Lansoprazole, Amoxicillin, Clarithromycin

LANSOPRAZOLE, AMOXICILLIN, CLARITHROMYCIN-
Citron Pharma LLC

To reduce the development of drug-resistant bacteria and maintain the effectiveness of lansoprazole delayed-release capsules, amoxicillin capsules, and clarithromycin tablets and other antibacterial drugs, lansoprazole delayed-release capsules, amoxicillin capsules, and clarithromycin tablets should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.
THESE PRODUCTS ARE INTENDED ONLY FOR USE AS DESCRIBED. The individual products contained in this package should not be used alone or in combination for other purposes. The information described in this labeling concerns only the use of these products as indicated in this daily administration pack. For information on use of the individual components when dispensed as individual medications outside this combined use for treating Helicobacter pylori (H. pylori) , please see the package inserts for each individual product.

DESCRIPTION

Lansoprazole delayed-release capsules USP, amoxicillin capsules USP, and clarithromycin tablets USP consist of a daily administration card containing two lansoprazole 30 mg delayed-release capsules USP, four amoxicillin 500 mg capsules USP, and two clarithromycin 500 mg tablets USP, for oral administration.

Lansoprazole Delayed-Release Capsules USP

The active ingredient in lansoprazole delayed-release capsules USP is lansoprazole, a substituted benzimidazole, 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl] methyl] sulfinyl] benzimidazole, a compound that inhibits gastric acid secretion. Its molecular formula is C16 H14 F3 N3 O2 S with a molecular weight of 369.37. Lansoprazole has the following structure:
lansoprazole-amoxicillin-clarithromycin-structure-1
Lansoprazole USP is a white to brownish-white odorless crystalline powder which melts with decomposition at approximately 166°C. Lansoprazole is freely soluble in dimethylformamide; soluble in methanol; sparingly soluble in ethanol; slightly soluble in ethyl acetate, dichloromethane and acetonitrile; very slightly soluble in ether; and practically insoluble in hexane and water.
Each delayed-release capsule contains enteric-coated pellets consisting of 30 mg of lansoprazole USP (active ingredient) and the following inactive ingredients: acetone, hypromellose, isopropyl alcohol, light magnesium carbonate, methacrylic acid copolymer, polyethylene glycol, polysorbate 80, sugar spheres (which contain sucrose and corn starch), talc, and titanium dioxide. Components of the gelatin capsule include D&C Red No. 28, FD&C Blue No. 1, FD&C Red No. 40, gelatin, sodium lauryl sulfate, and titanium dioxide.

Amoxicillin Capsules USP

Amoxicillin, is a semisynthetic antibiotic, an analogue of ampicillin, with a broad spectrum of bactericidal activity against many gram-positive and gram-negative microorganisms. Chemically it is (2S , 5R , 6R)-6-[(R)-(-)-2-amino-2-(p -hydroxyphenyl)acetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0] heptane-2-carboxylic acid trihydrate. Its molecular formula is C16 H19 N3 O5 S•3H2 O and the molecular weight of 419.45. Amoxicillin has the following structure:

lansoprazole-amoxicillin-clarithromycin-structure-2
(click image for full-size original)

Amoxicillin capsules USP are intended for oral administration.
The pink body with blue cap capsules contain amoxicillin trihydrate equivalent to 500 mg of amoxicillin USP.
Inactive ingredients: Capsule shells — D&C Red No. 28, FD&C Blue No. 1, FD&C Red No. 40, gelatin, sodium lauryl sulfate and titanium dioxide; Capsule contents – magnesium stearate, microcrystalline cellulose.
Meets USP Dissolution Test 2.

Clarithromycin Tablets USP
Clarithromycin is a semi-synthetic macrolide antibiotic. Chemically, it is 6-0 -methylerythromycin. The molecular formula is C38 H69 NO13 , and the molecular weight is 747.96. Clarithromycin has the following structure:

lansoprazole-amoxicillin-clarithromycin-structure-3
(click image for full-size original)

Clarithromycin USP is a white or almost white, crystalline powder. It is soluble in acetone, slightly soluble in methanol, ethanol, and acetonitrile, and practically insoluble in water.
Each light yellow colored, oval shaped, biconvex film-coated immediate-release tablet contains 500 mg of clarithromycin USP and the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hydroxypropyl cellulose, hypromellose, iron oxide yellow, magnesium stearate, microcrystalline cellulose, povidone, propylene glycol, sorbic acid, titanium dioxide, and vanillin.

CLINICAL PHARMACOLOGY

Pharmacokinetics

Pharmacokinetics when all three components of the lansoprazole delayed-release capsules, amoxicillin capsules, and clarithromycin tablets were coadministered has not been studied. Studies have shown no clinically significant interactions of lansoprazole delayed-release capsules and amoxicillin or lansoprazole delayed-release capsules and clarithromycin when administered together. There is no information about the gastric mucosal concentrations of lansoprazole delayed-release capsules, amoxicillin and clarithromycin after administration of these agents concomitantly. The systemic pharmacokinetic information presented below is based on studies in which each product was administered alone.
Lansoprazole Delayed-Release Capsules

Absorption
Lansoprazole delayed-release capsules contain an enteric-coated granule formulation of lansoprazole. Absorption of lansoprazole begins only after the granules leave the stomach. The absorption of lansoprazole is rapid, with the mean Cmax occurring approximately 1.7 hours after oral dosing, and the absolute bioavailability is over 80%. Both the Cmax and AUC are diminished by about 50 to 70% if lansoprazole is given 30 minutes after food, compared to the fasting condition. There is no significant food effect if lansoprazole is given before meals.

Distribution

Lansoprazole is 97% bound to plasma proteins. Plasma protein binding is constant over the concentration range of 0.05 to 5 mcg/mL.

Metabolism

Lansoprazole is extensively metabolized in the liver. Two metabolites have been identified in measurable quantities in plasma (the hydroxylated sulfinyl and sulfone derivatives of lansoprazole). These metabolites have very little or no antisecretory activity. Lansoprazole is thought to be transformed into two active species which inhibit acid secretion by blocking the proton pump [(H+ ,K+)-ATPase enzyme system] at the secretory surface of the gastric parietal cell. The two active species are not present in the systemic circulation. Therefore, the plasma elimination half-life of lansoprazole does not reflect its duration of suppression of gastric acid secretion.

Elimination

Following single-dose oral administration of lansoprazole delayed-release capsules, virtually no unchanged lansoprazole was excreted in the urine. In one study, after a single oral dose of 14 C-lansoprazole, approximately one-third of the administered radiation was excreted in the urine and two-thirds was recovered in the feces. This implies a significant biliary excretion of the lansoprazole metabolites.
Amoxicillin

Absorption

Amoxicillin is stable in the presence of gastric acid and may be given without regard to meals. It is rapidly absorbed after oral administration. Orally administered doses of 500 mg amoxicillin capsules result in average peak blood levels one to two hours after administration in the range of 5.5 mcg/mL to 7.5 mcg/mL.

Distribution
Amoxicillin diffuses readily into most body tissues and fluids, with the exception of brain and spinal fluid, except when meninges are inflamed. In blood serum, amoxicillin is approximately 20% protein-bound.

Metabolism/Elimination
The elimination half-life of amoxicillin is 61.3 minutes. Detectable serum levels are observed up to eight hours after an orally administered dose of amoxicillin. Approximately 60% of the orally administered dose of amoxicillin is excreted unchanged in the urine within six to eight hours post-dose; its excretion can be delayed by concurrent administration of probenecid.
Clarithromycin

Absorption

Clarithromycin is rapidly absorbed from the gastrointestinal tract after oral administration. The absolute bioavailability of 250 mg clarithromycin tablets was approximately 50%. For a single 500 mg dose of clarithromycin, food slightly delays the onset of clarithromycin absorption, increasing the peak time from approximately two to 2.5 hours. Food also increases the clarithromycin peak plasma concentration by about 24%, but does not affect the extent of clarithromycin bioavailability. Food does not affect the onset of formation of the antimicrobially active metabolite, 14-OH clarithromycin or its peak plasma concentration but does slightly decrease the extent of metabolite formation, indicated by an 11% decrease in area under the plasma concentration-time curve (AUC). Therefore, clarithromycin tablets may be given without regard to food.
In nonfasting, healthy human subjects (males and females), peak plasma concentrations were attained within two to three hours after oral dosing. Steady-state peak plasma clarithromycin concentrations were attained within three days and were approximately 3 to 4 mcg/mL with a 500 mg dose administered every eight to 12 hours.
Metabolism/Elimination
The elimination half-life of clarithromycin was five to seven hours with 500 mg administered every eight to 12 hours. The nonlinearity of clarithromycin pharmacokinetics is slight at the recommended dose of 500 mg administered every eight to 12 hours. With a 500 mg every eight to 12 hours dosing, the peak steady-state concentration of 14-OH clarithromycin is up to 1 mcg/mL, and its elimination half-life is about seven to nine hours. The steady-state concentration of this metabolite is generally attained within three to four days.
After a 500 mg tablet every 12 hours, the urinary excretion of clarithromycin is approximately 30%. The renal clearance of clarithromycin approximates the normal glomerular filtration rate. The major metabolite found in urine is 14-OH clarithromycin, which accounts for an additional 10% to 15% of the dose with a 500 mg tablet administered every 12 hours.
Steady-state concentrations of clarithromycin and 14-OH clarithromycin observed following administration of 500 mg doses of clarithromycin every 12 hours to adult patients with HIV were similar to those observed in healthy volunteers. In adult HIV-infected patients taking 500 mg doses of clarithromycin every 12 hours, steady-state clarithromycin Cmax values ranged from 2 to 4 mcg/mL.
The steady-state concentrations of clarithromycin in subjects with impaired hepatic function did not differ from those in normal subjects; however, the 14-OH clarithromycin concentrations were lower in the hepatically impaired subjects. The decreased formation of 14-OH clarithromycin was at least partially offset by an increase in renal clearance of clarithromycin in the subjects with impaired hepatic function when compared to healthy subjects.
The pharmacokinetics of clarithromycin was also altered in subjects with impaired renal function (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).
Clarithromycin and the 14-OH clarithromycin metabolite distribute readily into body tissues and fluids. There are no data available on cerebrospinal fluid penetration. Because of high intercellular concentrations, tissue concentrations are higher than serum concentrations.

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