Augmentin (Amoxicillin; clavulanate potassium) is an oral antibacterial combination consisting of the semisynthetic antibiotic amoxicillin and the β-lactamase inhibitor, clavulanate potassium (the potassium salt of clavulanic acid). Amoxicillin is an analog of ampicillin, derived from the basic penicillin nucleus, 6-aminopenicillanic acid. The amoxicillin molecular formula is CHNOS•3HO, and the molecular weight is 419.46. Chemically, amoxicillin is (256)-6-[()-(-)-2-Amino-2-(-hydroxyphenyl)acetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid trihydrate and may be represented structurally as:

Clavulanic acid is produced by the fermentation of . It is a β-lactam structurally related to the penicillins and possesses the ability to inactivate a wide variety of β-lactamases by blocking the active sites of these enzymes. Clavulanic acid is particularly active against the clinically important plasmid-mediated β-lactamases frequently responsible for transferred drug resistance to penicillins and cephalosporins. The clavulanate potassium molecular formula is CHKNO and the molecular weight is 237.25. Chemically, clavulanate potassium is potassium ()-(25)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo[3.2.0]-heptane-2-carboxylate, and may be represented structurally as:

Amoxicillin and clavulanate potassium are well absorbed from the gastrointestinal tract after oral administration of Augmentin (Amoxicillin; clavulanate potassium) . Dosing in the fasted or fed state has minimal effect on the pharmacokinetics of amoxicillin. While Augmentin (Amoxicillin; clavulanate potassium) can be given without regard to meals, absorption of clavulanate potassium when taken with food is greater relative to the fasted state. In 1 study, the relative bioavailability of clavulanate was reduced when Augmentin (Amoxicillin; clavulanate potassium) was dosed at 30 and 150 minutes after the start of a high-fat breakfast. The safety and efficacy of Augmentin (Amoxicillin; clavulanate potassium) have been established in clinical trials where Augmentin (Amoxicillin; clavulanate potassium) was taken without regard to meals.

Mean amoxicillin and clavulanate potassium pharmacokinetic parameters are shown in the table below:

Amoxicillin serum concentrations achieved with Augmentin (Amoxicillin; clavulanate potassium) are similar to those produced by the oral administration of equivalent doses of amoxicillin alone. The half-life of amoxicillin after the oral administration of Augmentin (Amoxicillin; clavulanate potassium) is 1.3 hours and that of clavulanic acid is 1.0 hour.

Approximately 50% to 70% of the amoxicillin and approximately 25% to 40% of the clavulanic acid are excreted unchanged in urine during the first 6 hours after administration of a single 250-mg or 500-mg tablet of Augmentin (Amoxicillin; clavulanate potassium) .

Concurrent administration of probenecid delays amoxicillin excretion but does not delay renal excretion of clavulanic acid.

Neither component in Augmentin (Amoxicillin; clavulanate potassium) is highly protein-bound; clavulanic acid has been found to be approximately 25% bound to human serum and amoxicillin approximately 18% bound.

Amoxicillin diffuses readily into most body tissues and fluids with the exception of the brain and spinal fluid. The results of experiments involving the administration of clavulanic acid to animals suggest that this compound, like amoxicillin, is well distributed in body tissues.

Augmentin (Amoxicillin; clavulanate potassium) is indicated in the treatment of infections caused by susceptible strains of the designated organisms in the conditions listed below:

− caused by β-lactamase−producing strains of , spp., and spp.

While Augmentin (Amoxicillin; clavulanate potassium) is indicated only for the conditions listed above, infections caused by ampicillin-susceptible organisms are also amenable to treatment with Augmentin (Amoxicillin; clavulanate potassium) due to its amoxicillin content; therefore, mixed infections caused by ampicillin-susceptible organisms and β-lactamase−producing organisms susceptible to Augmentin (Amoxicillin; clavulanate potassium) should not require the addition of another antibiotic. Because amoxicillin has greater in vitro activity against than does ampicillin or penicillin, the majority of strains with intermediate susceptibility to ampicillin or penicillin are fully susceptible to amoxicillin and Augmentin (Amoxicillin; clavulanate potassium) . (See Microbiology.)

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Augmentin (Amoxicillin; clavulanate potassium) and other antibacterial drugs, Augmentin (Amoxicillin; clavulanate potassium) should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

Bacteriological studies, to determine the causative organisms and their susceptibility to Augmentin (Amoxicillin; clavulanate potassium) , should be performed together with any indicated surgical procedures.

Augmentin (Amoxicillin; clavulanate potassium) is contraindicated in patients with a history of allergic reactions to any penicillin. It is also contraindicated in patients with a previous history of cholestatic jaundice/hepatic dysfunction associated with Augmentin (Amoxicillin; clavulanate potassium) .

SERIOUS AND OCCASIONALLY FATAL HYPERSENSITIVITY (ANAPHYLACTIC) REACTIONS HAVE BEEN REPORTED IN PATIENTS ON PENICILLIN THERAPY. THESE REACTIONS ARE MORE LIKELY TO OCCUR IN INDIVIDUALS WITH A HISTORY OF PENICILLIN HYPERSENSITIVITY AND/OR A HISTORY OF SENSITIVITY TO MULTIPLE ALLERGENS. THERE HAVE BEEN REPORTS OF INDIVIDUALS WITH A HISTORY OF PENICILLIN HYPERSENSITIVITY WHO HAVE EXPERIENCED SEVERE REACTIONS WHEN TREATED WITH CEPHALOSPORINS. BEFORE INITIATING THERAPY WITH Augmentin (Amoxicillin; clavulanate potassium) , CAREFUL INQUIRY SHOULD BE MADE CONCERNING PREVIOUS HYPERSENSITIVITY REACTIONS TO PENICILLINS, CEPHALOSPORINS, OR OTHER ALLERGENS. IF AN ALLERGIC REACTION OCCURS, Augmentin (Amoxicillin; clavulanate potassium) SHOULD BE DISCONTINUED AND THE APPROPRIATE THERAPY INSTITUTED.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of and surgical evaluation should be instituted as clinically indicated.

Augmentin (Amoxicillin; clavulanate potassium) should be used with caution in patients with evidence of hepatic dysfunction. Hepatic toxicity associated with the use of Augmentin (Amoxicillin; clavulanate potassium) is usually reversible. On rare occasions, deaths have been reported (less than 1 death reported per estimated 4 million prescriptions worldwide). These have generally been cases associated with serious underlying diseases or concomitant medications. (See CONTRAINDICATIONS and ADVERSE REACTIONS: Liver.)

While Augmentin (Amoxicillin; clavulanate potassium) possesses the characteristic low toxicity of the penicillin group of antibiotics, periodic assessment of organ system functions, including renal, hepatic, and hematopoietic function, is advisable during prolonged therapy.

A high percentage of patients with mononucleosis who receive ampicillin develop an erythematous skin rash. Thus, ampicillin-class antibiotics should not be administered to patients with mononucleosis.

The possibility of superinfections with mycotic or bacterial pathogens should be kept in mind during therapy. If superinfections occur (usually involving or ), the drug should be discontinued and/or appropriate therapy instituted.

Prescribing Augmentin (Amoxicillin; clavulanate potassium) in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Probenecid decreases the renal tubular secretion of amoxicillin. Concurrent use with Augmentin (Amoxicillin; clavulanate potassium) may result in increased and prolonged blood levels of amoxicillin. Coadministration of probenecid cannot be recommended.

Abnormal prolongation of prothrombin time (increased international normalized ratio [INR]) has been reported rarely in patients receiving amoxicillin and oral anticoagulants. Appropriate monitoring should be undertaken when anticoagulants are prescribed concurrently. Adjustments in the dose of oral anticoagulants may be necessary to maintain the desired level of anticoagulation.

The concurrent administration of allopurinol and ampicillin increases substantially the incidence of rashes in patients receiving both drugs as compared to patients receiving ampicillin alone. It is not known whether this potentiation of ampicillin rashes is due to allopurinol or the hyperuricemia present in these patients. There are no data with Augmentin (Amoxicillin; clavulanate potassium) and allopurinol administered concurrently.

In common with other broad-spectrum antibiotics, Augmentin (Amoxicillin; clavulanate potassium) may reduce the efficacy of oral contraceptives.

Oral administration of Augmentin (Amoxicillin; clavulanate potassium) will result in high urine concentrations of amoxicillin. High urine concentrations of ampicillin may result in false-positive reactions when testing for the presence of glucose in urine using CLINITEST, Benedict’s Solution, or Fehling’s Solution. Since this effect may also occur with amoxicillin and therefore Augmentin (Amoxicillin; clavulanate potassium) , it is recommended that glucose tests based on enzymatic glucose oxidase reactions (such as CLINISTIX) be used.

Following administration of ampicillin to pregnant women, a transient decrease in plasma concentration of total conjugated estriol, estriol-glucuronide, conjugated estrone and estradiol has been noted. This effect may also occur with amoxicillin and therefore Augmentin (Amoxicillin; clavulanate potassium) .

Patients should be counseled that antibacterial drugs including Augmentin (Amoxicillin; clavulanate potassium) , should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Augmentin (Amoxicillin; clavulanate potassium) 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 Augmentin (Amoxicillin; clavulanate potassium) or other antibacterial drugs in the future.

Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.

An analysis of clinical studies of Augmentin (Amoxicillin; clavulanate potassium) was conducted to determine whether subjects aged 65 and over respond differently from younger subjects. Of the 3,119 patients in this analysis, 68% were
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Augmentin (Amoxicillin; clavulanate potassium) is generally well tolerated. The majority of side effects observed in clinical trials were of a mild and transient nature and less than 3% of patients discontinued therapy because of drug-related side effects. The most frequently reported adverse effects were diarrhea/loose stools (9%), nausea (3%), skin rashes and urticaria (3%), vomiting (1%) and vaginitis (1%). The overall incidence of side effects, and in particular diarrhea, increased with the higher recommended dose. Other less frequently reported reactions include: Abdominal discomfort, flatulence, and headache.

The following adverse reactions have been reported for ampicillin-class antibiotics:

Following overdosage, patients have experienced primarily gastrointestinal symptoms including stomach and abdominal pain, vomiting, and diarrhea. Rash, hyperactivity, or drowsiness have also been observed in a small number of patients.

In the case of overdosage, discontinue Augmentin (Amoxicillin; clavulanate potassium) , treat symptomatically, and institute supportive measures as required. If the overdosage is very recent and there is no contraindication, an attempt at emesis or other means of removal of drug from the stomach may be performed. A prospective study of 51 pediatric patients at a poison center suggested that overdosages of less than 250 mg/kg of amoxicillin are not associated with significant clinical symptoms and do not require gastric emptying.

Interstitial nephritis resulting in oliguric renal failure has been reported in a small number of patients after overdosage with amoxicillin.

Crystalluria, in some cases leading to renal failure, has also been reported after amoxicillin overdosage in adult and pediatric patients. In case of overdosage, adequate fluid intake and diuresis should be maintained to reduce the risk of amoxicillin crystalluria.

Renal impairment appears to be reversible with cessation of drug administration. High blood levels may occur more readily in patients with impaired renal function because of decreased renal clearance of both amoxicillin and clavulanate. Both amoxicillin and clavulanate are removed from the circulation by hemodialysis. (See DOSAGE AND ADMINISTRATION for recommended dosing for patients with impaired renal function.)

Since both the 250-mg and 500-mg tablets of Augmentin (Amoxicillin; clavulanate potassium) contain the same amount of clavulanic acid (125 mg, as the potassium salt), two 250-mg tablets of Augmentin (Amoxicillin; clavulanate potassium) are not equivalent to one 500-mg tablet of Augmentin (Amoxicillin; clavulanate potassium) ; therefore, two 250-mg tablets of Augmentin (Amoxicillin; clavulanate potassium) should not be substituted for one 500-mg tablet of Augmentin (Amoxicillin; clavulanate potassium) .

Each white oval filmcoated tablet, debossed with Augmentin (Amoxicillin; clavulanate potassium) on 1 side and 250/125 on the other side, contains 250  mg amoxicillin as the trihydrate and 125  mg clavulanic acid as the potassium salt.

NDC 0029-6075-27     bottles of 30

NDC 0029-6075-31     Unit Dose (10x10) 100 tablets

Each white oval filmcoated tablet, debossed with Augmentin (Amoxicillin; clavulanate potassium) on 1 side and 500/125 on the other side, contains 500  mg amoxicillin as the trihydrate and 125  mg clavulanic acid as the potassium salt.

NDC 0029-6080-12     bottles of 20

NDC 0029-6080-31     Unit Dose (10x10) 100 tablets

Each scored white capsule-shaped tablet, debossed with Augmentin (Amoxicillin; clavulanate potassium) 875 on 1 side and scored on the other side, contains 875  mg amoxicillin as the trihydrate and 125  mg clavulanic acid as the potassium salt.

NDC 0029-6086-12     bottles of 20

NDC 0029-6086-21     Unit Dose (10x10) 100 tablets

Augmentin (Amoxicillin; clavulanate potassium) 125 mg/5 mL (125 mg amoxicillin/31.25 mg clavulanic acid) For Oral Suspension:

NDC 0029-6085-39     75 mL bottle

NDC 0029-6085-23     100 mL bottle

NDC 0029-6085-22     150 mL bottle

Augmentin (Amoxicillin; clavulanate potassium) 200 mg/5 mL (200 mg amoxicillin/28.5 mg clavulanic acid) For Oral Suspension:

NDC 0029-6087-29     50 mL bottle

NDC 0029-6087-39     75 mL bottle

NDC 0029-6087-51     100 mL bottle

Augmentin (Amoxicillin; clavulanate potassium) 250 mg/5 mL (250 mg amoxicillin/62.5 mg clavulanic acid) For Oral Suspension:

NDC 0029-6090-39     75 mL bottle

NDC 0029-6090-23     100 mL bottle

NDC 0029-6090-22     150 mL bottle

Augmentin (Amoxicillin; clavulanate potassium) 400 mg/5 mL (400 mg amoxicillin/57 mg clavulanic acid) For Oral Suspension:

NDC 0029-6092-29     50 mL bottle

NDC 0029-6092-39     75 mL bottle

NDC 0029-6092-51     100 mL bottle

Augmentin (Amoxicillin; clavulanate potassium) 125 mg (125 mg amoxicillin/31.25 mg clavulanic acid) Chewable Tablets:

NDC 0029-6073-47     carton of 30 (5x6) tablets

Augmentin (Amoxicillin; clavulanate potassium) 200 mg (200 mg amoxicillin/28.5 mg clavulanic acid) Chewable Tablets:

NDC 0029-6071-12     carton of 20 tablets

Augmentin (Amoxicillin; clavulanate potassium) 250 mg (250 mg amoxicillin/62.5 mg clavulanic acid) Chewable Tablets:

NDC 0029-6074-47     carton of 30 (5x6) tablets

Augmentin (Amoxicillin; clavulanate potassium) 400 mg (400 mg amoxicillin/57.0 mg clavulanic acid) Chewable Tablets:

NDC 0029-6072-12     carton of 20 tablets

Store tablets and dry powder at or below 25°C (77°F). Dispense in original container.

Data from 2 pivotal studies in 1,191 patients treated for either lower respiratory tract infections or complicated urinary tract infections compared a regimen of 875-mg tablets of Augmentin (Amoxicillin; clavulanate potassium) every 12 hours to 500-mg tablets of Augmentin (Amoxicillin; clavulanate potassium) dosed every 8 hours (584 and 607 patients, respectively). Comparable efficacy was demonstrated between the every 12 hours and every 8 hours dosing regimens. There was no significant difference in the percentage of adverse events in each group. The most frequently reported adverse event was diarrhea; incidence rates were similar for the 875-mg every 12 hours and 500-mg every 8 hours dosing regimens (14.9% and 14.3%, respectively); however, there was a statistically significant difference ( 

In 1 of these pivotal studies, 629 patients with either pyelonephritis or a complicated urinary tract infection (i.e., patients with abnormalities of the urinary tract that predispose to relapse of bacteriuria following eradication) were randomized to receive either 875-mg tablets of Augmentin (Amoxicillin; clavulanate potassium) every 12 hours or 500-mg tablets of Augmentin (Amoxicillin; clavulanate potassium) every 8 hours in the following distribution:

The number of bacteriologically evaluable patients was comparable between the 2 dosing regimens. Augmentin (Amoxicillin; clavulanate potassium) produced comparable bacteriological success rates in patients assessed 2 to 4 days immediately following end of therapy. The bacteriologic efficacy rates were comparable at 1 of the follow-up visits (5 to 9 days post-therapy) and at a late post-therapy visit (in the majority of cases, this was 2 to 4 weeks post-therapy), as seen in the table below:

As noted before, though there was no significant difference in the percentage of adverse events in each group, there was a statistically significant difference in rates of severe diarrhea or withdrawals with diarrhea between the regimens.

CLINITEST is a registered trademark of Miles, Inc.

CLINISTIX is a registered trademark of Bayer Corporation.

GlaxoSmithKline

Research Triangle Park, NC 27709

©2009, GlaxoSmithKline. All rights reserved.

September 2009                    AUT:17PI

NDC 0029-6075-27

Augmentin (Amoxicillin; clavulanate potassium)

AMOXICILLIN/CLAVULANATE POTASSIUM TABLETS

AMOXICILLIN, 250 MG, as the trihydrate

CLAVULANIC ACID, 125 MG, as clavulanate potassium

30 Tablets

R only

Store at room temperature. Dispense in original container; advise patients to keep in closed container. Each tablet contains 250 mg amoxicillin as the trihydrate, 125 mg clavulanic acid as clavulanate potassium.

Dosage: See accompanying prescribing information.

GlaxoSmithKline

Research Triangle Park, NC 27709

Use only if inner seal is intact.

10000000028425

NDC 0029-6080-12

Augmentin (Amoxicillin; clavulanate potassium)

AMOXICILLIN/CALVULANATE POTASSIUM TABLETS

AMOXICILLIN, 500 MG, as the trihydrate

CLAVULANIC ACID, 125 MG, as clavulanate potassium

20 Tablets

R only

Store at or below room temperature 25C (77F). Dispense in original container; advise patients to keep in closed container. Each tablet contains 500 mg amoxicillin as the trihydrate, 125 mg clavulanic acid as clavulanate potassium.

Dosage: One tablet every 12 hours. See prescribing information.

GlaxoSmithKline

Research Triangle Park, NC 27709

Use only if inner seal is intact.

Rev. 2/05

A009833

NDC 0029-6086-12

Augmentin (Amoxicillin; clavulanate potassium)

AMOXICILLIN/CALVULANATE POTASSIUM TABLETS

AMOXICILLIN, 875 MG, as the trihydrate

CLAVULANIC ACID, 125 MG, as clavulanate potassium

20 Tablets

R only

Store at or below room temperature 25C (77F). Dispense in original container; advise patients to keep in closed container. Each tablet contains 875 mg amoxicillin as the trihydrate, 125 mg clavulanic acid as clavulanate potassium.

Dosage: One tablet every 12 hours. See prescribing information.

GlaxoSmithKline

Research Triangle Park, NC 27709

Use only if inner seal is intact.

Rev. 2/05

A009834