AMOXICILLIN

Amoxicillin is stable in the presence of gastric acid and is rapidly absorbed after oral administration. The effect of food on the absorption of amoxicillin from the suspension of amoxicillin has been partially investigated. The 400 mg formulation has been studied only when administered at the start of a light meal. Amoxicillin diffuses readily into most body tissues and fluids, with the exception of brain and spinal fluid, except when meninges are inflamed. The half-life of amoxicillin is 61.3 minutes. Most of the amoxicillin is excreted unchanged in the urine; its excretion can be delayed by concurrent administration of probenecid. In blood serum, amoxicillin is approximately 20%  protein-bound.
 
Orally administered doses of amoxicillin suspension, 125 mg/5 mL and 250 mg/5 mL, result in average peak blood levels 1 to 2 hours after administration in the range of 1.5 mcg/mL to 3 mcg/mL and 3.5 mcg/mL to 5 mcg/mL, respectively.
 
Detectable serum levels are observed up to 8 hours after an orally administered dose of amoxicillin. Following a 1 gram dose and utilizing a special skin window technique to determine levels of the antibiotic, it was noted that therapeutic levels were found in the interstitial fluid. Approximately 60%  of an orally administered dose of amoxicillin is excreted in the urine within 6 to 8 hours.

Long-term studies in animals have not been performed to evaluate carcinogenic potential. Studies to detect mutagenic potential of amoxicillin alone have not been conducted; however, the following information is available from tests on a 4:1 mixture of amoxicillin and potassium clavulanate. Amoxicillin and clavulanic acid mixture was non-mutagenic in the Ames bacterial mutation assay, and the yeast gene conversion assay. Amoxicillin and clavulanic acid mixture was weakly positive in the mouse lymphoma assay, but the trend toward increased mutation frequencies in this assay occurred at doses that were also associated with decreased cell survival. Amoxicillin and clavulanic acid mixture was negative in the mouse micronucleus test, and in the dominant lethal assay in mice. Potassium clavulanate alone was tested in the Ames bacterial mutation assay and in the mouse micronucleus test, and was negative in each of these assays. In a multi-generation reproduction study in rats, no impairment of fertility or other adverse reproductive effects were seen at doses up to 500 mg/kg (approximately 3 times the human dose in mg/m²).

Oral ampicillin-class antibiotics are poorly absorbed during labor. Studies in guinea pigs showed that intravenous administration of ampicillin slightly decreased the uterine tone and frequency of contractions but moderately increased the height and duration of contractions. However, it is not known whether use of amoxicillin in humans during labor or delivery has immediate or delayed adverse effects on the fetus, prolongs the duration of labor, or increases the likelihood that forceps delivery or other obstetrical intervention or resuscitation of the newborn will be necessary.

Mucocutaneous candidiasis.

Nausea, vomiting, diarrhea, black hairy tongue, and hemorrhagic/pseudomembranous colitis.
 
Onset of pseudomembranous colitis symptoms may occur during or after antibiotic treatment. (See WARNINGS .)

Anaphylaxis (See WARNINGS .)
 
Serum sickness–like reactions, erythematous maculopapular rashes, erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, toxic epidermal necrolysis, acute generalized exanthematous pustulosis, hypersensitivity vasculitis and urticaria have been reported.

NOTE:  These hypersensitivity reactions may be controlled with antihistamines and, if necessary, systemic corticosteroids. Whenever such reactions occur, amoxicillin should be discontinued unless, in the opinion of the physician, the condition being treated is life-threatening and amenable only to amoxicillin therapy.

A moderate rise in AST (SGOT) and/or ALT (SGPT) has been noted, but the significance of this finding is unknown. Hepatic dysfunction including cholestatic jaundice, hepatic cholestasis and acute cytolytic hepatitis have been reported.

Crystalluria has also been reported (see OVERDOSAGE ).

Anemia, including hemolytic anemia, thrombocytopenia, thrombocytopenic purpura, eosinophilia, leukopenia, and agranulocytosis have been reported during therapy with penicillins. These reactions are usually reversible on discontinuation of therapy and are believed to be hypersensitivity phenomena.

Reversible hyperactivity, agitation, anxiety, insomnia, confusion, convulsions, behavioral changes, and/or dizziness have been reported rarely.

Tooth discoloration (brown, yellow, or gray staining) has been rarely reported. Most reports occurred in pediatric patients. Discoloration was reduced or eliminated with brushing or dental cleaning in most cases.

In clinical trials using combination therapy with amoxicillin plus clarithromycin and lansoprazole, and amoxicillin plus lansoprazole, no adverse reactions peculiar to these drug combinations were observed. Adverse reactions that have occurred have been limited to those that had been previously reported with amoxicillin, clarithromycin, or lansoprazole.

Triple Therapy Amoxicillin/Clarithromycin/Lansoprazole
The most frequently reported adverse events for patients who received triple therapy were diarrhea (7%), headache (6%), and taste perversion (5%). No treatment-emergent adverse events were observed at significantly higher rates with triple therapy than with any dual therapy regimen. Dual Therapy Amoxicillin/Lansoprazole
The most frequently reported adverse events for patients who received amoxicillin three times daily plus lansoprazole three times daily dual therapy were diarrhea (8%) and headache (7%). No treatment-emergent adverse events were observed at significantly higher rates with amoxicillin three times daily plus lansoprazole three times daily dual therapy than with lansoprazole alone.
 
For more information on adverse reactions with clarithromycin or lansoprazole, refer to their package inserts, ADVERSE REACTIONS.

Due to incompletely developed renal function affecting elimination of amoxicillin in this age group, the recommended upper dose of amoxicillin is 30 mg/kg/day divided q12h.

Infection	Severity *	Usual Adult Dose	Usual Dose for Children >3 Months+
Ear/Nose/Throat	Mild/Moderate	500 mg every 12 hours	25 mg/kg/day in divided
		or 250 mg every 8 hours	doses every 12 hours
			or
			20 mg/kg/day in divided
			doses every 8 hours
	Severe	875 mg every 12 hours	45 mg/kg/day in divided
		or 500 mg every 8 hours	doses every 12 hours
			or
			40 mg/kg/day in divided
			doses every 8 hours
Lower Respiratory Tract	Mild/Moderate or Severe	875 mg every 12 hours	45 mg/kg/day in divided
		or 500 mg every 8 hours	doses every 12 hours
			or
			40 mg/kg/day in divided
			doses every 8 hours
Skin/Skin Structure	Mild/Moderate	500 mg every 12 hours	25 mg/kg/day in divided
		or 250 mg every 8 hours	doses every 12 hours
			or
			20 mg/kg/day in divided
			doses every 8 hours
	Severe	875 mg every 12 hours	45 mg/kg/day in divided
		or 500 mg every 8 hours	doses every 12 hours
			or
			40 mg/kg/day in divided
			doses every 8 hours
Genitourinary Tract	Mild/Moderate	500 mg every 12 hours	25 mg/kg/day in divided
		or 250 mg every 8 hours	doses every 12 hours
			or
			20 mg/kg/day in divided
			doses every 8 hours
	Severe	875 mg every 12 hours	45 mg/kg/day in divided
		or 500 mg every 8 hours	doses every 12 hours
			or
			40 mg/kg/day in divided
			doses every 8 hours
Gonorrhea Acute,		3 grams as single oral	Prepubertal children:   50
uncomplicated		dose	mg/kg amoxicillin,
ano-genital and			combined with 25 mg/kg
urethral infections			probenecid as a single dose.
in males and			NOTE: SINCE
females			PROBENECID IS
			CONTRAINDICATED
			IN CHILDREN UNDER
			2 YEARS, DO NOT USE
			THIS REGIMEN IN
			THESE CASES.

* Dosing for infections caused by less susceptible organisms should follow the recommendations for severe infections.
+The children's dosage is intended for individuals whose weight is less that 40 kg or more should be dosed according to the adult recommendations.

After reconstitution, the required amount of suspension should be placed directly on the child’s tongue for swallowing. Alternate means of administration are to add the required amount of suspension to formula, milk, fruit juice, water, ginger ale, or cold drinks. These preparations should then be taken immediately. To be certain the child is receiving full dosage, such preparations should be consumed in entirety.
 
All patients with gonorrhea should be evaluated for syphilis. (See PRECAUTIONS: Laboratory Tests .)
 
Larger doses may be required for stubborn or severe infections.

It should be recognized that in the treatment of chronic urinary tract infections, frequent bacteriological and clinical appraisals are necessary. Smaller doses than those recommended above should not be used. Even higher doses may be needed at times. In stubborn infections, therapy may be required for several weeks. It may be necessary to continue clinical and/or bacteriological follow-up for several months after cessation of therapy. Except for gonorrhea, treatment should be continued for a minimum of 48 to 72 hours beyond the time that the patient becomes asymptomatic or evidence of bacterial eradication has been obtained. It is recommended that there be at least 10 days’ treatment for any infection caused by Streptococcus pyogenes to prevent the occurrence of acute rheumatic fever.

Triple Therapy Amoxicillin/clarithromycin/lansoprazole
The recommended adult oral dose is 1 gram amoxicillin, 500 mg clarithromycin, and 30 mg lansoprazole, all given twice daily (q12h) for 14 days. (See INDICATIONS AND USAGE .) Dual Therapy Amoxicillin/lansoprazole
The recommended adult oral dose is 1 gram amoxicillin and 30 mg lansoprazole, each given three times daily (q8h) for 14 days. (See INDICATIONS AND USAGE .)
 
Please refer to clarithromycin and lansoprazole full prescribing information for CONTRAINDICATIONS and WARNINGS, and for information regarding dosing in elderly and renally impaired patients.

Patients with impaired renal function do not generally require a reduction in dose unless the impairment is severe. Patients with a glomerular filtration rate of 10 to 30 mL/min. should receive 500 mg or 250 mg every 12 hours, depending on the severity of the infection. Patients with a less than 10 mL/min. glomerular filtration rate should receive 500 mg or 250 mg every 24 hours, depending on severity of the infection.
 
Hemodialysis patients should receive 500 mg or 250 mg every 24 hours, depending on severity of the infection. They should receive an additional dose both during and at the end of dialysis.

There are currently no dosing recommendations for pediatric patients with impaired renal function.

Prepare suspension at time of dispensing as follows: Tap bottle until all powder flows freely. Add approximately 1/3 of the total amount of water for reconstitution (see table below) and shake vigorously to wet powder. Add remainder of the water and again shake vigorously.

                                             200 mg/5 mL
                                                                                           Amount of Water
   Bottle Size                                                                  Required for Reconstitution
     50 mL                                                                                       35 mL
     75 mL                                                                                       52 mL
   100 mL                                                                                       69 mL

Each teaspoonful (5 mL) will contain 200 mg amoxicillin.
 
                                            400 mg/5 mL

                                                                                          Amount of Water
   Bottle Size                                                                  Required for Reconstitution
     50 mL                                                                                       35 mL
     75 mL                                                                                       52 mL
   100 mL                                                                                       69 mL

Each teaspoonful (5 mL) will contain 400 mg amoxicillin.

NOTE:  SHAKE ORAL SUSPENSION WELL BEFORE USING. Keep bottle tightly closed. Any unused portion of the reconstituted suspension must be discarded after 14 days. Refrigeration preferable, but not required.

H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence
Randomized, double-blind clinical studies performed in the United States in patients with H. pylori and duodenal ulcer disease (defined as an active ulcer or history of an ulcer within 1 year) evaluated the efficacy of lansoprazole in combination with amoxicillin capsules and clarithromycin tablets as triple 14-day therapy, or in combination with amoxicillin capsules as dual 14-day therapy, for the eradication of H. pylori. Based on the results of these studies, the safety and efficacy of 2 different eradication regimens were established: Triple Therapy
Amoxicillin 1 gram twice daily/clarithromycin 500 mg twice daily/lansoprazole 30 mg twice daily. Dual Therapy
Amoxicillin 1 gram three times daily/lansoprazole 30 mg three times daily.
 
All treatments were for 14 days. H. pylori eradication was defined as 2 negative tests (culture and histology) at 4 to 6 weeks following the end of treatment.
 
Triple therapy was shown to be more effective than all possible dual therapy combinations. Dual therapy was shown to be more effective than both monotherapies. Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence.

H. pylori Eradication Rates - Triple Therapy (amoxicillin/clarithromycin/lansoprazole)
Percent of Patients Cured [95% Confidence Interval]  (Number of Patients)

	Triple Therapy	Triple Therapy
Study	Evaluable Analysis*	Intent-to-Treat Analysis†
Study 1	92‡	86‡
	[80 - 97.7]	[73.3 - 93.5]
	(n = 48)	(n = 55)
Study 2	86§	83§
	[75.7 - 93.6]	[72 - 90.8]
	(n = 66)	(n = 70)

* This analysis was based on evaluable patients with confirmed duodenal ulcer (active or within 1 year) and H. pylori infection at baseline defined as at least 2 of 3 endoscopic tests from CLOtest®, (Delta West Ltd., Bently, Australia), histology, and/or culture. Patients were included in the analysis if they completed the study.  Additionaly, if patients dropped out of the study due to an adverse event related to the study drug, they were included in the analysis as failures of therapy.
+ Patients were included in the analysis if they had documented H. pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or with 1 year). All dropouts were included as failures of therapy.
++ (p less than 0.05) versus lansoprazole/amoxicilin/ and lansoprazole/clarithromycin dual therapy.
$   (p less than 0.05) versus clarithromycin/amoxicillin dual therapy.


H. pylori Eradication Rates – Dual Therapy (amoxicillin/lansoprazole) Percent of Patients Cured [95% Confidence Interval] (Number of Patients)

	Dual Therapy	Dual Therapy
Study	Evaluable Analysis*	Intent-to-Treat Analysis†
Study 1	77‡	70‡
	[62.5 - 87.2]	[56.8 - 81.2]
	(n = 51)	(n = 60)
Study 2	66§	61§
	[51.9 - 77.5]	[48.5 - 72.9]
	(n = 58)	(n = 67)

* This analysis was based on evaluable patients with confirmed duodenal ulcer (active or within 1 year) and H. pylori infection at baseline defined as at least 2 of 3 endoscopic tests from CLOtest®, (Delta West Ltd., Bently, Australia), histology, and/or culture. Patients were included in the analysis if they completed the study.  Additionaly, if patients dropped out of the study due to an adverse event related to the study drug, they were included in the analysis as failures of therapy.
+ Patients were included in the analysis if they had documented H. pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or with 1 year). All dropouts were included as failures of therapy.
++ (p less than 0.05) versus lansoprazole alone.
$   (p less than 0.05) versus lansoprazole or amoxicillin alone.