Amoxicillin and Clavulanate Potassium

Apotex Corp.
Apotex Inc.

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use amoxicillin and clavulanate potassium tablets, USP safely and effectively. See full prescribing information for amoxicillin and clavulanate potassium tablets, USP.Amoxicillin and clavulanate potassium tablets, USP Initial U.S. Approval: 1984  To reduce the development of drug-resistant bacteria and maintain the effectiveness of amoxicillin and clavulanate potassium tablets, USP and other antibacterial drugs, amoxicillin and clavulanate potassium tablets, USP should be used only to treat infections that are proven or strongly suspected to be caused by bacteria. INDICATIONS AND USAGEAmoxicillin and clavulanate potassium tablets, USP is a combination penicillin-class antibacterial and beta-lactamase inhibitor indicated for treatment of the following: Lower respiratory tract infections (1.1) Acute bacterial otitis media (1.2) Sinusitis (1.3) Skin and skin structure infections (1.4) Urinary tract infections (1.5) DOSAGE AND ADMINISTRATION Adults and Pediatric Patients >40 kg: 500 or 875 mg every 12 hours or 250 or 500 mg every 8 hours. (2.1, 2.2) Pediatric patients aged 12 weeks (3 months) and older:25 to 45 mg/kg/day every 12 hours or 20 to 40 mg/kg/day every 8 hours, up to the adult dose. (2.2) DOSAGE FORMS AND STRENGTHSAmoxicillin and clavulanate potassium tablets, USP: 250 mg/125 mg, 500 mg/125 mg and 875 mg/125 mgCONTRAINDICATIONS History of a serious hypersensitivity reaction (e.g., anaphylaxis or Stevens-Johnson syndrome) to amoxicillin and clavulanate potassium tablets or to other beta-lactams (e.g., penicillins or cephalosporins) (4) History of cholestatic jaundice/hepatic dysfunction associated with amoxicillin and clavulanate potassium tablets. (4) WARNINGS AND PRECAUTIONS Serious (including fatal) hypersensitivity reactions: Discontinue amoxicillin and clavulanate potassium tablets if a reaction occurs. (5.1) Hepatic dysfunction and cholestatic jaundice: Discontinue if signs/symptoms of hepatitis occur. Monitor liver function tests in patients with hepatic impairment. (5.2) Clostridium difficile-associated diarrhea (CDAD): Evaluate patients if diarrhea occurs. (5.3) Patients with mononucleosis who receive amoxicillin and clavulanate potassium tablets develop skin rash. Avoid amoxicillin and clavulanate potassium tablets use in these patients. (5.4) Overgrowth: The possibility of superinfections with fungal or bacterial pathogens should be considered during therapy. (5.5) Side EffectsThe most frequently reported adverse effects were diarrhea/loose stools (9%), nausea (3%), skin rashes and urticaria (3%), vomiting (1%) and vaginitis (1%) (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Apotex Corp., Drug Safety at 1-800-667-4708 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS Co-administration with probenecid is not recommended. (7.1) Concomitant use of amoxicillin and clavulanate potassium tablets and oral anticoagulants may increase the prolongation of prothrombin time. (7.2) Coadministration with allopurinol increases the risk of rash. (7.3) Amoxicillin and clavulanate potassium tablets may reduce efficacy of oral contraceptives. (7.4) USE IN SPECIFIC POPULATIONS Pediatric Use: Modify dose in patients 12 weeks or younger. (8.4) Renal impairment; Dosage adjustment is recommended for severe renal impairment (GFR< 30mL/min). (2.3, 8.6) See 17 for PATIENT COUNSELING INFORMATION and FDA- approved patient labeling.

FULL PRESCRIBING INFORMATION

To reduce the development of drug-resistant bacteria and maintain the effectiveness of amoxicillin and clavulanate potassium tablets, USP and other antibacterial drugs, amoxicillin and clavulanate potassium tablets, USP should be used only to treat 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.

Amoxicillin and clavulanate potassium tablets, USP is a combination penicillin-class antibacterial and beta-lactamase inhibitor indicated in the treatment of infections due to susceptible isolates of the designated bacteria in the conditions listed below:

caused by beta-lactamase–producing isolates of Haemophilus influenzae and Moraxella catarrhalis.

caused by beta-lactamase–producing isolates of H. influenzae and M. catarrhalis.

caused by beta-lactamase–producing isolates of H. influenzae and M. catarrhalis.

caused by beta-lactamase–producing isolates of Staphylococcus aureus, Escherichia coli, and Klebsiella species.

caused by beta-lactamase–producing isolates of E. coli, Klebsiella species, and Enterobacter species.

When susceptibility test results show susceptibility to amoxicillin, indicating no beta-lactamase production, amoxicillin and clavulanate potassium tablets, USP should not be used.

Amoxicillin and clavulanate potassium tablets may be taken without regard to meals; however, absorption of clavulanate potassium is enhanced when amoxicillin and clavulanate potassium tablets, USP are administered at the start of a meal. To minimize the potential for gastrointestinal intolerance, amoxicillin and clavulanate potassium tablets should be taken at the start of a meal.

The usual adult dose is one 500-mg tablet of amoxicillin and clavulanate potassium every 12 hours or one 250-mg tablet of amoxicillin and clavulanate potassium every 8 hours. For more severe infections and infections of the respiratory tract, the dose should be one 875-mg tablet of amoxicillin and clavulanate potassium every 12 hours or one 500-mg tablet of amoxicillin and clavulanate potassium every 8 hours. Adults who have difficulty swallowing may be given the 125 mg/5 mL or 250 mg/5 mL suspension in place of the 500-mg tablet. The 200 mg/5 mL suspension or the 400 mg/5 mL suspension may be used in place of the 875-mg tablet.

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

The 250-mg tablet of amoxicillin and clavulanate potassium and the 250-mg chewable tablet should not be substituted for each other, as they are not interchangeable. The 250-mg tablet of amoxicillin and clavulanate potassium and the 250-mg chewable tablet do not contain the same amount of clavulanic acid (as the potassium salt). The 250-mg tablet of amoxicillin and clavulanate potassium contains 125 mg of clavulanic acid, whereas the 250-mg chewable tablet contains 62.5 mg of clavulanic acid.

Based on the amoxicillin component, amoxicillin and clavulanate potassium tablets should be dosed as follows:  

Neonates and Infants Aged <12 weeks (<3 months): The recommended dose of amoxicillin and clavulanate potassium tablets is 30 mg/kg/day divided every 12 hours, based on the amoxicillin component. Experience with the 200 mg/5 mL formulation in this age group is limited, and thus, use of the 125 mg/5 mL oral suspension is recommended.

Patients Weighing 40 kg or More: Pediatric patients weighing 40 kg or more should be dosed according to adult recommendations.

The 250-mg tablet of amoxicillin and clavulanate potassium should not be used until the child weighs at least 40 kg, due to the different amoxicillin to clavulanic acid ratios in the 250-mg tablet of amoxicillin and clavulanate potassium (250/125) versus the 250-mg chewable tablet of amoxicillin and clavulanate potassium (250/62.5).

Patients with impaired renal function do not generally require a reduction in dose unless the impairment is severe. Renal impairment patients with a glomerular filtration rate of <30 mL/min should not receive the 875-mg dose. 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 glomerular filtration rate less than 10 mL/min 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.

• 250-mg/125-mg Tablets: Each white, oval, biconvex, film-coated tablets, engraved “APO” on one side, “250-125” on the other, contains 250 mg amoxicillin as the trihydrate and 125 mg clavulanic acid as the potassium salt.
• 500-mg/125-mg Tablets: as white, oval, biconvex, film-coated tablets, engraved “APO” on one side, “500-125” on the other, contains 500 mg amoxicillin as the trihydrate and 125 mg clavulanic acid as the potassium salt.
• 875-mg/125-mg Tablets: white, capsule-shaped, biconvex, film-coated tablets, engraved “APO” on one side, engraved “A” bisect “C” on the other, contains 875 mg amoxicillin as the trihydrate and 125 mg clavulanic acid as the potassium salt.

The 250-mg tablet of amoxicillin and clavulanate potassium and the 250-mg chewable tablet should NOT be substituted for each other, as they are not interchangeable and the 250-mg tablet should not be used in children weighing less than 40 kg. The 250-mg tablet of amoxicillin and clavulanate potassium and the 250-mg chewable tablet do not contain the same amount of clavulanic acid. The 250-mg tablet of amoxicillin and clavulanate potassium contains 125 mg of clavulanic acid whereas the 250-mg chewable tablet contains 62.5 mg of clavulanic acid.

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

Amoxicillin and clavulanate potassium tablets are contraindicated in patients with a history of serious hypersensitivity reactions (e.g., anaphylaxis or Stevens-Johnson syndrome) to amoxicillin, clavulanate or to other beta-lactam antibacterial drugs (e.g., penicillins and cephalosporins). 

Amoxicillin and clavulanate potassium tablets are contraindicated in patients with a previous history of cholestatic jaundice/hepatic dysfunction associated with amoxicillin and clavulanate potassium tablets. 

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving beta-lactam antibacterials, including amoxicillin and clavulanate potassium tablets. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and/or a history of sensitivity to multiple allergens. Before initiating therapy with amoxicillin and clavulanate potassium tablets, careful inquiry should be made regarding previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens. If an allergic reaction occurs, amoxicillin and clavulanate potassium tablets should be discontinued and appropriate therapy instituted.

Hepatic dysfunction, including hepatitis and cholestatic jaundice has been associated with the use of amoxicillin and clavulanate potassium tablets. Hepatic toxicity is usually reversible; however, deaths have been reported. Hepatic function should be monitored at regular intervals in patients with hepatic impairment.

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including amoxicillin and clavulanate potassium 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 antibacterial use. Careful medical history is necessary since CDAD has been reported to occur over 2 months after the administration of antibacterial agents.

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

A high percentage of patients with mononucleosis who receive amoxicillin develop an erythematous skin rash. Thus, amoxicillin and clavulanate potassium tablets should not be administered to patients with mononucleosis.

The possibility of superinfections with fungal or bacterial pathogens should be considered during therapy. If superinfection occurs, amoxicillin/clavulanate potassium should be discontinued and appropriate therapy instituted.

Prescribing amoxicillin and clavulanate potassium tablets in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient, and increases the risk of the development of drug-resistant bacteria. 

The following are discussed in more detail in other sections of the labeling:

• Anaphylactic reactions [see Warnings and Precautions (5.1)]
• Hepatic Dysfunction [see Warnings and Precautions (5.2)]
• CDAD [see Warnings and Precautions (5.3)]

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The most frequently reported adverse reactions were diarrhea/loose stools (9%), nausea (3%), skin rashes and urticaria (3%), vomiting (1%) and vaginitis (1%). Less than 3% of patients discontinued therapy because of drug-related adverse reactions. The overall incidence of adverse reactions, and in particular diarrhea, increased with the higher recommended dose. Other less frequently reported adverse reactions (<1%) include: Abdominal discomfort, flatulence, and headache.

In addition to adverse reactions reported from clinical trials, the following have been identified during postmarketing use of amoxicillin and clavulanate potassium tablets. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to amoxicillin and clavulanate potassium tablets.

Gastrointestinal: 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 and Precautions (5.3)]

Hypersensitivity Reactions: Pruritus, angioedema, serum sickness–like reactions (urticaria or skin rash accompanied by arthritis, arthralgia, myalgia, and frequently fever), erythema multiforme, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, hypersensitivity vasculitis, and cases of exfoliative dermatitis (including toxic epidermal necrolysis) have been reported. [see Warnings and Precautions ( 5.1 )]

Liver: Hepatic dysfunction, including hepatitis and cholestatic jaundice, increases in serum transaminases (AST and/or ALT), serum bilirubin, and/or alkaline phosphatase, has been reported with amoxicillin and clavulanate potassium 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. Deaths have been reported. [see Contraindications (4.2), Warnings and Precautions (5.2)]

Renal: Interstitial nephritis, hematuria, and crystalluria have been reported. [see Overdosage (10)]

Hemic and Lymphatic Systems: Anemia, including hemolytic anemia, thrombocytopenia, thrombocytopenic purpura, eosinophilia, leukopenia, and agranulocytosis have been reported. These reactions are usually reversible on discontinuation of therapy and are believed to be hypersensitivity phenomena. Thrombocytosis was noted in less than 1% of the patients treated with amoxicillin and clavulanate potassium tablets. There have been reports of increased prothrombin time in patients receiving amoxicillin and clavulanate potassium tablets and anticoagulant therapy concomitantly. [see Drug Interactions (7.2)] 

Central Nervous System: Agitation, anxiety, behavioral changes, confusion, convulsions, dizziness, insomnia, and reversible hyperactivity have been reported. 

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

Probenecid decreases the renal tubular secretion of amoxicillin but does not delay renal excretion of clavulanic acid. Concurrent use with amoxicillin and clavulanate potassium tablets may result in increased and prolonged blood concentrations of amoxicillin. Coadministration of probenecid is not recommended.

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

The concurrent administration of allopurinol and amoxicillin increases the incidence of rashes in patients receiving both drugs as compared to patients receiving amoxicillin alone. It is not known whether this potentiation of amoxicillin rashes is due to allopurinol or the hyperuricemia present in these patients.

Amoxicillin and clavulanate potassium tablets may affect intestinal flora, leading to lower estrogen reabsorption and reduced efficacy of combined oral estrogen/progesterone contraceptives.

High urine concentrations of amoxicillin 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 clavulanate potassium tablets, it is recommended that glucose tests based on enzymatic glucose oxidase reactions be used. 

Following administration of amoxicillin to pregnant women, a transient decrease in plasma concentration of total conjugated estriol, estriol-glucuronide, conjugated estrone, and estradiol has been noted.

Teratogenic effects: Pregnancy Category B.

Reproduction studies performed in pregnant rats and mice given amoxicillin and clavulanate potassium tablets (2:1 ratio formulation of amoxicillin:clavulanate) at oral doses up to 1200 mg/kg/day revealed no evidence of harm to the fetus due to amoxicillin and clavulanate potassium tablets. The amoxicillin doses in rats and mice (based on body surface area) were approximately 4 and 2 times the maximum recommended adult human oral dose (875 mg every 12 hours). For clavulanate, these dose multiples were approximately 9 and 4 times the maximum recommended adult human oral dose (125 mg every 8 hours). 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. 

Oral ampicillin-class antibiotics are poorly absorbed during labor. It is not known whether use of amoxicillin/clavulanate potassium in humans during labor or delivery has immediate or delayed adverse effects on the fetus, prolongs the duration of labor, or increases the likelihood of the necessity for an obstetrical intervention.

Amoxicillin has been shown to be excreted in human milk. Amoxicillin/clavulanate potassium use by nursing mothers may lead to sensitization of infants. Caution should be exercised when amoxicillin/clavulanate potassium is administered to a nursing woman.

Use of amoxicillin and clavulanate potassium tablets in pediatric patients is supported by evidence from studies of amoxicillin and clavulanate potassium tablets in adults with additional data from a study of amoxicillin and clavulanate potassium powder for oral suspension in pediatric patients aged 2 months to 12 years with acute otitis media. [see Clinical Studies (14.2)]

Because of incompletely developed renal function in neonates and young infants, the elimination of amoxicillin may be delayed; clavulanate elimination is unaltered in this age group. Dosing of amoxicillin and clavulanate potassium tablets should be modified in pediatric patients aged <12 weeks (<3 months). [see Dosage and Administration (2.2)]

Of the 3,119 patients in an analysis of clinical studies of amoxicillin and clavulanate potassium tablets, 32% were ≥65 years old, and 14% were ≥75 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but 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 adverse 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.

Amoxicillin is primarily eliminated by the kidney and dosage adjustment is usually required in patients with severe renal impairment (GFR <30 mL/min). See Patients with Renal Impairment (2.3) for specific recommendations in patients with renal impairment. 

In case of overdosage, discontinue medication, treat symptomatically, and institute supportive measures as required. 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 symptoms¹.

Interstitial nephritis resulting in oliguric renal failure has been reported in patients after overdosage with amoxicillin/clavulanate potassium.

Crystalluria, in some cases leading to renal failure, has also been reported after amoxicillin/clavulanate potassium overdosage in adult and pediatric patients. In case of overdosage, adequate fluid intake and diuresis should be maintained to reduce the risk of amoxicillin/clavulanate potassium 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 amoxicillin/clavulanate potassium. Amoxicillin/clavulanate potassium may be removed from circulation by hemodialysis. [see Dosage and Administration (2.3)]

Amoxicillin and clavulanate potassium tablets, USP is an oral antibacterial combination consisting of 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 C₁₆H₁₉N₃O₅S•3H₂O, and the molecular weight is 419.46. Chemically, amoxicillin 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:

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 some β-lactamases by blocking the active sites of these enzymes. 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:

Each 250 mg/125 mg film coated tablet contains 250 mg amoxicillin as the trihydrate and 125 mg clavulanic acid as clavulanate potassium. The potassium content is 0.63 mEq.

Each 500 mg/125 mg film coated tablet contains 500 mg amoxicillin as the trihydrate and 125 mg clavulanic acid as clavulanate potassium. The potassium content is 0.63 mEq.

Each 875 mg/125 mg film coated tablet contains 875 mg amoxicillin as the trihydrate and 125 mg clavulanic acid as clavulanate potassium. The potassium content is 0.63 mEq.

Inactive Ingredients

Colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, hydroxypropyl cellulose, methanol, polyethylene glycol, and titanium dioxide.

USP Drug Release Test 2

Amoxicillin and clavulanate potassium tablet is an antibacterial drug. [see Microbiology 12.4 ]

Mean amoxicillin and clavulanate potassium pharmacokinetic parameters in normal adults following administration of amoxicillin and clavulanate potassium tablets are shown in Table 1

Table 1: Mean (±S.D.) Amoxicillin and Clavulanate Potassium Pharmacokinetic Parameters ^a,b with Amoxicillin and Clavulanate Potassium Tablets

^a Mean (± standard deviation) values of 14 normal adults (N=15 for clavulanate potassium in the low-dose regimens). Peak concentrations occurred approximately 1.5 hours after the dose.
^b Amoxicillin/clavulanate potassium administered at the start of a light meal. 

Amoxicillin serum concentrations achieved with amoxicillin and clavulanate potassium tablets are similar to those produced by the oral administration of equivalent doses of amoxicillin alone. Time above the minimum inhibitory concentration of 1 mcg/mL for amoxicillin has been shown to be similar after corresponding every 12 hour and every 8 hour dosing regimens of amoxicillin and clavulanate potassium tablets in adults and children.

Absorption
Dosing in the fasted or fed state has minimal effect on the pharmacokinetics of amoxicillin. While amoxicillin and clavulanate potassium tablets can be given without regard to meals, absorption of clavulanate potassium when taken with food is greater relative to the fasted state. In one study, the relative bioavailability of clavulanate was reduced when amoxicillin and clavulanate potassium tablets was dosed at 30 and 150 minutes after the start of a high-fat breakfast.

Distribution
Neither component in amoxicillin and clavulanate potassium tablets is highly protein-bound; clavulanic acid is 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.

Metabolism and Excretion
The half-life of amoxicillin after the oral administration of amoxicillin and clavulanate potassium tablets is 1.3 hours and that of clavulanic acid is 1 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 amoxicillin and clavulanate potassium tablets.

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

The formulation of amoxicillin and clavulanic acid in amoxicillin and clavulanate potassium tablets protects amoxicillin from degradation by some beta-lactamase enzymes and extends the antibiotic spectrum of amoxicillin to include many bacteria normally resistant to amoxicillin.

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

Gram-positive bacteria
Staphylococcus aureus

Gram-negative bacteria
Enterobacter species
Escherichia coli
Haemophilus influenzae
Klebsiella species
Moraxella catarrhalis

 The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for amoxicillin/clavulanic acid. However, the efficacy of amoxicillin/clavulanic acid in treating clinical infections due to these bacteria has not been established in adequate and well-controlled clinical trials.

Gram-positive bacteria
Enterococcus faecalis
Staphylococcus epidermidis
Staphylococcus saprophyticus
Streptococcus pneumoniae
Streptococcus pyogenes
Viridans group Streptococcus

Gram-negative Bacteria
Eikenella corrodens
Proteus mirabilis

Anaerobic Bacteria
Bacteroides species including Bacteroides fragilis
Fusobacterium species
Peptostreptococcus species

Susceptibility Test Methods
When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drug products used in resident hospitals 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 an antibacterial drug product for treatment.

Dilution techniques
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 test method ^2,3 (broth and/or agar). The MIC values should be interpreted according to criteria provided in Table 2.

Diffusion techniques 
Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method ^3,4. This procedure uses paper disks impregnated with 30 mcg amoxicillin/clavulanic acid (20 mcg amoxicillin plus 10 mcg clavulanic acid) to test the susceptibility of bacteria to amoxicillin/clavulanic acid. The disc diffusion interpretive criteria are provided in Table 2.

Table 2: Susceptibility Test Interpretive Criteria for Amoxicillin Clavulanic Acid 

Quality Control
Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test ^2,3,4. Standard amoxicillin/clavulanic acid powder should provide the following range of MIC values noted in Table 3 for the diffusion technique using the 30 mcg amoxicillin/clavulanic acid (20 mcg amoxicillin plus 10 mcg clavulanic acid) disk, the criteria in Table 3 should be achieved.

Table 3: Acceptable Quality Control Ranges for Amoxicillin/Clavulanic Acid

Long-term studies in animals have not been performed to evaluate carcinogenic potential.

Amoxicillin and Clavulanate Potassium Tablets (4:1 ratio formulation of amoxicillin:clavulanate) was non-mutagenic in the Ames bacterial mutation assay, and the yeast gene conversion assay. Amoxicillin and clavulanate potassium tablets 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 clavulanate potassium tablets 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.

Amoxicillin and clavulanate potassium tablets (2:1 ratio formulation of amoxicillin:clavulanate) at oral doses of up to 1,200 mg/kg/day was found to have no effect on fertility and reproductive performance in rats. Based on body surface area, this dose of amoxicillin is approximately 4 times the maximum recommended adult human oral dose (875 mg every 12 hours). For clavulanate, the dose multiple is approximately 9 times higher than the maximum recommended adult human oral dose (125 mg every 8 hours), also based on body surface area.

Data from 2 pivotal trials in 1,191 patients treated for either lower respiratory tract infections or complicated urinary tract infections compared a regimen of 875-mg tablets of amoxicillin and clavulanate potassium tablets every 12 hours to 500-mg tablets of amoxicillin and clavulanate potassium tablets 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 (15% and 14%, respectively); however, there was a statistically significant difference (p < 0.05) in rates of severe diarrhea or withdrawals with diarrhea between the regimens: 1% for 875-mg every 12 hours regimen versus 2% for the 500-mg every 8 hours regimen. 

In one of these pivotal trials, patients with either pyelonephritis (n = 361) or a complicated urinary tract infection (i.e., patients with abnormalities of the urinary tract that predispose to relapse of bacteriuria following eradication, n = 268) were randomized (1:1) to receive either 875-mg tablets of amoxicillin and clavulanate potassium tablets every 12 hours (n=308) or 500-mg tablets of amoxicillin and clavulanate potassium tablets every 8 hours (n=321). 

The number of bacteriologically evaluable patients was comparable between the two dosing regimens. Amoxicillin and clavulanate potassium tablets produced comparable bacteriological success rates in patients assessed 2 to 4 days immediately following end of therapy. The bacteriologic efficacy rates were comparable at one 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 Table 4. 

Table 4: Bacteriologic efficacy rates for amoxicillin and clavulanate potassium tablets

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. 

One US/Canadian clinical trial was conducted which compared 45/6.4 mg/kg/day (divided every 12 hours) of amoxicillin and clavulanate potassium tablets for 10 days versus 40/10 mg/kg/day (divided every 8 hours) of amoxicillin and clavulanate potassium tablets for 10 days in the treatment of acute otitis media. Only the suspension formulations were used in this trial. A total of 575 pediatric patients (aged 2 months to 12 years) were enrolled, with an even distribution among the 2 treatment groups and a comparable number of patients were evaluable (i.e., ≥ 84%) per treatment group. Otitis media-specific criteria were required for eligibility and a strong correlation was found at the end of therapy and follow-up between these criteria and physician assessment of clinical response. The clinical efficacy rates at the end of therapy visit (defined as 2 to 4 days after the completion of therapy) and at the follow-up visit (defined as 22 to 28 days post-completion of therapy) were comparable for the 2 treatment groups, with the following cure rates obtained for the evaluable patients: At end of therapy, 87% (n = 265) and 82% (n = 260) for 45 mg/kg/day every 12 hours and 40 mg/kg/day every 8 hours, respectively. At follow-up, 67% (n = 249) and 69% (n = 243) for 45 mg/kg/day every 12 hours and 40 mg/kg/day every 8 hours, respectively.

Diarrhea was defined as either: (a) 3 or more watery or 4 or more loose/watery stools in 1 day; OR (b) 2 watery stools per day or 3 loose/watery stools per day for 2 consecutive days. The incidence of diarrhea was significantly lower in patients who received the every 12 hours regimen compared to patients who received the every 8 hours regimen (14% and 34%, respectively). In addition, the number of patients with either severe diarrhea or who were withdrawn with diarrhea was significantly lower in the every 12 hours treatment group (3% and 8% for the every 12 hours/10 day and every 8 hours/10 day, respectively). In the every 12 hours treatment group, 3 patients (1%) were withdrawn with an allergic reaction, while 1 patient in the every 8 hours group was withdrawn for this reason. The number of patients with a candidal infection of the diaper area was 4% and 6% for the every 12 hours and every 8 hours groups, respectively.

• 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. 
• Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard – 8th ed. CLSI Document M7-A9. CLSI, 940 West Valley Road, Suite 1400, Wayne, PA, 19087, 2012.
• Clinical and Laboratory Standards Institute (CLSI). Performance Standard for Antimicrobial Disk Susceptibility Tests; Approved Standard – 11th ed. CLSI Document M2-A11. CLSI, 940 West Valley Road, Suite 1400, Wayne, PA, 19087, 2012. 
• CLSI. Performance Standards for Antimicrobial Susceptibility Testing: 22^nd Informational Supplement. CLSI document M100-S22. CLSI, Wayne, PA, 2012.  

Amoxicillin and clavulanate potassium tablets, USP 250 mg/125 mg are available for oral administration as white, oval, biconvex, film-coated tablets, engraved “APO” on one side, “250-125” on the other. Each tablet contains 250 mg amoxicillin as the trihydrate and 125 mg clavulanic acid as the potassium salt.

Bottles of 20 (NDC 60505-2539-2)
Bottles of 30 (NDC 60505-2539-3)
Bottles of 500 (NDC 60505-2539-5)

Amoxicillin and clavulanate potassium tablets, USP 500 mg/125 mg are available for oral administration as white, oval, biconvex, film-coated tablets, engraved “APO” on one side, “500-125” on the other. Each tablet contains 500 mg amoxicillin as the trihydrate and 125 mg clavulanic acid as the potassium salt.

Bottles of 20 (NDC 60505-2540-2)
Bottles of 30 (NDC 60505-2540-3)
Bottles of 500 (NDC 60505-2540-5)

Amoxicillin and clavulanate potassium tablets, USP 875 mg/125 mg are available for oral administration as white, capsule-shaped, biconvex, film-coated tablets, engraved “APO” on one side, engraved “A” bisect “C” on the other. Each tablet contains 875 mg amoxicillin as the trihydrate and 125 mg clavulanic acid as the potassium salt.

Bottles of 20 (NDC 60505-2541-2)
Bottles of 30 (NDC 60505-2541-3)
Bottles of 500 (NDC 60505-2541-5)

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Dispense in a tight container.

Keep out of the reach of children.

Patients should be informed that amoxicillin and clavulanate potassium tablets may be taken every 8 hours or every 12 hours, depending on the dose prescribed. Each dose should be taken with a meal or snack to reduce the possibility of gastrointestinal upset.

Patients should be counseled that antibacterial drugs, including amoxicillin and clavulanate potassium 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 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 tablets or other antibacterial drugs in the future. 

Counsel patients that diarrhea is a common problem caused by antibacterials, and it usually ends when the antibacterial is discontinued. Sometimes after starting treatment with antibacterials, 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 their last dose of the antibacterial. If diarrhea is severe or lasts more than 2 or 3 days, patients should contact their physician.

Patients should be aware that amoxicillin and clavulanate potassium tablets contain a penicillin class drug product that can cause allergic reactions in some individuals.

CLINITEST is a registered trademark of Miles, Inc.

Manufactured by:                    Manufactured for:

Apotex Inc.                              Apotex Corp.

Toronto, Ontario                      Weston, Florida

Canada M9L 1T9                    33326

Revised: February 2013

Rev. 10

PRINCIPAL DISPLAY PANEL - 250 mg/125 mg BOTTLE

APOTEX CORP. NDC 60505-2539-3

AMOXICILLIN AND CLAVULANATE POTASSIUM TABLETS, USP

250 mg/125 mg *

Rx only

30 bottle count

PRINCIPAL DISPLAY PANEL - 500 mg/125 mg BOTTLE

APOTEX CORP. NDC 60505-2540-3

AMOXICILLIN AND CLAVULANATE POTASSIUM TABLETS, USP

500 mg/125 mg *

Rx only

30 bottle count

PRINCIPAL DISPLAY PANEL - 875 mg/125 mg BOTTLE

APOTEX CORP. NDC 60505-2541-3

AMOXICILLIN AND CLAVULANATE POTASSIUM TABLETS , USP

875 mg/125 mg *

Rx only

30 bottle count