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   • SPL 2 - Aug 23, 2019
   • SPL 1 - Sep 07, 2016

Generic: amoxicillin and clavulanate potassium

1 Indications And Usage

ToÂreduce the development of drug-resistant bacteria and maintain the effectiveness ofÂAmoxicillin and Clavulanate PotassiumÂTablets,ÂUSPÂand other antibacterial drugs,ÂAmoxicillin and Clavulanate PotassiumÂTablets,ÂUSPÂshould 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 PotassiumÂTablets,ÂUSPÂis 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 uled below*:

Amoxicillin and Clavulanate PotassiumÂTablets,ÂUSPÂare a combination penicillin-class antibacterial and beta-lactamase inhibitor indicated for treatment of the following:

LowerÂrespiratory 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)

1.1 Lower Respiratory Tract Infections

Â- caused by beta-lactamase-producing isolates ofÂHaemophilus influenzae and Moraxella catarrhalis.

1.2 Acute Bacterial Otitis Media

Â- caused byÂbeta-lactamase-producing isolates of H. influenzaÂand M. catarrhalis.

1.3 Sinusitis

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

1.4 Skin and Skin Structure Infections

-causedÂby beta-lactamase-producing isolates ofÂStaphylococcus aureus, Escherichia coli, and Klebsiella species.

1.5 Urinary Tract Infections

Â- caused by beta-lactamase-producing isolates of E. Â coli, KlebsiellaÂspecies, and Enterobacter species.

1.6 Limitations of Use

Â- When susceptibility test results show susceptibility to amoxicillin, indicating no beta-lactamase production,ÂAmoxicillin and Clavulanate PotassiumÂTablets,ÂUSPÂshould not be used.

2 Dosage And Administration

Amoxicillin and Clavulanate PotassiumÂTabletsÂmay be taken without regard to meals; however, absorption of clavulanate potassium is enhanced whenÂAmoxicillin and Clavulanate Potassium TabletsÂis administered at the start of a meal.ÂToÂminimize the potential for gastrointestinalÂintolerance,ÂAmoxicillin and Clavulanate PotassiumÂTabletsÂshould be taken at the start of a meal.

• Adults and Pediatric Patients > 40 kg: 875 mgÂevery 12 hoursÂ(2.1)

2.1 Adults

For severe infections and infections of the respiratory tract, the dose should be one 875-mg tablet ofÂAmoxicillin and Clavulanate Potassium every 12 hours.

2.3 Patients with Renal Impairment

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.

3 Dosage Forms And Strengths

T ablets

• 875-mg/125-mg T ablets:ÂEach scored white capsule-shaped tablet, debossed with WW949 on the upper side and scored on the other side, contains 875 mg amoxicillin and 125 mg clavulanic acid as the potassium salt.

Formulations and amoxicillin/clavulanate content are:

Tablets: 875 mg/125 mg.ÂTablets are scored. (

3)

4 Contraindications

• History of a serious hypersensitivity reaction (e.g., anaphylaxis or ÂStevens-Johnson syndrome) toÂAmoxicillin and Clavulanate PotassiumÂTabletsÂor to other beta-lactams (e.g., penicillins or cephalosporins) (4)
• History of cholestatic jaundice/hepatic dysfunction associated withÂAmoxicillin and Clavulanate PotassiumÂTabletsÂ(4)

4.1 Serious Hypersensitivity Reactions

Amoxicillin and Clavulanate PotassiumÂTabletsÂare 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).

4.2 Cholestatic Jaundice/Hepatic Dysfunction

Amoxicillin and Clavulanate PotassiumÂTabletsÂare contraindicated in patients with a previous history of cholestatic jaundice/hepatic dysfunction associated withÂAmoxicillin and Clavulanate PotassiumÂTablets.

5 Warnings And Precautions

• SeriousÂ(includingÂfatal)Âhypersensitivity reactions:ÂDiscontinueÂAmoxicillinÂand ClavulanateÂPotassiumÂTabletsÂifÂaÂreaction occurs.Â(5.1)
• HepaticÂdysfunctionÂandÂcholestaticÂjaundice:

DiscontinueÂifÂsigns/symptomsÂofÂhepatitisÂoccur.ÂMonitorÂliverÂfunctionÂtestsÂinÂpatientsÂwith hepaticÂimpairment.Â(5.2)

• Clostridiu m  difficile-associatedÂdiarrheaÂ(CDAD): EvaluateÂpatientsÂifÂdiarrheaÂoccurs.Â(5.3)
• PatientsÂwithÂmononucleosisÂwhoÂreceive AmoxicillinÂandÂClavulanateÂPotassiumÂTablets developÂskinÂrash.ÂAvoidÂAmoxicillinÂand ClavulanateÂPotassiumÂTabletsÂuseÂinÂthese patients.Â(5.4)
• Overgrowth:ÂTheÂpossibilityÂofÂsuperinfections withÂfungalÂorÂbacterialÂpathogensÂshouldÂbe consideredÂduringÂtherapy.Â(5.5)

5.1 Hypersensitivity Reactions

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving beta-lactam antibacterials, includingÂAmoxicillin and Clavulanate Potassium Tablets.ÂThese 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 PotassiumÂTablets,Âcareful inquiry should be made regarding previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens. If an allergic reaction occurs,ÂAmoxicillin and Clavulanate PotassiumÂTabletsÂshould be discontinued and appropriate therapy instituted.

5.2 Hepatic Dysfunction

Hepatic dysfunction, including hepatitis and cholestatic jaundice has been associated with the use ofÂAmoxicillin and Clavulanate PotassiumÂTablets.ÂHepatic toxicity is usually reversible; however, deaths have been reported. Hepatic function should be monitored at regular intervals in patients with hepatic impairment.

5.3 Clostridium difficile Associated Diarrhea (CDAD)

Clostridium difficile associated diarrhea (CDAD)Âhas been reported with use of nearly all antibacterial agents, includingÂAmoxicillin and Clavulanate PotassiumÂTablets,Âand may range in severity from mild diarrhea to fatal colitis.ÂTreatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxinsÂAÂand B which contribute to the development of CDAD. Hypertoxin-Âproducing strains of C. difficile cause increased morbidity and mortality, as these infections canÂbe refractory to antimicrobial therapy and may require colectomy. CDADÂmust be considered in all patients whoÂpresent with diarrhea following antibacterial use. Careful medical history is necessary since CDADÂhas been reported to occur over 2 months after the administration of antibacterial agents.

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

5.4 Skin Rash in Patients with Mononucleosis

AÂhigh percentage of patients with mononucleosis whoÂreceive amoxicillin develop an erythematous skin rash.ÂThus,ÂAmoxicillin and Clavulanate PotassiumÂTabletsÂshould not be administered to patients with mononucleosis.

5.5 Potential for Microbial Overgrowth

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.

5.7 Development of Drug-Resistant Bacteria

PrescribingÂAmoxicillin and Clavulanate PotassiumÂTabletsÂin 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.

6 Adverse Reactions

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

• Anaphylactic reactions [see W arnings  and Precautions ( 5.1 )]
• Hepatic Dysfunction [see W arnings  and Precautions ( 5.2 )]
• CDADÂ[see W arnings  and Precautions ( 5.3 )]

The most frequently reported adverse effects wereÂdiarrhea/loose stools (9%),Ânausea (3%), skin rashes and urticaria (3%),Âvomiting (1%)Âand vaginitis (1%)Â(6.1)

To report SUSPECTED ADVERSE REACTIONS, contact the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience

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 wereÂdiarrhea/loose stools (9%),Ânausea (3%),Âskin rashes and urticaria (3%),Âvomiting (1%)Âand vaginitis (1%).ÂLess than 3% of patients discontinued therapy because of drug-related adverse reactions.ÂThe overall incidence of adverse reactions, and in particular diarrhea, increased with the higher recommended dose. Other less frequently reported adverse reactions (<1%) include:ÂAbdominal discomfort, flatulence, and headache.

In pediatric patients (aged 2 months to 12 years), 1 US/CanadianÂclinical trial was conducted which compared 45/6.4 mg/kg/day (divided every 12 hours) ofÂAmoxicillin and Clavulanate Potassium forÂ10 days versus 40/10 mg/kg/day (divided every 8 hours) ofÂAmoxicillin and Clavulanate PotassiumÂfor 10 days in the treatment of acute otitis media.ÂAÂtotal of 575 patients were enrolled, and only the suspension formulations wereÂused in this trial. Overall, the adverse reactions seen were comparable to that noted above; however, there wereÂdifferences in the rates of diarrhea, skinÂrashes/urticaria, and diaper area rashes. [See Clinical Studies ( 14.2 )]

6.2 Postmarketing Experience

In addition to adverse reactions reported from clinical trials, the following have been identified during postmarketing use ofÂAmoxicillin and Clavulanate PotassiumÂTablets.ÂBecause they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made.ÂTheseÂevents have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection toÂAmoxicillin and Clavulanate PotassiumÂTablets.

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.Â[see W arnings and Precautions ( 5.3 )]

Hypersensitivity  Reactions: ÂPruritus, angioedema, serum sickness-like reactions (urticaria orÂskin 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 W arnings  and Precautions ( 5.1 )]

Liver: ÂHepatic dysfunction, including hepatitis and cholestatic jaundice, increases in serum transaminases (ASTÂand/orÂALT),Âserum bilirubin, and/or alkaline phosphatase, has been reported withÂAmoxicillin and Clavulanate PotassiumÂTablets.ÂIt has been reported more commonly in the elderly, in males, or in patients on prolonged treatment.ÂThe 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 afterÂtherapy has been discontinued.ÂThe hepatic dysfunction, which may be severe, is usually reversible. Deaths have been reported. [see Contraindications ( 4.2 ), W arnings  and Precautions ( 5.2 )]

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

Hemic  and L ymphatic  Systems: ÂAnemia, 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.ÂThrombocytosis was noted in less than 1% of the patients treated with Amoxicillin and Clavulanate PotassiumÂTablets.ÂThere have been reports of increased prothrombin time in patients receivingÂAmoxicillin and Clavulanate PotassiumÂTabletsÂand anticoagulant therapy concomitantly. [see Drug  Interactions ( 7.2 )]

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

Miscellaneous: ToothÂdiscoloration (brown,Âyellow, 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.

7 Drug Interactions

• Co-administration with probenecid is not recommended. (7.1)
• Concomitant use ofÂAmoxicillin and Clavulanate PotassiumÂTabletsÂand oral anticoagulants mayÂincrease the prolongation of prothrombin time. (7.2)
• Co-administration with allopurinol increases the risk of rash. (7.3)
• Amoxicillin and Clavulanate PotassiumÂTablets may reduce efficacy of oral contraceptives. (7.4)

7.1 Probenecid

Probenecid decreases the renal tubular secretion of amoxicillin but does not delay renal excretionÂof clavulanic acid. Concurrent use withÂAmoxicillin and Clavulanate PotassiumÂTabletsÂmay result in increased and prolonged blood concentrations of amoxicillin. Coadministration of probenecid is not recommended.

7.2 Oral Anticoagulants

Abnormal prolongation of prothrombin time (increased international normalized ratio [INR])Âhas been reported in patients receiving amoxicillin and oral anticoagulants.ÂAppropriate monitoring shouldÂbe undertaken whenÂanticoagulants are prescribed concurrently withÂAmoxicillin and Clavulanate PotassiumÂTablets.ÂAdjustments in the dose of oral anticoagulants may be necessary to maintain the desired level of anticoagulation.

7.3 Allopurinol

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 whetherÂthis potentiation of amoxicillin rashes is due to allopurinol or the hyperuricemia present in these patients.

7.4 Oral Contraceptives

Amoxicillin and Clavulanate PotassiumÂTabletsÂmay affect intestinal flora, leading to lower estrogen reabsorption and reduced efficacy of combined oral estrogen/progesterone contraceptives.

7.5 Effects on Laboratory Tests

High urine concentrations of amoxicillin may result in false-positive reactions when testing for the presence of glucose in urine using CLINITEST^®,ÂBenedict’s Solution, or Fehling’s Solution. Since this effect may also occur withÂAmoxicillin and Clavulanate PotassiumÂTablets,Âit 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.

8 Use In Specific Populations

• Pediatric Use: Modify dose in patients 12 weeks or younger. (8.4)
• Renal impairment; Dosage adjustment is recommended for sever renal impairment (GFR< 30mL/min). (2.3, 8.6)

8.1 Pregnancy

T eratogenic  E f fects:ÂPregnancy Category B.ÂReproduction studies performed in pregnant rats and mice givenÂAmoxicillin and Clavulanate PotassiumÂTabletsÂ(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 toÂAmoxicillin and Clavulanate PotassiumÂTablets.ÂThe amoxicillin doses in rats and mice (based on body surface area) wereÂapproximately 4 and 2 times the maximum recommendedÂadult 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).ÂThere 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.

8.2 Labor and Delivery

Oral ampicillin-class antibiotics are poorly absorbed during labor. It is not known whetherÂuse 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.

8.3 Nursing Mothers

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

8.4 Pediatric Use

The safety and effectiveness ofÂAmoxicillin and Clavulanate Potassium PowderÂfor Oral Suspension and ChewableÂTabletsÂhave been established in pediatric patients. Use ofÂAmoxicillin and Clavulanate Potassium in pediatric patients is supported by evidence from studies ofÂAmoxicillinÂand Clavulanate PotassiumÂTabletsÂin adults with additional data from a study ofÂAmoxicillin and Clavulanate Potassium PowderÂfor Oral Suspension in pediatric patients aged 2 months to 12 years with acute otitis media. [see Clinical Studies ( 14.2 )]ÂBecause 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 PotassiumÂTablets should be modified in pediatric patients aged <12 weeks (<3 months). [see Dosage andÂAdministration (2.2)]

8.5 Geriatric Use

Of the 3,119 patients in an analysis of clinical studies ofÂAmoxicillin and Clavulanate PotassiumÂTablets,Â32% were ≥65 years old, and 14% were ≥75 years old. No overall differences in safetyÂor 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.

8.6 Dosing in Renal Impairment

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 (2.2) for specific recommendations in patients with renal impairment.

10 Overdosage

In case of overdosage, discontinue medication, treat symptomatically, and institute supportiveÂmeasures as required.ÂAÂprospective study of 51 pediatric patients at a poison-control centerÂsuggested 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 bloodÂlevels may occur more readily in patients with impaired renal function because of decreased renal clearance of amoxicillin/ clavulanate potassium.ÂAmoxicillin/clavulanate potassium may be removed from circulation by hemodialysis. [see Dosage and  Administration ( 2.3 )]

11 Description

Amoxicillin and Clavulanate PotassiumÂTablets,ÂUSPÂis an oral antibacterial combination consisting of amoxicillin and the beta-lactamase inhibitor, clavulanate potassium (the potassium salt of clavulanic acid).ÂAmoxicillin is an analog of ampicillin, derived from the basic penicillin nucleus,Â6-aminopenicillanic acid.ÂThe amoxicillin molecular formula is C₁₆H₁₉N₃ÂO₅ÂS•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 beta-lactam structurally related to the penicillins and possesses the ability to inactivate some beta-lactamases by blocking the active sites of these enzymes. The clavulanate potassium molecular formula isÂC₈H₈KNO₅ , and the molecular weight is 237.25. Chemically, clavulanate potassium is potassium (Z)Â(2R,5R)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo[3.2.0]-heptane-2-carboxylate and mayÂbe represented structurally as:

Â

Inactive Ingredients:

Colloidal silicon dioxide, ethylcellulose, hypromellose, magnesium stearate, microcrystalline cellulose, propylene glycol, sodium starch glycolate, and titanium dioxide.

Each tablet of amoxicillin/clavulanate potassium contains 0.63 mEq potassium.

12 Clinical Pharmacology

12.1 Mechanism of Action

Amoxicillin and Clavulanate PotassiumÂTabletsÂare antibacterial drugs. [see Microbiology 12.4 ]

12.3 Pharmaco*kinetics

Mean amoxicillin and clavulanate potassium pharmaco*kinetic parameters in normal adults following administration ofÂAmoxicillin and Clavulanate PotassiumÂTabletsÂare shown inÂTableÂ1 and following administration ofÂAmoxicillin and Clavulanate Potassium PowderÂfor Oral Suspension and Chewable TabletsÂare shown inÂTableÂ2.

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

Dose and Regimen	CmaxÂ(mcg/mL)		AUC0-24Â(mcg*h/mL)
Amoxicillin/Clavulanate potassium	Amoxicillin	Clavulanate potassium	Amoxicillin	Clavulanate potassium
250/125 mg every 8 hours	3.3 ±Â1.12	1.5 ± 0.70	26.7 ± 4.56	12.6 ±Â3.25
500/125 mg every 12 hours	6.5 ±Â1.41	1.8 ± 0.61	33.4 ± 6.76	8.6 ± 1.95
500/125 mg every 8 hours	7.2 ± 2.26	2.4 ± 0.83	53.4 ± 8.87	15.7 ± 3.86
875/125 mg every 12 hours	11.6 ± 2.78	2.2 ± 0.99	53.5 ±Â12.31	10.2 ± 3.04

^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.

Table 2: Mean (±S.D.) Amoxicillin and Clavulanate Potassium Pharmaco*kinetic Parameters^a,b with Amoxicillin and Clavulanate Potassium Powder for Oral Suspension and Chewable Tablets

Dose	Cmax (mcg/mL)		AUC0-24(mcg*h/mL)
Amoxicillin/Clavulanate potassium	Amoxicillin	Clavulanate potassium	Amoxicillin	Clavulanate potassium
400/57 mg (5 mLÂofsuspension)	6.94 ±Â1.24	1.10 ± 0.42	17.29 ± 2.28	2.34 ± 0.94
400/57 mg (1 chewabletablet)	6.67 ± 1.37	1.03 ± 0.33	17.24 ± 2.64	2.17 ± 0.73

^a Mean (± standard deviation) values of 28 normal adults. Peak concentrations occurredÂapproximately 1 hours after the dose. ^bAmoxicillin/clavulanate potassium administered at the start of a light meal.

Oral administration of 5 mLÂof 250 mg/5 mLÂsuspension ofÂAmoxicillin and Clavulanate Potassium or the equivalent dose of 10 mLÂof 125 mg/5 mLÂsuspension ofÂAmoxicillin and Clavulanate Potassium provides average peak serum concentrations approximately 1 hour after dosing of 6.9 mcg/mLÂfor amoxicillin and 1.6 mcg/mLÂfor clavulanic acid.ÂThe areas under the serum concentration curves obtained during the first 4 hours after dosing were 12.6 mcg*h/mLÂfor amoxicillin and 2.9 mcg*h/mL for clavulanic acid when 5 mLÂof 250 mg/5 mLÂsuspension ofÂAmoxicillin and Clavulanate Potassium or equivalent dose of 10 mLÂof 125 mg/5 mLÂsuspension ofÂAmoxicillin and Clavulanate Potassium were administered to normal adults. One 250-mg chewable tablet ofÂAmoxicillin and Clavulanate Potassium or twoÂ125-mg chewable tablets ofÂAmoxicillin and Clavulanate Potassium are equivalent to 5 mLÂof 250 mg/5 mLÂsuspension ofÂAmoxicillin and Clavulanate Potassium and provide similar serum concentrations of amoxicillin and clavulanic acid.

Amoxicillin serum concentrations achieved withÂAmoxicillin and Clavulanate PotassiumÂTablets are similar to those produced by the oral administration of equivalent doses of amoxicillin alone. TimeÂabove the minimum inhibitory concentration of 1 mcg/mLÂfor amoxicillin has been shown to be similar after corresponding every 12 hour and every 8 hour dosing regimens ofÂAmoxicillin and Clavulanate PotassiumÂTabletsÂin adults and children.

Absorption: Dosing in the fasted or fed state has minimal effect on the pharmaco*kinetics of amoxicillin. WhileÂAmoxicillin and Clavulanate PotassiumÂTabletsÂcan be given without regard to meals, absorption of clavulanate potassium whenÂtaken with food is greater relative to the fasted state. In one study, the relative bioavailability of clavulanate was reduced whenÂAmoxicillin and Clavulanate PotassiumÂTabletsÂwas dosed at 30 and 150 minutes after the start of a high-fat breakfast.Distribution: Neither component inÂAmoxicillin and Clavulanate PotassiumÂTabletsÂare highly protein- bound; clavulanic acid is approximately 25% bound to human serum and amoxicillin approximatelyÂ18% bound.ÂAmoxicillin diffuses readily into most body tissues and fluids with the exception of the brain and spinal fluid.ÂTwoÂhours after oral administration of a single 35 mg/kg dose of suspension ofÂAmoxicillin and Clavulanate PotassiumÂTabletsÂto fasting children, average concentrations of 3 mcg/mLÂof amoxicillin and 0.5 mcg/mLÂof clavulanic acid were detected in middle ear effusions.Metabolism and Excretion:ÂThe half-life of amoxicillin after the oral administration ofÂAmoxicillin andÂClavulanate PotassiumÂTabletsÂis 1.3 hours and that of clavulanic acid is 1 hour.ÂApproximately 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 orÂ500-mg tablet ofÂAmoxicillin and Clavulanate PotassiumÂTablets.

12.4 Microbiology

Amoxicillin is a semisynthetic antibiotic with in vitro bactericidal activity against Gram-positive and Gram-negative bacteria.ÂAmoxicillin is, however, susceptible to degradation by beta-lactamases, and therefore, the spectrum of activity does not include organisms which produce these enzymes.ÂClavulanic 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.ÂThe formulation of amoxicillin and clavulanic acid inÂAmoxicillin and Clavulanate PotassiumÂTablets 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 INDICATIONSÂANDÂUSAGE section.Gram-positive bacteria Staphylococcus aureus Gram-negative bacteria Enterobacter species Escherichia coli Haemophilus influenza Klebsiella species Moraxella catarrhalis

The following in vitro data are available, but their clinical significance is unknown.ÂAt least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC)Âless 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 bacteriaÂhas 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. TheÂMICs 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 3.

Diffusion techniques:

Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds.ÂThe zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds.ÂThe zone size should be determined using a standardized test method^3,4.ÂThis procedure uses paper disks impregnatedÂwith 30 mcg amoxicillin/clavulanic acid (20 mcg amoxicillin plus 10 mcg clavulanic acid) to test theÂsusceptibility of bacteria to amoxicillin/clavulanic acid.ÂThe disc diffusion interpretive criteria are provided inÂTableÂ3.

Table 3: Susceptibility Test Interpretive Criteria for Amoxicillin Clavulanic Acid

Minimum Inhibitory Concentrations (mcg/mL)				Disk Diffusion(zone diameters in mm)
Pathogen	S	I	R	S	I	R
Enterobacteriaceae	8/4	16/8	32/16	≥18	14-17	≤13
Haemophilus influenzae and Staphylococcus aureus	4/2	--	8/4	≥20	--	≤19

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.ÂStandard amoxicillin/clavulanic acid powderÂshould provide the following range of MIC values noted inÂTable 4 for the diffusion technique using the 30 mcg amoxicillin/clavulanic acid (20 mcg amoxicillin plus 10 mcg clavulanic acid) disk, the criteria inÂTableÂ4 should be achieved.

Table 4: Acceptable Quality Control Ranges for Amoxicillin/Clavulanic Acid

QCÂStrain	Minimum InhibitoryConcentration (mcg/mL)	Disk DiffusionÂ(zone diameter in mm)
Escherichia coli ÂATCCÂ25922	2/1 to 8/4	18 to 24
Escherichia coli ÂATCC 35218	4/2 to 16/8	17 to 22
Haemophilus influenzae ÂATCC49247	2/1 to 16/8	15 to 23
Staphylococcus aureus ÂATCC29213	0.12/0.06 to 0.5/0.25	-
Staphylococcus aureus ÂATCC29523	-	28 to 36

13 Nonclinical Toxicology

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have not been performed to evaluate carcinogenic potential. Amoxicillin and Clavulanate PotassiumÂTabletsÂ(4:1 ratio formulation of amoxicillin:clavulanate) was non-mutagenic in theÂAmes bacterial mutation assay, and the yeast gene conversion assay.

Amoxicillin and Clavulanate PotassiumÂTabletsÂwas weakly positive in the mouse lymphoma assay, but the trend towardÂincreased mutation frequencies in this assay occurred at doses that wereÂalso associated with decreased cell survival.

Amoxicillin and Clavulanate PotassiumÂTabletsÂwas negative in the mouse micronucleus test, andÂin the dominant lethal assay in mice. Potassium clavulanate alone was tested in theÂAmes bacterial mutation assay and in the mouse micronucleus test, and was negative in each of these assays. Amoxicillin and Clavulanate PotassiumÂTabletsÂ(2:1 ratio formulation of amoxicillin:clavulanate)Âat 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.

14 Clinical Studies

14.1 Lower Respiratory Tract and Complicated Urinary Tract Infections

DataÂfrom 2 pivotal trials in 1,191 patients treated for either lowerÂrespiratory tract infections or complicated urinary tract infections compared a regimen of 875-mg tablets ofÂAmoxicillin and Clavulanate Potassium every 12 hours to 500-mg tablets ofÂAmoxicillin and 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.ÂThere was no significant difference in the percentage of adverse events in each group.ÂThe most frequently reported adverse eventÂwas 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:Â1% 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 every 12 hours (n=308) or 500-mg tablets ofÂAmoxicillin and Clavulanate Potassium every 8 hours (n=321).

The number of bacteriologically evaluable patients was comparable between the twoÂdosing regimens.ÂAmoxicillin and Clavulanate Potassium produced comparable bacteriological success rates in patients assessed 2 to 4 days immediately following end of therapy.ÂThe 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 inÂTable 5.

Table 5: Bacteriologic efficacy rates for Amoxicillin and Clavulanate Potassium

T ime  Post  Therapy	875 mg  every 12 hours  % (n)	500 mg  every 8 hours  % (n)
2 to 4 days	81% (58)	80% (54)
5 to 9 days	58% (41)	52% (52)
2 to 4 weeks	52% (101)	55% (104)

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.

14.2 Acute Bacterial Otitis Media and Diarrhea in Pediatric Patients

One US/Canadian clinical trial was conducted which compared 45/6.4 mg/kg/day (divided everyÂ12 hours) of Amoxicillin and Clavulanate Potassium for 10 days versus 40/10 mg/kg/day (divided every 8 hours) of Amoxicillin and Clavulanate Potassium for 10 days in the treatment of acute otitisÂmedia. Only the suspension formulations were used in this trial. A total of 575 pediatric patientsÂ(aged 2 months to 12 years) wereÂenrolled, 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.ÂTheÂclinical efficacy rates at the end of therapy visit (defined as 2-4 days after the completion of therapy) and at the follow-up visit (defined as 22-28 days post-completion of therapy) were comparable for the 2 treatment groups, with the following cure rates obtained for the evaluable patients:ÂAtÂend ofÂtherapy, 87% (n = 265) and 82% (n = 260) for 45 mg/kg/day every 12 hours and 40 mg/kg/day everyÂ8 hours, respectively.ÂAt 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)Â2 watery stools per day or 3 loose/watery stools per day for 2 consecutive days.ÂThe 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, theÂnumber 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.

It is not known if the finding of a statistically significant reduction in diarrhea with the oral suspensions dosed every 12 hours, versus suspensions dosed every 8 hours, can be extrapolated to the chewable tablets.ÂThe presence of mannitol in the chewable tablets may contribute to a different diarrhea profile.ÂThe every 12 hour oral suspensions (200 mg/5 mLÂand 400 mg/5 mL) are sweetened with aspartame.

15 References

• Swanson-Biearman B, Dean BS, Lopez G, Krenzelok EP. The effects of penicillin andÂcephalosporin 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 DiskÂSusceptibility Tests;Approved Standard - 11th ed. CLSI Document M2-A11. CLSI, 940 West ValleyÂRoad, Suite 1400, Wayne, PA, 19087, 2012.
• CLSI.ÂPerformance Standards forÂAntimicrobial SusceptibilityÂTesting:Â22^nd Informational Supplement. CLSI document M100-S22. CLSI, Wayne, PA, 2012.

16 How Supplied/storage And Handling

NDC 59115-025-22 ........... 20 tablets bottle

875-mg/125-mg T ablets:ÂEach scored white capsule-shaped tablet, debossed with WW949 on the upper side and scored on the other side, contains 875 mg amoxicillin as the trihydrate and 125 mg clavulanic acid as the potassium salt.

Store at 20° to 25°C (68° to 77°F) [See USPÂControlled RoomÂTemperature].

Dispense in a tight container as defined in the USP, with a child-resistant closure (as required).

Advise patients to keep in a closed container.

17 Patient Counseling Information

17.1 Information for Patients

Patients should be informed thatÂAmoxicillin and Clavulanate PotassiumÂTabletsÂmay be taken everyÂ8 hours or every 12 hours, depending on the dose prescribed. Each dose should be taken with aÂmeal or snack to reduce the possibility of gastrointestinal upset.

Patients should be counseled that antibacterial drugs, includingÂAmoxicillin and Clavulanate PotassiumÂTabletsÂshould only be used to treat bacterial infections.ÂThey do not treat viral infections (e.g., the common cold). WhenÂAmoxicillin and Clavulanate PotassiumÂTabletsÂare prescribed to treat a bacterial infection, patients should be told that although it is common to feel better earlyÂin the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may: (1)Âdecrease the effectiveness of the immediate treatment, and (2)Âincrease the likelihood that bacteria will develop resistance and will not be treatable byÂAmoxicillin and Clavulanate PotassiumÂTabletsÂor other antibacterial drugs in the future. Counsel patients that diarrhea is a common problem caused by antibacterials, and it usually ends whenÂthe antibacterial is discontinued. Sometimes after starting treatment with antibacterials, patients can develop watery and bloody stools (withÂor 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 awareÂthatÂAmoxicillin and Clavulanate PotassiumÂTabletsÂcontain a penicillin class drug product that can cause allergic reactions in some individuals.

Manufactured by: HIKMA  Pharmaceuticals ÂP.O.Box 182400Amman 11118 – JordanRevisedÂApril 2015

Package Label.principal Display Panel

PRINCIPAL DISPLAY PANEL NDC 59115-025-22Amoxicillin and ClavulanatePotassuim Tablets, USP875 mg/ 125 mgRx Only20 Tablets