Aemcolo (Page 2 of 4)

8.2 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 [see Clinical Pharmacology (12.3)]. There are no animal lactation data following oral rifamycin administration. Following single intravenous injection of rifamycin to lactating ewes, rifamycin has been shown to pass into milk.1

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.

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.

10 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.

11 DESCRIPTION

AEMCOLO, delayed-release tablet, for oral administration, contains 194 mg of rifamycin equivalent to 200 mg of rifamycin sodium.

Rifamycin sodium is a rifamycin antibacterial. It is designated chemically as: Sodium (2S,12Z,14E,16S,17S,18R,19R,20R,21S,22R,23S,24E)-21-(acetyloxy)-6,9,17,19-tetrahydroxy-23-methoxy-2,4,12,16,18,20,22-heptamethyl-1,11-dioxo-1,2-dihydro-2,7-(epoxypentadeca[1,11,13]trienimino)naphtho[2,1-b ]furan-5-olate. Its empirical formula is C37 H46 NNaO12 . The molecular weight is 720 g/mol.

Its structural formula is:

Chemical Structure
(click image for full-size original)

Rifamycin sodium is a fine or slightly granular powder, soluble in water, and freely soluble in anhydrous ethanol.

AEMCOLO, delayed-release tablets are enteric coated with a pH-resistant polymer film which breaks down above pH 7. The tablet core contains rifamycin. The tablets are yellow brown and ellipsoidal.

Each tablet contains the following inactive ingredients: ammonio methacrylate copolymer (Type B), ascorbic acid, glyceryl distearate, lecithin, magnesium stearate, mannitol, methacrylic acid and methyl methacrylate copolymer (1:2), polyethylene glycol 6000, colloidal silicon dioxide, talc, titanium dioxide, triethylcitrate, yellow ferric oxide.

12 CLINICAL PHARMACOLOGY

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

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 [see Dosage and Administration (2.2)].

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 Microbiology

Mechanism of Action

Rifamycin belongs to the ansamycin class of antibacterial drugs and acts by inhibiting the beta-subunit of the bacterial DNA-dependent RNA polymerase, blocking one of the steps in DNA transcription. This results in inhibition of bacterial synthesis and consequently growth of bacteria.

Resistance

Resistance to rifamycin is associated with mutations in the RNA polymerase beta subunit. Among E. coli strains, the spontaneous mutation frequency rate of rifamycin ranged from 10-6 to 10-10 at 4× – 16× MIC; the mutation frequency was independent of rifamycin concentration. Increases in the minimum inhibitory concentrations were observed both in vitro and while on treatment following exposure to rifamycin. Cross-resistance between rifamycin and other ansamycins have been observed.

Antibacterial Activity

Rifamycin has been shown to be active against most isolates of the following pathogen both in vitro and in clinical studies of travelers’ diarrhea:

Escherichia coli (enterotoxigenic and enteroaggregative isolates)

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