEMCOLO, 1.9% ciprofloxacin)

Adverse reactions reported in <2% of patients receiving AEMCOLO 388 mg twice daily with a higher incidence than the comparator group was dyspepsia.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The safety and effectiveness of AEMCOLO has not been established in pediatric patients less than 18 years of age with travelers' diarrhea.

8.5 Geriatric Use

Clinical studies with AEMCOLO for travelers' diarrhea did not include sufficient numbers of patients aged 65 and older to determine whether they respond differently than younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

8.6 Renal Impairment

The pharmacokinetics of AEMCOLO in patients with impaired renal function has not been studied. Given the minimal systemic exposure of rifamycin (taken as AEMCOLO) and minor role of renal excretion in elimination of rifamycin, renal impairment is not expected to have a clinically meaningful effect on rifamycin systemic exposure necessitating a dose adjustment.

8.7 Hepatic Impairment

The pharmacokinetics of AEMCOLO in patients with impaired hepatic function has not been studied. Given the minimal systemic exposure of rifamycin (taken as AEMCOLO) hepatic impairment is not expected to have a clinically meaningful effect on rifamycin systemic exposure necessitating a dose adjustment.

12.1 Mechanism of Action

Rifamycin is an antibacterial drug [see Microbiology (12.4)] .

12.2 Pharmacodynamics

AEMCOLO exposure-response relationships and time course of pharmacodynamic response are unknown.

12.3 Pharmacokinetics

12.4 Microbiology

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14.1 Travelers' Diarrhea

The efficacy of AEMCOLO given as 388 mg orally, taken two times a day, for 3 days was evaluated in one multi-center, randomized, double-blind, placebo-controlled trial in adults with travelers' diarrhea. Trial 1 (NCT01142089) was conducted at clinical sites in Guatemala and Mexico, and provides the primary evidence for the efficacy of AEMCOLO. A second active-controlled trial (Trial 2 – NCT01208922) conducted in India, Guatemala and Ecuador, provided supportive evidence for the efficacy of AEMCOLO. Although patients with fever and/or bloody stool at baseline were to be excluded from both trials, 18 subjects treated with AEMCOLO had fever and bloody diarrhea at enrollment in Trial 2. Stool specimens were collected before treatment and 1 to 2 days following the end of treatment to identify enteric pathogens. The predominant pathogen in both trials was E. coli.

The clinical efficacy of AEMCOLO was assessed using an endpoint of time to last unformed (watery or soft) stool (TLUS) before achieving clinical cure. The endpoint of clinical cure was defined as two or fewer soft stools and minimal enteric symptoms at the beginning of a 24-hour period or no unformed stools at the beginning of a 48-hour period. Kaplan-Meier estimates of TLUS for the intent-to-treat (ITT) Population, which includes all randomized subjects, in Trial 1 (Figure 1) show that AEMCOLO significantly reduced the TLUS compared to placebo (p=0.0008).

Figure 1: Kaplan-Meier Estimates of Time to Last Unformed Stool (TLUS) in Trial 1 (ITT Population)

Table 1 displays the median TLUS and the number of patients who achieved clinical cure for the ITT population in Trial 1. The median duration of diarrhea was significantly shorter in patients treated with AEMCOLO than in the placebo group. More patients treated with AEMCOLO were classified as clinical cures than were those in the placebo group.

The results of Trial 2 supported the results presented for Trial 1. In addition, this trial provided evidence that AEMCOLO-treated subjects with fever and/or bloody diarrhea at baseline had prolonged TLUS. [see Warnings and Precautions (5.1)]

Store at 20° to 25°C (68 to 77°F) excursions permitted to 15 to 30°C (59° to 86°F) [See USP Controlled Room temperature].

Persistent Diarrhea

Inform the patient being treated for travelers' diarrhea to discontinue AEMCOLO if diarrhea persists more than 48 hours or worsens. Advise the patient to seek medical care for fever and/or blood in the stool [see Warnings and Precautions (5.1)].

Fever and/or Bloody Stool

Inform the patient that AEMCOLO is not recommended for use if they have fever and/or bloody stool [see Warnings and Precautions (5.1)] .

Clostridium difficile-Associated Diarrhea

Advise patients that diarrhea is a common problem caused by antibacterial drugs, which usually ends when the antibacterial drugs is discontinued. Sometimes after starting treatment with antibacterial drugs, patients can develop watery or bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of AEMCOLO. Inform the patient that if diarrhea occurs after therapy or does not improve or worsens during therapy, patients should contact their physician as soon as possible [see Warnings and Precautions (5.2)].

Important Administration Instructions

Instruct the patients that:

• AEMCOLO tablets should be swallowed whole with a full glass of liquid (6-8 ounces).
• AEMCOLO must not be taken concomitantly with alcohol.
• AEMCOLO tablets must not be chewed, crushed or broken.
• AEMCOLO may be taken with or without food.

Antibacterial Resistance

Patients should be counseled that antibacterial drugs including AEMCOLO should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When AEMCOLO is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by AEMCOLO or other antibacterial drugs in the future.