Aemcolo (Page 3 of 4)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

No carcinogenicity studies have been conducted in animals with rifamycin.

Mutagenesis

Rifamycin was not genotoxic in the bacterial reverse mutation assays, mouse lymphoma cell mutation assay, or mouse bone marrow micronucleus assay.

Impairment of Fertility

No fertility studies have been conducted in animals with rifamycin.

14 CLINICAL STUDIES

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)

Figure 1
(click image for full-size original)

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.

Table 1: Clinical Response in Trial 1 (ITT Population)
AEMCOLO(N=199)Placebo(N=65)DifferenceP value
ITT = Intent-to-Treat; TLUS = time to last unformed stool (in hours)
*
log-rank test. A 95% confidence interval for the difference in medians cannot be computed due to the amount of censored observations in the placebo group.
chi-square test, 95% confidence interval on the difference is (11.3, 37.7).
Median TLUS (hrs)46.068.0-22.0p = 0.0008*
Clinical cure, n (%)162 (81.4%)37 (56.9%)24.5%p =0.0001

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)]

15 REFERENCES

  1. Ziv G, Sulman FG. Evaluation of rifamycin SV and rifampin kinetics in lactating ewes. Antimicrob Agents Chemother. 1974;5(2):139-142.

16 HOW SUPPLIED/STORAGE AND HANDLING

AEMCOLO delayed-release tablets contain 194 mg of rifamycin (equivalent to 200 mg of rifamycin sodium), and are yellow brown, ellipsoidal and film coated. These are packaged in blister cards of 6 tablets contained in a cardboard carton. They are supplied as follows:

NDC (57841-1200-1) : carton of 12 tablets (2 blister cards of 6 tablets)
NDC (57841-1200-2) : carton of 36 tablets (6 blister cards of 6 tablets)

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].

17 PATIENT COUNSELING INFORMATION

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.

Manufactured for:
RedHill Biopharma Inc.
Raleigh, NC 27617
833-ADR-HILL (833-237-4455)

Manufactured by:
Cosmo S.p.A.
Lainate, Milan, Italy
Made in Italy

U.S. Patents:
http://www.cosmopharma.com/activities/patents
ARTW-0008-000

PRINCIPAL DISPLAY PANEL — 194 mg Tablet Blister Pack Carton

Rx only
NDC 57841-1200-1

194 mg tablets*

Swallow tablet whole.
Do not chew or break.

Aemcolo®
(rifamycin)
delayed
release tablets

*Each tablet contains:
Rifamycin 194 mg
(equivalent to 200 mg Rifamycin Sodium Salt)

aemcolo.com

12 tablets
(2 cards x 6 tablets each)

PRINCIPAL DISPLAY PANEL -- 194 mg Tablet Blister Pack Carton
(click image for full-size original)

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