Drug Interaction Studies                                                                                            Clinical drug-drug interaction studies of rifamycin (taken as AEMCOLO) have not been conducted.

BRIEF SUMMARY

RIFAMYCIN- (Nov 2018)

Indn-     To treat travelers diarrhea

Comp-      Delayed-Release Tablets: 194 mg rifamycin. • The recommended dosage of AEMCOLO is 388 mg (two tablets) orally twice daily for three days.

ADR-     Most common adverse reactions (incidence > 2%) are headache and constipation. 

CI-     is contraindicated in patients with a known hypersensitivity to rifamycin, any of the other rifamycin class antimicrobial agents (e.g. rifaximin), or any of the components 

WARNINGS -

 Risk of Persistent or Worsening Diarrhea Complicated by Fever and/or Bloody Stool:  was not shown to be effective in patients with diarrhea complicated by fever and/or bloody stool or diarrhea due to pathogens other than noninvasive strains of E. coli and is not recommended for use in such patients.

Pat Infm-

Persistent Diarrhea Inform the patient being treated for travelers’ diarrhea to discontinue  if diarrhea persists more than 48 hours or worsens.

Advise the patient to seek medical care for fever and/or blood in the stool.

Fever and/or Bloody Stool                                                                                          Inform the patient that it  is not recommended for use if they have fever and/or bloody stool

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U.S. FDA APPROVED  DRUGS DURING 2018

Sr.No-  50

ADVERSE REACTIONS

­ Most common adverse reactions (incidence > 2%) are headache and constipation. 

CONTRAINDICATIONS

­ AEMCOLO is contraindicated in patients with a known hypersensitivity to rifamycin, any of the other rifamycin class antimicrobial agents (e.g. rifaximin), or any of the components in AEMCOLO  

WARNINGS AND PRECAUTIONS-

 Risk of Persistent or Worsening 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 or diarrhea due to pathogens other than noninvasive strains of E. coli and is not recommended for use in such patients.

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

• Clostridium difficile-associated Diarrhea:                                                         Evaluate if diarrhea occurs after therapy or does not improve or worsens during therapy. 

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.

Fever and/or Bloody Stool                                                                                          Inform the patient that AEMCOLO is not recommended for use if they have fever and/or bloody stool.

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

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: Cosmo Technologies, Ltd. Dublin, Ireland Manufactured by: Cosmo S.p.A. Lainate, Milan, Italy Made in Italy

Distributed by: Aries Pharmaceuticals, Inc. 9276 Scranton Rd. Suite 600 San Diego, CA 92121 (USA) 888-ARIES-08 (888-274-3708)

 CLINICAL PHARMACOLOGY

1. Mechanism of Action

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

2 Pharmacodynamics

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

3.Pharmacokinetics

Plasma Concentrations In healthy adults receiving the recommended dose of 388 mg rifamycin (taken as AEMCOLO) twice daily for 3 days, the maximum observed rifamycin concentration in plasma was 8.72 ng/mL (6 hours after the last dose).

A majority (67%) of rifamycin concentrations in plasma were below the limit of quantification (< 2 ng/mL) at this time point.

Absorption                                                                                                                Rifamycin (taken as AEMCOLO) has limited systemic exposure after oral administration of the recommended dosage. Based on total urinary excretion data, bioavailability was < 0.1% under fasting conditions.

Food Effect                                                                                                                        A food-effect study involving administration of AEMCOLO to healthy volunteers under a fasted state and with a meal (approximately 1,000 kcal including 500 kcal from fat) indicated that food decreased systemic exposure of rifamycin.

The decrease in systemic exposure of rifamycin is not expected to be clinically relevant.

Distribution                                                                                                              Plasma protein binding was approximately 80% in vitro. Binding was primarily to albumin and was inversely proportional to concentration.

Elimination                                                                                                                     The apparent half-life of orally administered rifamycin (taken as AEMCOLO) in plasma is unknown.

Metabolism                                                                                                        Cytochrome P450 (CYP) based metabolism of rifamycin was not observed in vitro.

Excretion                                                                                                                       After a single oral dose of 400 mg AEMCOLO (388 mg rifamycin base) in fasting healthy adults, fecal excretion of rifamycin was on average 86% of the nominal dose.

Specific Populations                                                                                                        The pharmacokinetics of rifamycin (taken as AEMCOLO) in patients with impaired renal or hepatic function have not been studied.

Drug Interaction Studies                                                                                            Clinical drug-drug interaction studies of rifamycin (taken as AEMCOLO) have not been conducted.

In Vitro Transporter-                                                                                     Studies  where Drug Interaction Potential Was Not Further evaluated.                        Clinically Rifamycin is a substrate of P-glycoprotein (P-gp) and anticipated to be an inhibitor of P-gp and breast cancer resistant protein (BCRP) in the gut.

Rifamycin is an inhibitor of renal transporters organic anion transporter (OAT) 3, multidrug and toxin extrusion (MATE) 1, and MATE2-K transporters in vitro, however, based on systemic concentrations of rifamycin observed after administration of the recommended dose, clinically relevant inhibition of these transporters in vivo is unlikely.

In Vitro Cytochrome P450 (CYP)                                                                              Studies where Drug Interaction Potential Was Not Further Evaluated Clinically      Rifamycin is an inhibitor of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4/5 in vitro, however, based on systemic concentrations of rifamycin observed after administration of the recommended dose clinically relevant inhibition of these enzymes in vivo is unlikely.

Rifamycin is an inducer of CYP3A4 and CYP2B6 but not CYP1A2 in vitro, however, based on systemic concentrations of rifamycin observed after administration of the recommended dose, clinically relevant induction of these enzymes in vivo is unlikely. Rifamycin is not a substrate of CYPs 1A2, 2B6, 2C9, 2C19, 2D6, 2E1, and 3A4/5. 12.4

 USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary                                                                                       There are no available data on AEMCOLO use in pregnant women to inform any drug associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes. 

Systemic absorption of AEMCOLO in humans is negligible following oral administration of the recommended dose of AEMCOLO.                                                                       Due to the negligible systemic exposure, it is not expected that maternal use of AEMCOLO will result in fetal exposure to the drug.

 All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the U.S. general population, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Advise pregnant women of the potential risk to a fetus.

2. Lactation Risk Summary                                                                                        There is no information regarding the presence of AEMCOLO in human milk, the effects on the breastfed infant, or the effects on milk production.

Systemic absorption of AEMCOLO in humans is negligible following oral administration of the recommended dose of AEMCOLO; therefore, exposure to a breastfed infant through breastmilk is expected to be negligible

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for AEMCOLO and any potential adverse effects on the breast-fed infant from AEMCOLO or from the underlying maternal condition.

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

4.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.

5. 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.

6.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.

 OVERDOSAGE

No specific information is available on the treatment of overdose with AEMCOLO. In the case of overdose, discontinue AEMCOLO, treat symptomatically, and institute supportive measures as required.