Your browser does not support JavaScript! AMOXICILLIN AND CLAVULANATE POTASSIUM TABLET, MULTILAYER, EXTENDED RELEASE [SANDOZ INC]
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AMOXICILLIN AND CLAVULANATE POTASSIUM tablet, multilayer, extended release
[Sandoz Inc]


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HUMAN PRESCRIPTION DRUG LABEL Abbreviated New Drug Application
Drug Label Sections

1000 mg/ 62.5 mg

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Amoxicillin and Clavulanate Potassium Extended Release Tablets and other antibacterial drugs, Amoxicillin and Clavulanate Potassium Extended Release Tablets should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

DESCRIPTION

Amoxicillin and Clavulanate Potassium Extended Release Tablets are an oral antibacterial combination consisting of the semisynthetic antibiotic amoxicillin (present as amoxicillin trihydrate and amoxicillin sodium) 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 trihydrate molecular formula is C16H19N3O5S•3H2O, and the molecular weight is 419.45. Chemically, amoxicillin trihydrate 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 and may be represented structurally as:

Amoxicillin Trihydrate Chemical Structure

The amoxicillin sodium molecular formula is C16H18N3NaO5S, and the molecular weight is 387.39. Chemically, amoxicillin sodium is [2S-[2α,5α,6β(S*)]]-6-[[Amino(4-hydroxyphenyl)acetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid monosodium salt and may be represented structurally as:

Amoxicillin Sodium Chemical Structure

Clavulanic acid is produced by the fermentation of Streptomyces clavuligerus. 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 C8H8KNO5, and the molecular weight is 237.25. Chemically, clavulanate potassium is potassium (Z)-(2R,5R)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo[3.2.0]-heptane-2-carboxylate, and may be represented structurally as:

Clavulanic Acid Chemical Structure

Inactive Ingredients: Anhydrous citric acid, colloidal silicon dioxide, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, sodium starch glycolate, titanium dioxide, and xanthan gum.

Each film coated tablet contains amoxicillin trihydrate and amoxicillin sodium equivalent to 1000 mg of amoxicillin and clavulanate potassium equivalent to 62.5 mg of clavulanic acid.

Each tablet of Amoxicillin and Clavulanate Potassium Extended Release Tablets contains 12.3 mg (0.31 mEq) of potassium and 28.7 mg (1.25 mEq) of sodium.

CLINICAL PHARMACOLOGY

Amoxicillin and clavulanate potassium are well absorbed from the gastrointestinal tract after oral administration of Amoxicillin and Clavulanate Potassium Extended Release Tablets.

Amoxicillin and Clavulanate Potassium Extended Release Tablets are an extended-release formulation which provides sustained plasma concentrations of amoxicillin. Amoxicillin systemic exposure achieved with Amoxicillin and Clavulanate Potassium Extended Release Tablets are similar to that produced by the oral administration of equivalent doses of amoxicillin alone. In a study of healthy adult volunteers, the pharmacokinetics of Amoxicillin and Clavulanate Potassium Extended Release Tablets were compared when administered in a fasted state, at the start of a standardized meal (612 kcal, 89.3 g carb, 24.9 g fat, and 14.0 g protein), or 30 minutes after a high-fat meal. When the systemic exposure to both amoxicillin and clavulanate is taken into consideration, Amoxicillin and Clavulanate Potassium Extended Release Tablets are optimally administered at the start of a standardized meal. Absorption of amoxicillin is decreased in the fasted state.

Amoxicillin and Clavulanate Potassium Extended Release Tablets are not recommended to be taken with a high-fat meal, because clavulanate absorption is decreased. The pharmacokinetics of the components of Amoxicillin and Clavulanate Potassium Extended Release Tablets following administration of two Amoxicillin and Clavulanate Potassium Extended Release Tablets at the start of a standardized meal are presented in Table 1.

Table 1. Mean (SD) Pharmacokinetic Parameters for Amoxicillin and Clavulanate Following Oral Administration of Two Amoxicillin and Clavulanate Potassium Extended Release Tablets (2,000 mg/125 mg) to Healthy Adult Volunteers (n = 55) Fed a Standardized Meal
Parameter (units)AmoxicillinClavulanate
*
Median (range).

AUC(0-inf) (mcg∙hr/mL)

71.6 (16.5)

5.29 (1.55)

Cmax (mcg/mL)

17.0 (4.0)

2.05 (0.80)

Tmax (hours)*

1.50 (1.00-6.00)

1.03 (0.75-3.00)

T1/2 (hours)

1.27 (0.20)

1.03 (0.17)

The half-life of amoxicillin after the oral administration of Amoxicillin and Clavulanate Potassium Extended Release Tablet is approximately 1.3 hours, and that of clavulanate is approximately 1 hour.

Clearance of amoxicillin is predominantly renal, with approximately 60% to 80% of the dose being excreted unchanged in urine, whereas clearance of clavulanate has both a renal (30% to 50%) and a non-renal component.

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

In a study of adults, the pharmacokinetics of amoxicillin and clavulanate were not affected by administration of an antacid (MAALOX®), either simultaneously with or 2 hours after Amoxicillin and Clavulanate Potassium Extended Release Tablets.

Neither component in Amoxicillin and Clavulanate Potassium Extended Release Tablets are highly protein-bound; clavulanate 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.

In a study of pediatric patients with acute bacterial sinusitis, 7 to 15 years of age, and weighing at least 40 kg, the pharmacokinetics of amoxicillin and clavulanate were assessed following administration of Amoxicillin and Clavulanate Extended Release Tablets 2000 mg/125 mg (as two 1000 mg/62.5 mg tablets) every 12 hours with food (Table 2).

Table 2. Mean (SD) Pharmacokinetic Parameters for Amoxicillin and Clavulanate Following Oral Administration of Two Amoxicillin and Clavulanate Potassium Extended Release Tablets (2,000 mg/125 mg) Every 12 Hours With Food to Pediatric Patients (7 to 15 Years of Age and Weighing ≥ 40kg) With Acute Bacterial Sinusitis

Parameter (units)
Amoxicillin
(n=24)
Clavulanate
(n=23)
*
Median (range).
n=18.
n=17.

AUC(0-τ) (mcg•hr/mL)

57.8 (15.6)

3.18 (1.37)

Cmax (mcg/mL)

11.0 (3.34)

1.17 (0.67)

Tmax (hours)*

2.0 (1.0 – 5.0)

2.0 (1.0 – 4.0)

T1/2 (hours)

3.32 (2.21)

0.94 (0.13)

Microbiology

Amoxicillin is a semisynthetic antibiotic with a broad spectrum of bactericidal activity against many gram-positive and gram-negative microorganisms. Amoxicillin is, however, susceptible to degradation by β-lactamases, and therefore, its spectrum of activity does not include organisms which produce these enzymes. Clavulanic acid is a β-lactam, structurally related to penicillin, which possesses the ability to inactivate a wide range of β-lactamase enzymes commonly found in microorganisms resistant to penicillins and cephalosporins. In particular, it has good activity against the clinically important plasmid-mediated β-lactamases frequently found responsible for transferred drug resistance.

The clavulanic acid component of Amoxicillin and Clavulanate Potassium Extended Release Tablets protect amoxicillin from degradation by β-lactamase enzymes and effectively extends the antibiotic spectrum of amoxicillin to include many bacteria normally resistant to amoxicillin and other β-lactam antibiotics.

Amoxicillin/clavulanic acid has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section.

Aerobic Gram-Positive Microorganisms

Streptococcus pneumoniae (including isolates with penicillin MICs ≤ 2 mcg/mL)

Staphylococcus aureus (including β-lactamase–producing isolates)

NOTE: Staphylococci which are resistant to methicillin/oxacillin must be considered resistant to amoxicillin/clavulanic acid.

Aerobic Gram-Negative Microorganisms

Haemophilusinfluenzae (including β-lactamase–producing isolates)

Moraxella catarrhalis (including β-lactamase–producing isolates)

Haemophilusparainfluenzae (including β-lactamase–producing isolates)

Klebsiellapneumoniae (all known isolates are β-lactamase–producing)

The following in vitro data are available, but their clinical significance is unknown.

At least 90% of the following microorganisms exhibit in vitro minimum inhibitory concentrations (MICs) less than or equal to the susceptible breakpoint for amoxicillin/clavulanic acid.1,2However, the safety and efficacy of amoxicillin/clavulanic acid in treating infections due to these microorganisms have not been established in adequate and well-controlled trials.

Aerobic Gram-Positive Microorganisms

Streptococcus pyogenes

Anaerobic Microorganisms

Bacteroidesfragilis (including β-lactamase–producing isolates)

Fusobacteriumnucleatum (including β-lactamase–producing isolates)

Peptostreptococcusmagnus

Peptostreptococcus micros

NOTE: S. pyogenes, P. magnus, and P. micros do not produce β-lactamase, and therefore, are susceptible to amoxicillin alone. Adequate and well-controlled clinical trials have established the effectiveness of amoxicillin alone in treating certain clinical infections due to S. pyogenes.

Susceptibility Test Methods

When available, the clinical microbiology laboratory should provide cumulative results of in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting the most effective antimicrobial.

Dilution Technique

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure.1,3 Standardized procedures are based on dilution methods (broth or agar; broth for S. pneumoniae and H. influenzae) or equivalent with standardized inoculum concentration and standardized concentrations of amoxicillin/clavulanate potassium powder.

The recommended dilution pattern utilizes a constant amoxicillin/clavulanate potassium ratio of 2 to 1 in all tubes with varying amounts of amoxicillin. MICs are expressed in terms of the amoxicillin concentration in the presence of clavulanic acid at a constant 2 parts amoxicillin to 1 part clavulanic acid. The MIC values should be interpreted according to criteria provided in Table 3.

Diffusion Technique

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobials. One such standardized technique requires the use of a standardized inoculum concentration.1,4 This procedure uses paper disks impregnated with 30 mcg amoxicillin/clavulanate potassium (20 mcg amoxicillin plus 10 mcg clavulanate potassium) to test susceptibility of microorganisms to amoxicillin/clavulanate potassium. Disk diffusion zone sizes should be interpreted according to criteria provided in Table 3.

Table 3. Susceptibility Test Result Interpretive Criteria for Amoxicillin/Clavulanate Potassium
Minimum Inhibitory Concentration
(mcg/mL)

Disk Diffusion
(Zone Diameter in mm)
PathogenSIRSIR

Haemophilusspp.

≤4/2

Not applicable (NA)

≥8/4

≥20

NA

≤19

Klebsiellapneumoniae

≤8/4

16/8

≥32/16

≥18

14 to 17

≤13

Staphylococcus spp.

≤4/2

NA

≥8/4

≥20

NA

≤19

Streptococcus pneumoniae(non-meningitis isolates)

≤2/1

4/2

≥8/4

NA

NOTE: Susceptibility of S. pneumoniae should be determined using a 1-mcg oxacillin disk. Isolates with oxacillin zone sizes of ≥20 mm are susceptible to amoxicillin/clavulanate acid. An amoxicillin/clavulanate acid MIC should be determined on isolates of S. pneumoniae with oxacillin zone sizes of ≤19 mm.

NOTE: β-lactamase–negative, ampicillin-resistant H. influenzae isolates must be considered resistant to amoxicillin/clavulanic acid.

A report of S (“Susceptible”) indicates that the antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial compound in the blood reaches the concentration usually achievable. A report of I (“Intermediate”) indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible antimicrobials, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high doses of antimicrobial can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of R (“Resistant”) indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial compound in the blood reaches the concentration usually achievable; other therapy should be selected.

Standardized susceptibility test procedures require the use of quality control microorganisms to determine the performance of the test procedures.1,3,4 Standard amoxicillin/clavulanate potassium powder should provide the MIC ranges for the quality control organisms in Table 4. For the disk diffusion technique, the 30 mcg amoxicillin/clavulanate potassium disk should provide the zone diameter ranges for the quality control organisms in Table 4.

Table 4. Acceptable Quality Control Ranges for Amoxicillin/Clavulanate Potassium



Quality Control Organism
Minimum
Inhibitory
Concentration
Range (mcg/mL)

Disk Diffusion
(Zone Diameter
Range in mm)

Escherichia coli ATCC® 35218
(H. influenzae quality control)

4/2 to 16/8

17 to 22

Escherichia coli ATCC 25922

2/1 to 8/4

18 to 24

Haemophilusinfluenzae ATCC 49247

2/1 to 16/8

15 to 23

Staphylococcus aureus ATCC 29213

0.12/0.06 to 0.5/0.25

Not applicable (NA)

Staphylococcus aureus ATCC 25923

NA

28 to 36

Streptococcus pneumoniae ATCC 49619

0.03/0.015 to 0.12/0.06

NA

INDICATIONS AND USAGE

Amoxicillin and Clavulanate Potassium Extended Release Tablets are indicated for the treatment of patients with community-acquired pneumonia or acute bacterial sinusitis due to confirmed, or suspected β-lactamase–producing pathogens (i.e., H. influenzae, M. catarrhalis, H. parainfluenzae, K. pneumoniae, or methicillin-susceptible S. aureus) and S. pneumoniae with reduced susceptibility to penicillin (i.e., penicillin MICs = 2 mcg/mL). Amoxicillin and Clavulanate Potassium Extended Release Tablets are not indicated for the treatment of infections due to S. pneumoniae with penicillin MICs ≥4 mcg/mL. Data are limited with regard to infections due to S. pneumoniae with penicillin MICs ≥4 mcg/mL (see CLINICAL STUDIES).

Of the common epidemiological risk factors for patients with resistant pneumococcal infections, only age >65 years was studied. Patients with other common risk factors for resistant pneumococcal infections (e.g., alcoholism, immune-suppressive illness, and presence of multiple co-morbid conditions) were not studied.

In patients with community-acquired pneumonia in whom penicillin-resistant S. pneumoniae is suspected, bacteriological studies should be performed to determine the causative organisms and their susceptibility when Amoxicillin and Clavulanate Potassium Extended Release Tablets are prescribed.

Acute bacterial sinusitis or community-acquired pneumonia due to a penicillin-susceptible strain of S. pneumoniae plus a β-lactamase–producing pathogen can be treated with another Amoxicillin and Clavulanate Potassium product containing lower daily doses of amoxicillin (i.e., 500 mg every 8 hours or 875 mg every 12 hours). Acute bacterial sinusitis or community-acquired pneumonia due to S. pneumoniae alone can be treated with amoxicillin.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Amoxicillin and Clavulanate Potassium Extended Release Tablets and other antibacterial drugs, Amoxicillin and Clavulanate Potassium Extended Release Tablets 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.

CONTRAINDICATIONS

Amoxicillin and Clavulanate Potassium Extended Release Tablets are 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 treatment with amoxicillin/clavulanate potassium.

Amoxicillin and Clavulanate Potassium Extended Release Tablets are contraindicated in patients with severe renal impairment (creatinine clearance <30 mL/min.) and in hemodialysis patients.

WARNINGS

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 AMOXICILLIN AND CLAVULANATE POTASSIUM EXTENDED RELEASE TABLETS, CAREFUL INQUIRY SHOULD BE MADE CONCERNING PREVIOUS HYPERSENSITIVITY REACTIONS TO PENICILLINS, CEPHALOSPORINS, OR OTHER ALLERGENS. IF AN ALLERGIC REACTION OCCURS, AMOXICILLIN AND CLAVULANATE POTASSIUM EXTENDED RELEASE TABLETS SHOULD BE DISCONTINUED AND THE APPROPRIATE THERAPY INSTITUTED. SERIOUS ANAPHYLACTIC REACTIONS REQUIRE IMMEDIATE EMERGENCY TREATMENT WITH EPINEPHRINE. OXYGEN, INTRAVENOUS STEROIDS, AND AIRWAY MANAGEMENT, INCLUDING INTUBATION, SHOULD ALSO BE ADMINISTERED AS INDICATED.

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Amoxicillin and Clavulanate Potassium Extended Release Tablets, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

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

Amoxicillin and Clavulanate Potassium Extended Release Tablets should be used with caution in patients with evidence of hepatic dysfunction. Hepatic toxicity associated with the use of 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).

PRECAUTIONS

General

While 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 if therapy is for longer than the drug is approved for administration.

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 Pseudomonas spp. or Candida spp.), the drug should be discontinued and/or appropriate therapy instituted.

Prescribing Amoxicillin and Clavulanate Potassium Extended Release Tablets 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.

Information for Patients

Amoxicillin and Clavulanate Potassium Extended Release Tablets should be taken every 12 hours with a meal or snack to reduce the possibility of gastrointestinal upset. If diarrhea develops and is severe or lasts more than 2 or 3 days, call your doctor.

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 2 or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.

Patients should be counseled that antibacterial drugs, including Amoxicillin and Clavulanate Potassium Extended Release Tablets, should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Amoxicillin and Clavulanate Potassium Extended Release Tablets are 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 Amoxicillin and Clavulanate Potassium Extended Release Tablets or other antibacterial drugs in the future. Discard any unused medicine.

Drug Interactions

Probenecid decreases the renal tubular secretion of amoxicillin. Concurrent use with Amoxicillin and Clavulanate Potassium Extended Release Tablets 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. In controlled clinical trials of Amoxicillin and Clavulanate Potassium Extended Release Tablets, 25 patients received concomitant allopurinol and Amoxicillin and Clavulanate Potassium Extended Release Tablets. No rashes were reported in these patients. However, this sample size is too small to allow for any conclusions to be drawn regarding the risk of rashes with concomitant Amoxicillin and Clavulanate Potassium Extended Release Tablets and allopurinol use.

In common with other broad-spectrum antibiotics, Amoxicillin and Clavulanate Potassium Extended Release Tablets may reduce the efficacy of oral contraceptives.

Drug/Laboratory Test Interactions

Oral administration of Amoxicillin and Clavulanate Potassium Extended Release Tablets 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 Amoxicillin and Clavulanate Potassium Extended Release Tablets, 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, Amoxicillin and Clavulanate Potassium Extended Release Tablets.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have not been performed to evaluate carcinogenic potential. The mutagenic potential of Amoxicillin and Clavulanate Potassium Tablets was investigated in vitro with an Ames test, a human lymphocyte cytogenetic assay, a yeast test, and a mouse lymphoma forward mutation assay, and in vivo with mouse micronucleus tests and a dominant lethal test. All were negative apart from the in vitro mouse lymphoma assay, where weak activity was found at very high, cytotoxic concentrations. Amoxicillin and Clavulanate Potassium Tablets at oral doses of up to 1,200 mg/kg/day (1.9 times the maximum human dose of amoxicillin and 15 times the maximum human dose of clavulanate based on body surface area) was found to have no effect on fertility and reproductive performance in rats dosed with a 2:1 ratio formulation of amoxicillin:clavulanate.

Pregnancy

Teratogenic Effects

Pregnancy Category B

Reproduction studies performed in pregnant rats and mice given Amoxicillin and Clavulanate Potassium Tablets at oral doses up to 1,200 mg/kg/day revealed no evidence of harm to the fetus due to Amoxicillin and Clavulanate Potassium Tablets. In terms of body surface area, the doses in rats were 1.6 times the maximum human oral dose of amoxicillin and 13 times the maximum human dose for clavulanate. For mice, these doses were 0.9 and 7.4 times the maximum human oral dose of amoxicillin and clavulanate, respectively. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Labor and Delivery

Oral ampicillin-class antibiotics are generally poorly absorbed during labor. Studies in guinea pigs have shown that intravenous administration of ampicillin decreased the uterine tone, frequency of contractions, height of contractions, and duration of contractions. However, it is not known whether the use of Amoxicillin and Clavulanate Potassium Extended Release Tablets 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. In a single study in women with premature rupture of fetal membranes, it was reported that prophylactic treatment with Amoxicillin and Clavulanate Potassium Tablets may be associated with an increased risk of necrotizing enterocolitis in neonates.

Nursing Mothers

Ampicillin-class antibiotics are excreted in the milk; therefore, caution should be exercised when Amoxicillin and Clavulanate Potassium Extended Release Tablets are administered to a nursing woman.

Pediatric Use

The safety and effectiveness of Amoxicillin and Clavulanate Potassium Extended Release Tablets have been established for pediatric patients weighing ≥ 40 kg who are able to swallow tablets. Use of Amoxicillin and Clavulanate Potassium Extended Release Tablets in these pediatric patients is supported by evidence from adequate and well-controlled trials of adults with acute bacterial sinusitis and community-acquired pneumonia with additional data from a pediatric pharmacokinetic study.

A pharmacokinetic study in pediatric patients (7 to 15 years of age and weighing ≥ 40 kg) was conducted (see CLINICAL PHARMACOLOGY).

The adverse event profile in 44 pediatric patients who received at least one dose of Amoxicillin and Clavulanate Potassium Extended Release Tablets was consistent with the established adverse event profile for the product in adults.

Geriatric Use

Of the total number of subjects in clinical studies of Amoxicillin and Clavulanate Potassium Extended Release Tablets, 18.4% were 65 years or older and 7.2% were 75 years or older. No overall differences in safety and effectiveness were observed between these subjects and younger subjects, and other clinical experience has not reported differences in responses between the elderly and younger patients, but a greater sensitivity of some older individuals cannot be ruled out.

This drug is known to be substantially excreted by the kidney, and the risk of dose-dependent 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, it may be useful to monitor renal function.

Each tablet of Amoxicillin and Clavulanate Potassium Extended Release Tablets contains 28.7 mg (1.25 mEq) of sodium.

ADVERSE REACTIONS

In clinical trials, 5,643 patients have been treated with Amoxicillin and Clavulanate Potassium Extended Release Tablets. The majority of side effects observed in clinical trials were of a mild and transient nature; 2% of patients discontinued therapy because of drug-related side effects. The most frequently reported adverse effects which were suspected or probably drug-related were diarrhea (14.5%), vaginal mycosis (3.3%) nausea (2.1%), and loose stools (1.6%). Amoxicillin and Clavulanate Potassium Extended Release Tablets had a higher rate of diarrhea which required corrective therapy (3.8% versus 2.6% for Amoxicillin and Clavulanate Potassium Extended Release Tablets and all comparators, respectively).

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

Gastrointestinal

Diarrhea, nausea, vomiting, indigestion, gastritis, stomatitis, glossitis, black “hairy” tongue, mucocutaneous candidiasis, enterocolitis, and hemorrhagic/pseudomembranous colitis. Onset of pseudomembranous colitis symptoms may occur during or after antibiotic treatment (see WARNINGS).

Hypersensitivity Reactions

Skin rashes, pruritus, urticaria, angioedema, serum sickness-like reactions (urticaria or skin rash accompanied by arthritis, arthralgia, myalgia, and frequently fever), erythema multiforme (rarely Stevens-Johnson syndrome), acute generalized exanthematous pustulosis, hypersensitivity vasculitis, and an occasional case of exfoliative dermatitis (including toxic epidermal necrolysis) have been reported. Whenever such reactions occur, the drug should be discontinued, unless the opinion of the physician dictates otherwise. Serious and occasional fatal hypersensitivity (anaphylactic) reactions can occur with oral penicillin (see WARNINGS).

Liver

A moderate rise in AST (SGOT) and/or ALT (SGPT) has been noted in patients treated with ampicillin-class antibiotics, but the significance of these findings is unknown. Hepatic dysfunction, including hepatitis and cholestatic jaundice, (see CONTRAINDICATIONS), increases in serum transaminases (AST and/or ALT), serum bilirubin, and/or alkaline phosphatase, has been infrequently reported with Amoxicillin and Clavulanate Potassium Tablets or Amoxicillin and Clavulanate Potassium Extended Release Tablets. It has been reported more commonly in the elderly, in males, or in patients on prolonged treatment. The histologic findings on liver biopsy have consisted of predominantly cholestatic, hepatocellular, or mixed cholestatic-hepatocellular changes. The onset of signs/symptoms of hepatic dysfunction may occur during or several weeks after therapy has been discontinued. The hepatic dysfunction, which may be severe, 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.

Renal

Interstitial nephritis and hematuria have been reported rarely. Crystalluria has also been reported (see OVERDOSAGE).

Hemic and Lymphatic Systems

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. There have been reports of increased prothrombin time in patients receiving Amoxicillin and Clavulanate Potassium Tablets and anticoagulant therapy concomitantly.

Central Nervous System

Agitation, anxiety, behavioral changes, confusion, convulsions, dizziness, headache, insomnia, and reversible hyperactivity have been reported rarely.

Miscellaneous

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.

OVERDOSAGE

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 Amoxicillin and Clavulanate Potassium Extended Release Tablets, 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 control 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.5

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).

DOSAGE AND ADMINISTRATION

Amoxicillin and Clavulanate Potassium Extended Release Tablets 1000 mg/62.5 mg should be taken at the start of a meal to enhance the absorption of amoxicillin and to minimize the potential for gastrointestinal intolerance. Absorption of the amoxicillin component is decreased when Amoxicillin and Clavulanate Potassium Extended Release Tablets 1000 mg/62.5 mg are taken on an empty stomach (see CLINICAL PHARMACOLOGY).

The recommended dose of Amoxicillin and Clavulanate Potassium Extended Release Tablets 1000 mg/62.5 mg is 4,000 mg/250 mg daily according to the following table:

IndicationDoseDuration

Acute bacterial sinusitis

2 tablets q12h

10 days

Community-acquired pneumonia

2 tablets q12h

7-10 days

Tablets of Amoxicillin and Clavulanate Potassium (250 mg or 500 mg) CANNOT be used to provide the same dosages as Amoxicillin and Clavulanate Potassium Extended Release Tablets 1000 mg/62.5 mg. This is because Amoxicillin and Clavulanate Potassium Extended Release Tablets 1000 mg/62.5 mg contain 62.5 mg of clavulanic acid, while the Amoxicillin and Clavulanate Potassium 250 mg and 500 mg tablets each contain 125 mg of clavulanic acid. In addition, the Extended Release Tablet provides an extended time course of plasma amoxicillin concentrations compared to immediate-release Tablets. Thus, two Amoxicillin and Clavulanate Potassium 500 mg tablets are not equivalent to one Amoxicillin and Clavulanate Potassium Extended Release Tablet 1000 mg/62.5 mg.

Scored Amoxicillin and Clavulanate Potassium Extended Release Tablets 1000 mg/62.5 mg are available for greater convenience for adult patients who have difficulty swallowing. The scored tablet is not intended to reduce the dosage of medication taken; as stated in the table above, the recommended dose of Amoxicillin and Clavulanate Potassium Extended Release Tablets 1000 mg/62.5 mg is two tablets twice a day (every 12 hours).

Renally Impaired Patients

The pharmacokinetics of Amoxicillin and Clavulanate Potassium Extended Release Tablets 1000 mg/62.5 mg have not been studied in patients with renal impairment. Amoxicillin and Clavulanate Potassium Extended Release Tablets 1000 mg/62.5 mg are contraindicated in patients with a creatinine clearance of <30 mL/min. and in hemodialysis patients (see CONTRAINDICATIONS).

Hepatically Impaired Patients

Hepatically impaired patients should be dosed with caution and hepatic function monitored at regular intervals (see WARNINGS).

Pediatric Use

Pediatric patients who weigh 40 kg or more and can swallow tablets should receive the adult dose.

Geriatric Use

No dosage adjustment is required for the elderly (see PRECAUTIONS: Geriatric Use).

HOW SUPPLIED

Amoxicillin and Clavulanate Potassium Extended Release Tablets

Each white to cream tinged, oval, film-coated bilayer tablet, debossed SZ 137 on one side and scored on the reverse side, contains amoxicillin trihydrate and amoxicillin sodium equivalent to a total of 1,000 mg of amoxicillin and clavulanate potassium equivalent to 62.5 mg of clavulanic acid.

NDC 0781-1943-82 Bottles of 28 (7 day Extended Release Tablets pack)

NDC 0781-1943-39 Bottles of 40 (10 day Extended Release Tablets pack)

STORAGE

Store tablets at 20°-25°C (68°-77°F) [See USP Controlled Room Temperature]. Dispense in original container.

CLINICAL STUDIES

Acute Bacterial Sinusitis

Adults with a diagnosis of acute bacterial sinusitis (ABS) were evaluated in 3 clinical studies. In one study, 363 patients were randomized to receive either Amoxicillin and Clavulanate Potassium Extended Release Tablets 2,000 mg/125 mg orally every 12 hours or levofloxacin 500 mg orally daily for 10 days in a double-blind, multicenter, prospective trial. These patients were clinically and radiologically evaluated at the test of cure (day 17 to 28) visit. The combined clinical and radiological responses were 83.7% for Amoxicillin and Clavulanate Potassium Extended Release Tablets and 84.3% for levofloxacin at the test of cure visit in clinically evaluable patients (95% CI for the treatment difference = -9.4, 8.3). The clinical response rates at the test of cure were 87.0% and 88.6%, respectively.

The other 2 trials were non-comparative, multicenter studies designed to assess the bacteriological and clinical efficacy of Amoxicillin and Clavulanate Potassium Extended Release Tablets (2,000 mg/125 mg orally every 12 hours for 10 days) in the treatment of 2288 patients with ABS. Evaluation timepoints were the same as in the prior study. Patients underwent maxillary sinus puncture for culture prior to receiving study medication. At test of cure, the clinical success rates were 87.5% and 86.6% (intention-to-treat) and 92.5% and 92.1% (per protocol populations).

Patients with acute bacterial sinusitis due to S. pneumoniae with reduced susceptibility to penicillin were accrued through enrollment in these 2 open-label non-comparative clinical trials. Microbiologic eradication rates for key pathogens in these studies are shown in the following table:

Clinical Outcome for ABS
Penicillin MICs of S.
pneumoniae Isolates
Intent-To-TreatClinically Evaluable
n/N*%95% Cln/N*%95% Cl
*
n/N = patients with pathogen eradicated or presumed eradicated/total number of patients.
Confidence limits calculated using exact probabilities.
S. pneumoniae strains with penicillin MICs of ≥2 mcg/mL are considered resistant to penicillin.
§
Includes one patient each with S. pneumoniae penicillin MICs of 8 and 16 mcg/mL.

All S. pneumoniae

344/370

93.0

318/326

97.5

  MIC ≥2.0 mcg/mL

35/36

97.2

85.5, 99.9

30/31

95.8

83.3, 99.9

  MIC = 2.0 mcg/mL

23/24

95.8

78.9, 99.9

19/20

95.0

75.1, 99.9

  MIC ≥4.0 mcg/mL§

12/12

100

73.5, 100

11/11

100

71.5, 100

H. influenzae

265/305

86.9

242/259

93.4

M. catarrhalis

94/105

89.5

86/90

95.6

Community-Acquired Pneumonia

Four randomized, controlled, double-blind clinical studies and one non-comparative study were conducted in adults with community-acquired pneumonia (CAP). In comparative studies, 904 patients received Amoxicillin and Clavulanate Potassium Extended Release Tablets at a dose of 2,000 mg/125 mg orally every 12 hours for 7 or 10 days. In the non-comparative study to assess both clinical and bacteriological efficacy, 1,122 patients received Amoxicillin and Clavulanate Potassium Extended Release Tablets 2,000 mg/125 mg orally every 12 hours for 7 days. In the 4 comparative studies, the combined clinical success rate at test of cure ranged from 86.3% to 94.7% in clinically evaluable patients who received Amoxicillin and Clavulanate Potassium Extended Release Tablets; in the non-comparative study, the clinical success rate was 85.6%.

Data on the efficacy of Amoxicillin and Clavulanate Potassium Extended Release Tablets in the treatment of community-acquired pneumonia due to S. pneumoniae with reduced susceptibility to penicillin were accrued from the 4 controlled clinical studies and the 1 non-comparative study. The majority of these cases were accrued from the non-comparative study.

Clinical Outcome for CAP due to S. pneumoniae
Penicillin MICs of S.
pneumoniae Isolates
Intent-To-TreatClinically Evaluable
n/N*%95% Cln/N*%95% Cl
*
n/N = patients with pathogen eradicated or presumed eradicated/total number of patients.
Confidence limits calculated using exact probabilities.
S. pneumoniae strains with penicillin MICs of ≥2 mcg/mL are considered resistant to penicillin.
§
Includes one patient each with S. pneumoniae penicillin MICs of 8 and 16 mcg/mL in the Intent-To-Treat group only.

All S. pneumoniae

318/367

86.6

275/297

92.6

  MIC ≥2.0 mcg/mL

30/35

85.7

69.7, 95.2

24/25

96.0

79.6, 99.9

  MIC = 2.0 mcg/mL

22/24

91.7

73.0, 99.0

18/18

100

81.5, 100

  MIC =≥ 4.0 mcg/mL§

8/11

72.7

39.0, 94.0

6/7

85.7

42.1, 99.6

Safety

In 2 randomized, double-blind, multicenter studies, Amoxicillin and Clavulanate Potassium Extended Release Tablets (2,000 mg/125 mg orally every 12 hours, n = 577) was compared to Amoxicillin and Clavulanate Potassium Tablets (875 mg/125 mg orally every 12 hours, n = 570), administered for 7 days for the treatment of community-acquired pneumonia. Adverse events, regardless of relationship to test drug, were reported by 44.4% of patients who received Amoxicillin and Clavulanate Potassium Extended Release Tablets (versus 46.3% in comparator group). Treatment-related adverse events were reported in 21.7% of patients who received Amoxicillin and Clavulanate Potassium Extended Release Tablets (versus 21.2% in comparator group); most were mild and transient in nature. Adverse events which led to withdrawal were reported by 2.8% of patients who received Amoxicillin and Clavulanate Potassium Extended Release Tablets (versus 5.3% in comparator group). In each group, the most frequently reported adverse events were diarrhea (14.4% versus 13.0%, p = 0.47), nausea (3.5 % versus 4.4%), and headache (3.5% versus 3.2%). Only 2 patients (0.3%) who received Amoxicillin and Clavulanate Potassium Extended Release Tablets and 3 patients (0.5%) in the comparator group withdrew due to diarrhea. Serious adverse events considered suspected or probably related to test drug were reported in 0.3% of patients (versus 0.5% in comparator).

REFERENCES

1.
Clinical and Laboratory Standards Institute (CLSI) Performance Standards for Antimicrobial Susceptibility Testing – 21st Informational Supplement. CSLI Document M100-S21. CLSI, 940 West Valley Rd., Suite 1400, Wayne, PA 19087, 2011.
2.
Clinical and Laboratory Standards Institute (CLSI) (formerly the National Committee for Clinical Laboratory Standards). Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria – Seventh Edition. Approved Standard CSLI Document M11-A7, Vol. 27, No. 2. CLSI, Wayne, PA, 2007.
3.
Clinical and Laboratory Standards Institute (CLSI) (formerly the National Committee for Clinical Laboratory Standards). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically – Eighth Edition. Approved Standard CLSI Document M7-A8, Vol. 29, No. 2. CLSI, Wayne, PA, 2009.
4.
Clinical and Laboratory Standards Institute (CLSI) (formerly the National Committee for Clinical Laboratory Standards). Performance Standards for Antimicrobial Disk Susceptibility Tests – Tenth Edition. Approved Standard CLSI Document M2-A10, Vol. 29, No. 1. CLSI, Wayne, PA, 2009.
5.
Swanson-Biearman B, Dean BS, Lopez G, Krenzelok EP. The effects of penicillin and cephalosporin ingestions in children less than six years of age. Vet Hum Toxicol 1988;30:66-67.

MAALOX® is a registered trademark of Novartis Consumer Health, Inc.

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46096403

10-2012M

Manufactured in Austria by Sandoz GmbH

for Sandoz Inc., Princeton, NJ 08540

1000 mg/62.5 mg Label

NDC 0781-1943-82

Amoxicillin

and Clavulanate

Potassium

Extended

Release Tablets

1000 mg/62.5 mg*

AMOXICILLIN, 1000 mg,

CLAVULANIC ACID, 62.5 mg,

as clavulanate potassium

7 day Extended Release Pack

Rx only

28 Scored Tablets

SANDOZ

Amoxicillin and Clavulnate Potassium 1000 mg/62.5 mg Label
AMOXICILLIN AND CLAVULANATE POTASSIUM 
amoxicillin and clavulanate potassium tablet, multilayer, extended release
Product Information
Product TypeHUMAN PRESCRIPTION DRUG LABELItem Code (Source)NDC:0781-1943
Route of AdministrationORALDEA Schedule    
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
AMOXICILLIN (AMOXICILLIN ANHYDROUS) AMOXICILLIN ANHYDROUS562.5 mg
AMOXICILLIN SODIUM (AMOXICILLIN ANHYDROUS) AMOXICILLIN ANHYDROUS437.5 mg
CLAVULANATE POTASSIUM (CLAVULANIC ACID) CLAVULANIC ACID62.5 mg
Inactive Ingredients
Ingredient NameStrength
CITRIC ACID MONOHYDRATE 
SILICON DIOXIDE 
HYPROMELLOSES 
MAGNESIUM STEARATE 
CELLULOSE, MICROCRYSTALLINE 
POLYETHYLENE GLYCOLS 
SODIUM STARCH GLYCOLATE TYPE A POTATO 
TITANIUM DIOXIDE 
XANTHAN GUM 
Product Characteristics
ColorWHITE (white to cream tinged) Score2 pieces
ShapeOVALSize22mm
FlavorImprint Code SZ137
Contains    
Packaging
#Item CodePackage DescriptionMarketing Start DateMarketing End Date
1NDC:0781-1943-3940 in 1 BOTTLE
2NDC:0781-1943-8228 in 1 BOTTLE
Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
ANDAANDA09022704/21/2010
Labeler - Sandoz Inc (110342024)

Revised: 10/2012
 
Sandoz Inc

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