DOSAGE FORMS & STRENGTHS SECTION.


3 DOSAGE FORMS AND STRENGTHS T ablets 875-mg/125-mg T ablets:Each 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.Tablets are scored. (3)

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


Principal Display Panel NDC 0143-9249-20 Amoxicillin and Clavulanate Potassium Tablets, USP 875 mg/125 mg* 20 TABLETS Rx Only

ADVERSE REACTIONS SECTION.


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 )] CDAD[see W arnings and Precautions ( 5.3 )] The most frequently reported adverse effects werediarrhea/loose stools (9%),nausea (3%), skin rashes and urticaria (3%),vomiting (1%)and vaginitis (1%)(6.1) To REPORT SUSPECTED ADVERSE REACTIONS, contact West-Ward Pharmaceuticals Corp. at 1-877-233-2001, or 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 werediarrhea/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 (6.2 Postmarketing Experience In addition to adverse reactions reported from clinical trials, the following have been identified during postmarketing use ofAmoxicillin and Clavulanate PotassiumTablets.Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made.Theseevents have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection toAmoxicillin and Clavulanate PotassiumTablets. 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 W arnings and Precautions ( 5.3 )] Hypersensitivity Reactions: Pruritus, angioedema, serum sickness-like reactions (urticaria orskin 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: Hepatic dysfunction, including hepatitis and cholestatic jaundice, increases in serum transaminases (ASTand/orALT),serum bilirubin, and/or alkaline phosphatase, has been reported withAmoxicillin and Clavulanate PotassiumTablets.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 aftertherapy has been discontinued.The hepatic dysfunction, which may be severe, is usually reversible. Deaths have been reported. [see Contraindications ( 4.2 ), W arnings and Precautions ( 5.2 )] Renal: Interstitial nephritis, hematuria, and crystalluria have been reported. [see Overdosage ( 10 )] Hemic and L ymphatic 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 PotassiumTablets.There have been reports of increased prothrombin time in patients receivingAmoxicillin and Clavulanate PotassiumTabletsand 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: Toothdiscoloration (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.

INDICATIONS & USAGE SECTION.


1 INDICATIONS AND USAGE Toreduce the development of drug-resistant bacteria and maintain the effectiveness ofAmoxicillin and Clavulanate PotassiumTablets,USPand other antibacterial drugs,Amoxicillin and Clavulanate PotassiumTablets,USPshould 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 PotassiumTablets,USPis 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*: Amoxicillin and Clavulanate PotassiumTablets,USPare a combination penicillin-class antibacterial and beta-lactamase inhibitor indicated for treatment of the following: Lowerrespiratory 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 - caused by beta-lactamase-producing isolates ofHaemophilus influenzae and Moraxella catarrhalis. 1.2 Acute Bacterial Otitis Media - caused bybeta-lactamase-producing isolates of H. influenzaand M. catarrhalis. 1.3 Sinusitis - caused by beta-lactamase-producing isolates of H. influenzae and M. catarrhalis. 1.4 Skin and Skin Structure Infections- causedby beta-lactamase-producing isolates ofStaphylococcus aureus, Escherichia coli, and Klebsiella species. 1.5 Urinary Tract Infections - caused by beta-lactamase-producing isolates of E. coli, Klebsiellaspecies, and Enterobacter species. 1.6 Limitations of Use - When susceptibility test results show susceptibility to amoxicillin, indicating no beta-lactamase production,Amoxicillin and Clavulanate PotassiumTablets,USPshould not be used.

DOSAGE & ADMINISTRATION SECTION.


2 DOSAGE AND ADMINISTRATION Amoxicillin and Clavulanate PotassiumTabletsmay be taken without regard to meals; however, absorption of clavulanate potassium is enhanced whenAmoxicillin and Clavulanate Potassium Tabletsis administered at the start of a meal.Tominimize the potential for gastrointestinalintolerance,Amoxicillin and Clavulanate PotassiumTabletsshould be taken at the start of a meal. Adults and Pediatric Patients > 40 kg: 875 mg every 12 hours(2.1) 2.1 Adults For severe infections and infections of the respiratory tract, the dose should be one 875-mg tablet ofAmoxicillin 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.

HOW SUPPLIED SECTION.


16 HOW SUPPLIED/STORAGE AND HANDLING 875-mg/125-mg T ablets:Each 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. NDC 0143-9249-20 ........... 20 tablets bottle Store at 20 to 25C (68 to 77F) [See USPControlled RoomTemperature]. 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. KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.

DESCRIPTION SECTION.


11 DESCRIPTION Amoxicillin and Clavulanate PotassiumTablets,USPis an oral antibacterial combination consisting of amoxicillin and the beta-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 C16H19 N3O5S3H2O, 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 isC8H8KNO5 , 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 maybe represented structurally as: 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.

CONTRAINDICATIONS SECTION.


4 CONTRAINDICATIONS History of a serious hypersensitivity reaction (e.g., anaphylaxis or Stevens-Johnson syndrome) toAmoxicillin and Clavulanate PotassiumTabletsor to other beta-lactams(e.g., penicillins or cephalosporins) (4) History of cholestatic jaundice/hepatic dysfunction associated withAmoxicillin and Clavulanate PotassiumTablets(4) 4.1 Serious Hypersensitivity Reactions Amoxicillin and Clavulanate PotassiumTabletsare 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 PotassiumTabletsare contraindicated in patients with a previous history of cholestatic jaundice/hepatic dysfunction associated withAmoxicillin and Clavulanate PotassiumTablets.

OVERDOSAGE SECTION.


10 OVERDOSAGE In case of overdosage, discontinue medication, treat symptomatically, and institute supportivemeasures as required.Aprospective study of 51 pediatric patients at a poison-control centersuggested 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 bloodlevels 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 )]

WARNINGS AND PRECAUTIONS SECTION.


5 WARNINGS AND PRECAUTIONS Serious(includingfatal)hypersensitivity reactions:DiscontinueAmoxicillinand ClavulanatePotassiumTabletsifareaction occurs.(5.1) Hepaticdysfunctionandcholestaticjaundice: Discontinueifsigns/symptomsofhepatitisoccur.Monitorliverfunctiontestsinpatientswith hepaticimpairment.(5.2) Clostridiu m difficile-associateddiarrhea(CDAD): Evaluatepatientsifdiarrheaoccurs.(5.3) Patientswithmononucleosiswhoreceive AmoxicillinandClavulanatePotassiumTablets developskinrash.AvoidAmoxicillinand ClavulanatePotassiumTabletsuseinthese patients.(5.4) Overgrowth:Thepossibilityofsuperinfections withfungalorbacterialpathogensshouldbe consideredduringtherapy.(5.5) 5.1 Hypersensitivity Reactions Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving beta-lactam antibacterials, includingAmoxicillin 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 PotassiumTablets,careful inquiry should be made regarding previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens. If an allergic reaction occurs,Amoxicillin and Clavulanate PotassiumTabletsshould be discontinued and appropriate therapy instituted. 5.2 Hepatic Dysfunction Hepatic dysfunction, including hepatitis and cholestatic jaundice has been associated with the use ofAmoxicillin and Clavulanate PotassiumTablets.Hepatic 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)has been reported with use of nearly all antibacterial agents, includingAmoxicillin and Clavulanate PotassiumTablets,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 toxinsAand B which contribute to the development of CDAD. Hypertoxinproducing strains of C. difficile cause increased morbidity and mortality, as these infections canbe refractory to antimicrobial therapy and may require colectomy. CDADmust be considered in all patients whopresent with diarrhea following antibacterial use. Careful medical history is necessary since CDADhas been reported to occur over 2 months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibacterial use not directed againstC. 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. 5.4 Skin Rash in Patients with Mononucleosis Ahigh percentage of patients with mononucleosis whoreceive amoxicillin develop an erythematous skin rash.Thus,Amoxicillin and Clavulanate PotassiumTabletsshould 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 PrescribingAmoxicillin and Clavulanate PotassiumTabletsin 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.

DRUG INTERACTIONS SECTION.


7 DRUG INTERACTIONS Co-administration with probenecid is not recommended. (7.1) Concomitant use ofAmoxicillin and Clavulanate PotassiumTabletsand oral anticoagulants mayincrease the prolongation of prothrombin time. (7.2) Co-administration with allopurinol increases the risk of rash. (7.3) Amoxicillin and Clavulanate PotassiumTablets may reduce efficacy of oral contraceptives. (7.4) 7.1 Probenecid Probenecid decreases the renal tubular secretion of amoxicillin but does not delay renal excretionof clavulanic acid. Concurrent use withAmoxicillin and Clavulanate PotassiumTabletsmay 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])has been reported in patients receiving amoxicillin and oral anticoagulants.Appropriate monitoring shouldbe undertaken whenanticoagulants are prescribed concurrently withAmoxicillin and Clavulanate PotassiumTablets.Adjustments 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 whetherthis potentiation of amoxicillin rashes is due to allopurinol or the hyperuricemia present in these patients. 7.4 Oral Contraceptives Amoxicillin and Clavulanate PotassiumTabletsmay 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,Benedicts Solution, or Fehlings Solution. Since this effect may also occur withAmoxicillin and Clavulanate PotassiumTablets,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.

NONCLINICAL TOXICOLOGY SECTION.


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 PotassiumTablets(4:1 ratio formulation of amoxicillin:clavulanate) was non-mutagenic in theAmes bacterial mutation assay, and the yeast gene conversion assay. Amoxicillin and Clavulanate PotassiumTabletswas weakly positive in the mouse lymphoma assay, but the trend towardincreased mutation frequencies in this assay occurred at doses that werealso associated with decreased cell survival. Amoxicillin and Clavulanate PotassiumTabletswas negative in the mouse micronucleus test, andin the dominant lethal assay in mice. Potassium clavulanate alone was tested in theAmes bacterial mutation assay and in the mouse micronucleus test, and was negative in each of these assays. Amoxicillin and Clavulanate PotassiumTablets(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.

USE IN SPECIFIC POPULATIONS SECTION.


8 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) 8.1 Pregnancy T eratogenic E f fects:Pregnancy Category B.Reproduction studies performed in pregnant rats and mice givenAmoxicillin and Clavulanate PotassiumTablets(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 toAmoxicillin and Clavulanate PotassiumTablets.The amoxicillin doses in rats and mice (based on body surface area) wereapproximately 4 and 2 times the maximum recommendedadult 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. 8.2 Labor and Delivery Oral ampicillin-class antibiotics are poorly absorbed during labor. It is not known whetheruse 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.Amoxicillin/clavulanate potassium use by nursing mothers may lead to sensitization of infants. Caution should be exercised whenamoxicillin/ clavulanate potassium is administered to a nursing woman. 8.4 Pediatric Use The safety and effectiveness ofAmoxicillin and Clavulanate Potassium Powderfor Oral Suspension and ChewableTabletshave been established in pediatric patients. Use ofAmoxicillin and Clavulanate Potassium in pediatric patients is supported by evidence from studies ofAmoxicillinand Clavulanate PotassiumTabletsin adults with additional data from a study ofAmoxicillin and Clavulanate Potassium Powderfor 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 PotassiumTablets should be modified in pediatric patients aged 8.5 Geriatric Use Of the 3,119 patients in an analysis of clinical studies ofAmoxicillin and Clavulanate PotassiumTablets,32% were 65 years old, and 14% were 75 years old. No overall differences in safetyor 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 (2.3) for specific recommendations in patients with renal impairment.

REFERENCES SECTION.


15 REFERENCES Swanson-Biearman B, Dean BS, Lopez G, Krenzelok EP. The effects of penicillin andcephalosporin 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 DiskSusceptibility Tests;Approved Standard - 11th ed. CLSI Document M2-A11. CLSI, 940 West ValleyRoad, Suite 1400, Wayne, PA, 19087, 2012. CLSI.Performance Standards forAntimicrobial SusceptibilityTesting:22nd Informational Supplement. CLSI document M100-S22. CLSI, Wayne, PA, 2012.

INFORMATION FOR PATIENTS SECTION.


17 PATIENT COUNSELING INFORMATION 17.1 Information for Patients Patients should be informed thatAmoxicillin and Clavulanate PotassiumTabletsmay be taken every8 hours or every 12 hours, depending on the dose prescribed. Each dose should be taken with ameal or snack to reduce the possibility of gastrointestinal upset. Patients should be counseled that antibacterial drugs, includingAmoxicillin and Clavulanate PotassiumTabletsshould only be used to treat bacterial infections.They do not treat viral infections (e.g., the common cold). WhenAmoxicillin and Clavulanate PotassiumTabletsare prescribed to treat a bacterial infection, patients should be told that although it is common to feel better earlyin 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 byAmoxicillin and Clavulanate PotassiumTabletsor other antibacterial drugs in the future. Counsel patients that diarrhea is a common problem caused by antibacterials, and it usually ends whenthe antibacterial is discontinued. Sometimes after starting treatment with antibacterials, patients can develop watery and bloody stools (withor 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 awarethatAmoxicillin and Clavulanate PotassiumTabletscontain a penicillin class drug product that can cause allergic reactions in some individuals. Distributed by: West-Ward Pharmaceuticals Corp. Eatontown, NJ 07724 U.S.A. Manufactured by: HIKMA Pharmaceuticals P.O.Box 182400 Amman 11118 - Jordan RevisedOctober 2016

CLINICAL STUDIES SECTION.


14 CLINICAL STUDIES 14.1 Lower Respiratory Tract and Complicated Urinary Tract Infections Datafrom 2 pivotal trials in 1,191 patients treated for either lowerrespiratory tract infections or complicated urinary tract infections compared a regimen of 875-mg tablets ofAmoxicillin and Clavulanate Potassium every 12 hours to 500-mg tablets ofAmoxicillin 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.There was no significant difference in the percentage of adverse events in each group.The most frequently reported adverse eventwas 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 every 12 hours (n=308) or 500-mg tablets ofAmoxicillin and Clavulanate Potassium every 8 hours (n=321). The number of bacteriologically evaluable patients was comparable between the twodosing regimens.Amoxicillin and Clavulanate Potassium produced comparable bacteriological success rates in patients assessed 2 to 4 days immediately following end of therapy.The bacteriologic efficacy rates were comparable at 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 inTable 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 every12 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 otitismedia. Only the suspension formulations were used in this trial. A total of 575 pediatric patients(aged 2 months to 12 years) wereenrolled, 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.Theclinical 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:Atend oftherapy, 87% (n = 265) and 82% (n = 260) for 45 mg/kg/day every 12 hours and 40 mg/kg/day every8 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, thenumber 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.The presence of mannitol in the chewable tablets may contribute to a different diarrhea profile.The every 12 hour oral suspensions (200 mg/5 mLand 400 mg/5 mL) are sweetened with aspartame.

CLINICAL PHARMACOLOGY SECTION.


12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Amoxicillin and Clavulanate PotassiumTabletsare antibacterial drugs. [see Microbiology 12.4 ] 12.3 Pharmacokinetics Mean amoxicillin and clavulanate potassium pharmacokinetic parameters in normal adults following administration ofAmoxicillin and Clavulanate PotassiumTabletsare shown inTable1 and following administration ofAmoxicillin and Clavulanate Potassium Powderfor Oral Suspension and Chewable Tabletsare shown inTable2. Table 1: Mean (S.D.) Amoxicillin and Clavulanate Potassium Pharmacokinetic Parametersa,b with Amoxicillin and Clavulanate Potassium Tablets. Dose and Regimen Cmax (mcg/mL) AUC0-24 (mcg*h/mL) Amoxicillin/Clavulanate potassium Amoxicillin Clavulanate potassium Amoxicillin Clavulanate potassium 250/125 mg every 8 hours 3.3 1.12 1.5 0.70 26.7 4.56 12.6 3.25 500/125 mg every 12 hours 6.5 1.41 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 12.31 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 Pharmacokinetic Parametersa,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 mLof suspension) 6.94 1.24 1.10 0.42 17.29 2.28 2.34 0.94 400/57 mg (1 chewable tablet) 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 occurredapproximately 1 hour after the dose. b Amoxicillin/clavulanate potassium administered at the start of a light meal. Oral administration of 5 mLof 250 mg/5 mLsuspension ofAmoxicillin and Clavulanate Potassium or the equivalent dose of 10 mLof 125 mg/5 mLsuspension ofAmoxicillin and Clavulanate Potassium provides average peak serum concentrations approximately 1 hour after dosing of 6.9 mcg/mLfor amoxicillin and 1.6 mcg/mLfor clavulanic acid.The areas under the serum concentration curves obtained during the first 4 hours after dosing were 12.6 mcg*h/mLfor amoxicillin and 2.9 mcg*h/mL for clavulanic acid when 5 mLof 250 mg/5 mLsuspension ofAmoxicillin and Clavulanate Potassium or equivalent dose of 10 mLof 125 mg/5 mLsuspension ofAmoxicillin and Clavulanate Potassium were administered to normal adults. One 250-mg chewable tablet ofAmoxicillin and Clavulanate Potassium or two125-mg chewable tablets ofAmoxicillin and Clavulanate Potassium are equivalent to 5 mLof 250 mg/5 mLsuspension ofAmoxicillin and Clavulanate Potassium and provide similar serum concentrations of amoxicillin and clavulanic acid. Amoxicillin serum concentrations achieved withAmoxicillin and Clavulanate PotassiumTablets are similar to those produced by the oral administration of equivalent doses of amoxicillin alone. Timeabove the minimum inhibitory concentration of 1 mcg/mLfor amoxicillin has been shown to be similar after corresponding every 12 hour and every 8 hour dosing regimens ofAmoxicillin and Clavulanate PotassiumTabletsin adults and children. Absorption: Dosing in the fasted or fed state has minimal effect on the pharmacokinetics of amoxicillin. WhileAmoxicillin and Clavulanate PotassiumTabletscan be given without regard to meals, absorption of clavulanate potassium whentaken with food is greater relative to the fasted state. In one study, the relative bioavailability of clavulanate was reduced whenAmoxicillin and Clavulanate PotassiumTabletswas dosed at 30 and 150 minutes after the start of a high-fat breakfast. Distribution: Neither component inAmoxicillin and Clavulanate PotassiumTabletsare highly protein- bound; clavulanic acid is approximately 25% bound to human serum and amoxicillin approximately18% bound. Amoxicillin diffuses readily into most body tissues and fluids with the exception of the brain and spinal fluid. Twohours after oral administration of a single 35 mg/kg dose of suspension ofAmoxicillin and Clavulanate PotassiumTabletsto fasting children, average concentrations of 3 mcg/mLof amoxicillin and 0.5 mcg/mLof clavulanic acid were detected in middle ear effusions. Metabolism and Excretion:The half-life of amoxicillin after the oral administration ofAmoxicillin and Clavulanate PotassiumTabletsis 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 or500-mg tablet ofAmoxicillin and Clavulanate PotassiumTablets. 12.4 Microbiology 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 inAmoxicillin and Clavulanate PotassiumTablets 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 INDICATIONSANDUSAGE section. Gram-positive bacteria Staphylococcus aureus Gram-negative bacteria Enterobacter species Escherichia coli Haemophilus influenza e 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 bacteriahas 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. TheMICs should be determined using a standardized test method2,3 (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.The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds.The zone size should be determined using a standardized test method3,4.This procedure uses paper disks impregnatedwith 30 mcg amoxicillin/clavulanic acid (20 mcg amoxicillin plus 10 mcg clavulanic acid) to test thesusceptibility of bacteria to amoxicillin/clavulanic acid.The disc diffusion interpretive criteria are provided inTable3. 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 test2,3,4.Standard amoxicillin/clavulanic acid powdershould provide the following range of MIC values noted inTable 4 for the diffusion technique using the 30 mcg amoxicillin/clavulanic acid (20 mcg amoxicillin plus 10 mcg clavulanic acid) disk, the criteria inTable4 should be achieved. Table 4: Acceptable Quality Control Ranges for Amoxicillin/Clavulanic Acid QCStrain Minimum Inhibitory Concentration (mcg/mL) Disk Diffusion(zone diameter in mm) Escherichia coli ATCC25922 2/1 to 8/4 18 to 24 Escherichia coli ATCC 35218 4/2 to 16/8 17 to 22 Haemophilus influenzae ATCC 49247 2/1 to 16/8 15 to 23 Staphylococcus aureus ATCC 29213 0.12/0.06 to 0.5/0.25 - Staphylococcus aureus ATCC 29523 - 28 to 36