AMOXICILLIN AND CLAVULANATE POTASSIUM tablet, film coated

AMOXICILLIN AND CLAVULANATE POTASSIUM by

Drug Labeling and Warnings

AMOXICILLIN AND CLAVULANATE POTASSIUM by is a Prescription medication manufactured, distributed, or labeled by Medsource Pharmaceuticals, Micro Labs Limited. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

  • 1 INDICATIONS AND USAGE

    Amoxicillin and clavulanate potassium tablets are indicated for the treatment of infections in adults and pediatric patients, due to susceptible isolates of the designated bacteria in the conditions listed below:

    Lower Respiratory Tract Infections- caused by beta‑lactamase‑producing isolates of Haemophilus influenzaeand Moraxella catarrhalis.
    Acute Bacterial Otitis Media- caused by beta‑lactamase‑producing isolates of H. influenzaeand M. catarrhalis.
    Sinusitis- caused by beta‑lactamase‑producing isolates of H. influenzaeand M. catarrhalis.
    Skin and Skin Structure Infections- caused by beta‑lactamase‑producing isolates of Staphylococcus aureus, Escherichia coliand Klebsiellaspecies.
    Urinary Tract Infections- caused by beta‑lactamase‑producing isolates of E. coli, Klebsiellaspecies, and Enterobacterspecies.
    Limitations of Use
    When susceptibility test results show susceptibility to amoxicillin, indicating no beta-lactamase production, amoxicillin and clavulanate potassium tablets should not be used.
    Usage
    To reduce the development of drug‑resistant bacteria and maintain the effectiveness of amoxicillin and clavulanate potassium tablets and other antibacterial drugs, amoxicillin and clavulanate potassium tablets should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

  • 2 DOSAGE AND ADMINISTRATION

    2.1 Important Administration Instructions

    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 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.

    2.2 Adult Patients

    See dosing regimens of amoxicillin and clavulanate potassium (based on the amoxicillin component) provided in Table 1 below.
    Table 1. Dosing Regimens of Amoxicillin and Clavulanate Potassium in Adult Patients

     

    TYPE OF INFECTION
    		DOSING REGIMEN OFAMOXICILLIN AND CLAVULANATE POTASSIUM
    Severe infections and infections of the respiratory tract
    		one 875 mg tablet aof amoxicillin and clavulanate potassium every 12 hours
    or
    one 500 mg tablet b,cof amoxicillin and clavulanate potassium every 8 hours
    Less severe infections
    		one 500 mg tablet b,cof amoxicillin and clavulanate potassium every 12 hours
    or
    one 250 mg tablet dof amoxicillin and clavulanate potassium every 8 hours

    a   Adults who have difficulty swallowing may be given the amoxicillin and clavulanate potassium 200 mg/28.5 mg per 5 mL suspension or the amoxicillin and clavulanate potassium 400 mg/57 mg per 5 mL suspension may be used in place of the 875 mg/125 mg tablet.

    b  Adults who have difficulty swallowing may be given the amoxicillin and clavulanate potassium 125 mg/31.25 mg per 5 mL suspension or amoxicillin and clavulanate potassium 250 mg/62.5 mg per 5 mL suspension in place of the 500 mg/125 mg tablet.

    c  Two amoxicillin and clavulanate potassium 250 mg/125 mg tablets are NOT substitutable with one 500 mg/125 mg amoxicillin and clavulanate potassium tablet [see Dosage and Administration ( 2.6)] .

    d  Amoxicillin and clavulanate potassium 250 mg/125 mg tablet is NOT substitutable with amoxicillin and clavulanate potassium 250 mg/62.5 mg chewable tablet [see Dosage and Administration ( 2.6)] . 

    2.3 Pediatric Patients

    Based on the amoxicillin component, amoxicillin and clavulanate potassium should be dosed as follows:
    Neonates and Infants Aged less than 12 weeks (less than 3 months):See dosing regimens of amoxicillin and clavulanate potassium provided in Table 2 below.
    Table 2: Dosing Regimens of Amoxicillin and Clavulanate Potassium in Neonates and Infants Aged Less than 12 Weeks (Less than 3 Months)

     

    PATIENT POPULATION
    		DOSING REGIMEN
    Amoxicillin and Clavulanate Potassium 125 mg/31.25 mg per 5 mL for oral suspensiona
    Neonates and Infants aged less than 12 weeks (less than 3 months)
    		30 mg/kg/day every 12 hours

    a  Experience with the amoxicillin and clavulanate potassium for oral suspension 200 mg/28.5 mg per 5 mL formulation in this age group is limited, and thus, use of the amoxicillin and clavulanate potassium 125 mg/31.25 mg per 5 mL for oral suspension is recommended.


    Patients Aged 12 weeks (3 months) and Older and Weighing Less than 40 kg:See dosing regimens provided in Table 3 below.

      The every 12 hour regimen is recommended as it is associated with significantly less diarrhea [see Clinical Studies ( 14.2)] .  Table 3: Dosing in Patients Aged 12 Weeks (3 Months) and Older and Weighing Less than 40 kg

     

    INFECTION
    		DOSING REGIMEN
    Every 12 hours
    		Every 8 hours
    Amoxicillin and clavulanate potassium for oral suspension 200 mg/28.5 mg per 5 mL
    or
    Amoxicillin and clavulanate potassium 400 mg/57 mg per 5 mL for oral suspension a
    		Amoxicillin and clavulanate potassium for oral suspension 125 mg/31.25 mg per 5 mL
    or
    Amoxicillin and clavulanate potassium 250 mg/62.5 mg per 5 mL for oral suspension a
    Otitis media b, sinusitis, lower respiratory tract infections, and more severe infections
    		45 mg/kg/day every 12 hours
    		40 mg/kg/day every 8 hours
    Less severe infections
    		25 mg/kg/day every 12 hours
    		20 mg/kg/day every 8 hours

    a  Each strength of amoxicillin and clavulanate potassium for oral suspension is available as a chewable tablet for use by older children.

    b  Duration of therapy studied and recommended for acute otitis media is 10 days.


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

      The 250 mg/125 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/125 mg tablet of amoxicillin and clavulanate potassium versus the 250 mg/62.5 mg chewable tablet of amoxicillin and clavulanate potassium.  

    2.4 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 (GFR) of less than 30 mL/min should NOT receive the 875 mg dose (based on the amoxicillin component) of amoxicillin and clavulanate potassium tablet. See dosing regimens in patients with severe renal impairment provided in Table 4.
    Table 4. Dosing Regimens of Amoxicillin and Clavulanate Potassium in Patients with Severe Renal Impairment

     

    Patients with Renal Impairment
    		Dosing Regimen
    GFR 10 mL/min to 30 mL/min
    		500 mg or 250 mg every 12 hours, depending on the severity of the infection
    GFR less than 10 mL/min
    		500 mg or 250 mg every 24 hours, depending on severity of the infection
    Hemodialysis
    		500 mg or 250 mg every 24 hours, depending on severity of the infection
     
    Administer an additional dose both during and at the end of dialysis

    2.6 Switching between Dosage Forms and between Strengths

    Amoxicillin and Clavulanate Potassium 250 mg/125 mg Tablet is NOT Substitutable with Amoxicillin and Clavulanate Potassium 250 mg/62.5 mg Chewable Tablet

    The 250 mg/125 mg tablet of amoxicillin and clavulanate potassium and the 250 mg/62.5 mg chewable tablet of amoxicillin and clavulanate potassium should NOT be substituted for each other and the 250 mg/125 mg tablet of amoxicillin and clavulanate potassium should NOT be used in pediatric patients weighing less than 40 kg [see Dosage and Administration ( 2.3)]. The 250 mg/125 mg tablet of amoxicillin and clavulanate potassium and the 250 mg/62.5 mg chewable tablet of amoxicillin and clavulanate potassium do not contain the same amount of clavulanic acid. The 250 mg/125 mg tablet of amoxicillin and clavulanate potassium contains 125 mg of clavulanic acid whereas the 250 mg/62.5 mg chewable tablet of amoxicillin and clavulanate potassium contains 62.5 mg of clavulanic acid.

    Two Amoxicillin and Clavulanate Potassium 250 mg/125 mg Tablets are NOT Substitutable with One 500 mg/125 mg Amoxicillin and Clavulanate Potassium Tablet

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

  • 3 DOSAGE FORMS AND STRENGTHS

    Amoxicillin and Clavulanate Potassium Tablets, USP:

     

    • 250 mg/125 mg Tablets:White to off-white colored, capsule shaped, biconvex, film-coated tablets, debossed with “I 05” on one side and plain on the other side. Each tablet contains 250 mg of amoxicillin as the trihydrate and 125 mg clavulanic acid as the potassium salt.
    • 500 mg/125 mg Tablets:White to off-white colored, capsule shaped, biconvex, film-coated tablets debossed with “I 06” on one side and plain on the other side. Each tablet contains 500 mg amoxicillin as the trihydrate and 125 mg clavulanic acid as the potassium salt.
    • 875 mg/125 mg Tablets:  White to off-white colored, capsule shaped, biconvex, film-coated tablets debossed with “I 07” on one side and score line on the other side. Each tablet contains 875 mg amoxicillin as the trihydrate and 125 mg clavulanic acid as the potassium salt.

  • 4 CONTRAINDICATIONS

    4.1 Serious Hypersensitivity Reactions

    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).

    4.2 Cholestatic Jaundice/Hepatic Dysfunction

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

  • 5 WARNINGS AND PRECAUTIONS

    5.1 Hypersensitivity Reactions


    Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving beta-lactam antibacterials, including amoxicillin and clavulanate potassium. 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, careful inquiry should be made regarding previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens. If an allergic reaction occurs, amoxicillin and clavulanate potassium should be discontinued, and appropriate therapy instituted.

    5.2 Severe Cutaneous Adverse Reactions


    Amoxicillin and clavulanate potassium may cause severe cutaneous adverse reactions (SCAR), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP). If patients develop a skin rash, they should be monitored closely, and amoxicillin and clavulanate potassium discontinued if lesions progress.

    5.3 Drug-Induced Enterocolitis Syndrome (DIES)


    Drug-induced enterocolitis syndrome (DIES) has been reported with amoxicillin use [see Adverse Reactions ( 6.2)] , with most cases occurring in pediatric patients ≤18 years of age. DIES is a non-IgE mediated hypersensitivity reaction characterized by protracted vomiting occurring 1 to 4 hours after drug ingestion in the absence of skin or respiratory symptoms. DIES may be associated with pallor, lethargy, hypotension, shock, diarrhea within 24 hours after ingesting amoxicillin, and leukocytosis with neutrophilia. If DIES occurs, discontinue amoxicillin and clavulanate potassium and institute appropriate therapy.

    5.4 Hepatic Dysfunction


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

    5.5 Clostridioides difficileAssociated Diarrhea (CDAD)


    Clostridioides difficileassociated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including amoxicillin and clavulanate potassium, 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. difficileproduces toxins A and B which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficilecause 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. difficilemay 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.


    5.6 Skin Rash in Patients with Mononucleosis


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

    5.7 Potential for Microbial Overgrowth


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

    5.8 Development of Drug-Resistant Bacteria


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

  • 6 ADVERSE REACTIONS

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

    • Anaphylactic reactions [see Warnings and Precautions ( 5.1)]
    • Severe Cutaneous Adverse Reactions [see Warnings and Precautions ( 5.2)]
    • Drug-Induced Enterocolitis Syndrome (DIES) [see Warnings and Precautions ( 5.3)] 
    • Hepatic Dysfunction [see Warnings and Precautions ( 5.4)]
    • Clostridioides difficileAssociated Diarrhea (CDAD) [see Warnings and Precautions ( 5.5)]

    6.1 Clinical Trial 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 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 (less than 1%) include: Abdominal discomfort, flatulence, and headache.


    In pediatric patients (aged 2 months to 12 years), 1 US/Canadian clinical trial was conducted which compared 45/6.4 mg/kg/day (divided every 12 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 otitis media. A total of 575 patients were enrolled, and only the suspension formulations were used in this trial. Overall, the adverse reactions seen were comparable to that noted above; however, there were differences in the rates of diarrhea, skin rashes/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 of amoxicillin and clavulanate potassium. 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.


    Gastrointestinal:Indigestion, gastritis, stomatitis, glossitis, Drug-induced enterocolitis syndrome (DIES), black “hairy” tongue, mucocutaneous candidiasis, enterocolitis, and hemorrhagic/pseudomembranous colitis. Onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment [see Warnings and Precautions ( 5.5)].


    Immune:Hypersensitivity reactions, anaphylactic/anaphylactoid reactions (including shock), angioedema, serum sickness-like reactions (urticaria or skin rash accompanied by arthritis, arthralgia, myalgia, and frequently fever), hypersensitivity vasculitis [see Warnings and Precautions ( 5.1)].


    Skin and Appendages:Rashes, pruritus, urticaria, erythema multiforme, SJS, TEN, DRESS, AGEP, exfoliative dermatitis and linear IgA bullous dermatosis.


    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. 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 ( 5.4)] .


    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. There have been reports of increased prothrombin time in patients receiving amoxicillin and clavulanate potassium and anticoagulant therapy concomitantly [see Drug Interactions ( 7.2)] .


    Central Nervous System:Agitation, anxiety, behavioral changes, aseptic meningitis, 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.

  • 7 DRUG INTERACTIONS

    7.1 Probenecid

    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. Co-administration 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 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.

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

    7.4 Oral Contraceptives

    Amoxicillin and clavulanate potassium may 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 ®, 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.

  • 8 USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy

    Teratogenic Effects:Reproduction studies performed in pregnant rats and mice given amoxicillin and clavulanate potassium (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. 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.

    8.2 Labor and Delivery

    Oral ampicillin‑class antibacterials are poorly absorbed during labor. It is not known whether use of amoxicillin and 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 and clavulanate potassium use by nursing mothers may lead to sensitization of infants. Caution should be exercised when amoxicillin and clavulanate potassium is administered to a nursing woman.

    8.4 Pediatric Use

    The safety and effectiveness of amoxicillin and clavulanate potassium for oral suspension and chewable tablets have been established in pediatric patients. Use of amoxicillin and clavulanate potassium 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 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 should be modified in pediatric patients aged less than 12 weeks (less than 3 months) [see Dosage and Administration ( 2.3)] .

    8.5 Geriatric Use

    Of the 3,119 patients in an analysis of clinical studies of amoxicillin and clavulanate potassium, 32% were greater than or equal to 65 years old, and 14% were greater than or equal to 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.

    8.6 Renal Impairment

    Amoxicillin is primarily eliminated by the kidney and dosage adjustment is usually required in patients with severe renal impairment (GFR less than 30 mL/min). See Patients with Renal Impairment [see Dosage and Administration ( 2.4)] for specific recommendations in patients with renal impairment.

  • 10 OVERDOSAGE

    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 symptoms 1.


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


    Crystalluria, in some cases leading to renal failure, has also been reported after amoxicillin and 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 and 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 and clavulanate potassium. Amoxicillin and clavulanate potassium may be removed from circulation by hemodialysis [see Dosage and Administration ( 2.4)] .


  • 11 DESCRIPTION

    Amoxicillin and clavulanate potassium tablets, USP is an oral antibacterial combination consisting of amoxicillin and the beta‑lactamase inhibitor, clavulanate potassium (the potassium salt of clavulanic acid).


    Amoxicillin, USP is an analog of ampicillin, derived from the basic penicillin nucleus, 6‑aminopenicillanic acid. The amoxicillin molecular formula is C 16H 19N 3O 5S3H 2O, and the molecular weight is 419.46. Chemically, amoxicillin, USP 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:

     

    amoxi-stra.jpg


    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 is C 8H 8KNO 5, and the molecular weight is 237.25. Chemically, clavulanate potassium, USP 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:


    amoxi-strb.jpg

    Amoxicillin and Clavulanate Potassium Tablets, USP:

    • 250 mg/125 mg: Each tablet contains 250 mg of amoxicillin, USP as the trihydrate, and 125 mg of clavulanic acid (equivalent to 149 mg of clavulanate potassium, USP).
    • 500 mg/125 mg:Each tablet contains 500 mg of amoxicillin, USP as the trihydrate, and 125 mg of clavulanic acid (equivalent to 149 mg of clavulanate potassium, USP).
    • 875 mg/125 mg:Each tablet contains 875 mg of amoxicillin, USP as the trihydrate, and 125 mg of clavulanic acid (equivalent to 149 mg of clavulanate potassium, USP).  

    Inactive Ingredients:colloidal silicon dioxide, ethylcellulose, hypromellose, magnesium stearate, microcrystalline cellulose, propylene glycol, sodium starch glycolate, talc and titanium dioxide.


    Each tablet of amoxicillin and clavulanate potassium tablets contains 0.63 mEq potassium.

  • 12 CLINICAL PHARMACOLOGY

    12.1 Mechanism of Action

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

    12.3 Pharmacokinetics

    Mean amoxicillin and clavulanate potassium pharmacokinetic parameters in normal adults following administration of amoxicillin and clavulanate potassium tablets are shown in Table 6 and following administration of amoxicillin and clavulanate potassium for oral suspension and chewable tablets are shown in Table 7.


    Table 6: Mean (±S.D.) Amoxicillin and Clavulanate Potassium Pharmacokinetic Parameters a,bwith Amoxicillin and Clavulanate PotassiumTablets

     

    Dose and Regimen of Amoxicillin and Clavulanate Potassium
    		C max(mcg/mL)
    		AUC 0 to 24(mcg*h/mL)
    Amoxicillin and Clavulanate potassium
    		Amoxicillin
    		Clavulanate potassium
    		Amoxicillin
    		Clavulanate potassium
    250 mg/125 mg every 8 hours
    		3.3 ± 1.12
    		1.5 ± 0.70
    		26.7 ± 4.56
    		12.6 ± 3.25
    500 mg/125 mg every 12 hours
    		6.5 ± 1.41
    		1.8 ± 0.61
    		33.4 ± 6.76
    		8.6 ± 1.95
    500 mg/125 mg every 8 hours
    		7.2 ± 2.26
    		2.4 ± 0.83
    		53.4 ± 8.87
    		15.7 ± 3.86
    875 mg/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 equals 15 for clavulanate potassium in the low-dose regimens). Peak concentrations occurred approximately 1.5 hours after the dose.

    b  Amoxicillin and clavulanate potassium administered at the start of a light meal.


    Table 7: Mean (±S.D.) Amoxicillin and Clavulanate Potassium Pharmacokinetic Parameters a,bwith Amoxicillin and Clavulanate Potassium for Oral Suspension and Chewable Tablets

     

    Dose of Amoxicillin and Clavulanate Potassium
    		C max(mcg/mL)
    		AUC 0 to 24(mcg*h/mL)
    Amoxicillin and Clavulanate potassium
    		Amoxicillin
    		Clavulanate potassium
    		Amoxicillin
    		Clavulanate potassium
    400 mg/57 mg (5 mL of suspension)
    		6.94 ± 1.24
    		1.10 ± 0.42
    		17.29 ± 2.28
    		2.34 ± 0.94
    400 mg/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 occurred approximately 1 hour after the dose.

    b  Amoxicillin and clavulanate potassium administered at the start of a light meal.


    Oral administration of 5 mL of the 250 mg/62.5 mg suspension of amoxicillin and clavulanate potassium or the equivalent dose of 10 mL of the 125 mg/31.25 mg suspension of amoxicillin and clavulanate potassium provides average peak serum concentrations approximately 1 hour after dosing of 6.9 mcg/mL for amoxicillin and 1.6 mcg/mL for clavulanic acid. The areas under the serum concentration curves obtained during the first 4 hours after dosing were 12.6 mcg*h/mL for amoxicillin and 2.9 mcg*h/mL for clavulanic acid when 5 mL of the 250 mg/62.5 mg suspension of amoxicillin and clavulanate potassium or equivalent dose of 10 mL of the 125 mg/31.25 mg suspension of amoxicillin and clavulanate potassium were administered to normal adults. One 250 mg/62.5 mg chewable tablet of amoxicillin and clavulanate potassium or two 125 mg/31.25 mg chewable tablets of amoxicillin and clavulanate potassium are equivalent to 5 mL of the 250 mg/62.5 mg suspension of amoxicillin and clavulanate potassium and provide similar serum concentrations of amoxicillin and clavulanic acid.


    Amoxicillin serum concentrations achieved with amoxicillin and clavulanate potassium tablet 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 tablet 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.


    Two hours after oral administration of a single 35 mg/kg dose of suspension of amoxicillin and clavulanate potassium to fasting children, average concentrations of 3 mcg/mL of amoxicillin and 0.5 mcg/mL of clavulanic acid were detected in middle ear effusions.


    Metabolism and Excretion:The half‑life of amoxicillin after the oral administration of amoxicillin and clavulanate potassium tablet 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/125 mg or 500 mg/125 mg tablet of amoxicillin and clavulanate potassium.

    12.4 Microbiology

    Amoxicillin is a semisynthetic antibacterial with in vitrobactericidal 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 antibacterial spectrum of amoxicillin to include many bacteria normally resistant to amoxicillin.


    Amoxicillin and clavulanic acid has been shown to be active against most isolates of the following bacteria, both in vitroand in clinical infections [see Indications and Usage ( 1)] .


    Gram-positive bacteria

    Staphylococcus aureus


    Gram-negative bacteria

    Enterobacterspecies  

    Escherichia coli

    Haemophilus influenzae

    Klebsiellaspecies

    Moraxella catarrhalis


    The following in vitrodata are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitrominimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for amoxicillin and clavulanic acid. However, the efficacy of amoxicillin and clavulanic acid in treating clinical infections due to these bacteria has not beenestablished 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

    Bacteroidesspecies  including Bacteroides fragilis

    Fusobacteriumspecies

    Peptostreptococcusspecies


    Susceptibility Test Methods

    For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

  • 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 potassium (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 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 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 (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.

  • 14 CLINICAL STUDIES

    14.1 Lower Respiratory Tract and Complicated Urinary Tract Infections

    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/125 mg tablets of amoxicillin and clavulanate potassium every 12 hours to 500 mg/125 mg tablets of amoxicillin 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 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 less than 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 equals 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 equals 268) were randomized (1:1) to receive either 875 mg/125 mg tablets of amoxicillin and clavulanate potassium every 12 hours (n equals 308) or 500 mg/125 mg tablets of amoxicillin and clavulanate potassium every 8 hours (n equals 321).


    The number of bacteriologically evaluable patients was comparable between the two dosing 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 in Table 8.


    Table 8: Bacteriologic Efficacy Rates for Amoxicillin and Clavulanate Potassium

     

    Time 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 every 12 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 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., greater than or equal to 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 equals 265) and 82% (n equals 260) for 45 mg/kg/day every 12 hours and 40 mg/kg/day every 8 hours, respectively. At follow‑up, 67% (n equals 249) and 69% (n equals 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.


    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 of amoxicillin and clavulanate potassium, can be extrapolated to the chewable tablets of amoxicillin and clavulanate potassium. The presence of mannitol in the chewable tablets of amoxicillin and clavulanate potassium may contribute to a different diarrhea profile.

  • 15 REFERENCES

    1. 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.

  • 16 HOW SUPPLIED/STORAGE AND HANDLING

    Amoxicillin and Clavulanate Potassium Tablets, USP:

     

    250 mg/125 mg Tablets:  White to off-white colored, capsule shaped, biconvex, film-coated tablets, debossed with “I 05” on one side and plain on the other side. Each tablet contains 250 mg of amoxicillin as the trihydrate and 125 mg of clavulanic acid as the potassium salt (equivalent to 149 mg of clavulanate potassium).



    Bottles of 30:                                                  NDC: 42571-160-30

    Bottles of 100:                                                NDC: 42571-160-01

    Carton of 100 (10x10 unit-dose tablets):        NDC: 42571-160-11


    500 mg/125 mg Tablets:  White to off-white colored, capsule shaped, biconvex, film-coated tablets debossed with “I 06” on one side and plain on the other side. Each tablet contains 500 mg of amoxicillin as the trihydrate and 125 mg of clavulanic acid as the potassium salt (equivalent to 149 mg of clavulanate potassium).


    Bottles of 20:                                                  NDC: 42571-161-42

    Bottles of 100:                                                NDC: 42571-161-01

    Carton of 100 (10x10 unit-dose tablets):        NDC: 42571-161-11


    875 mg/125 mg Tablets:  White to off-white colored, capsule shaped, biconvex, film-coated tablets debossed with “I 07” on one side and score line on the other side. Each tablet contains 875 mg of amoxicillin as the trihydrate and 125 mg of clavulanic acid as the potassium salt (equivalent to 149 mg of clavulanate potassium).


    Bottles of 20:                                                  NDC: 42571-162-42

    Bottles of 100:                                                NDC: 42571-162-01

    Carton of 40 (4x10 unit-dose tablets):            NDC: 42571-162-44


    Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Dispense in original container. Advise patients to keep in closed container.


    Keep out of the reach of children.

  • 17 PATIENT COUNSELING INFORMATION

    Administration Instructions

    Inform patients 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


    Allergic Reactions

    Counsel patients that amoxicillin and clavulanate potassium tablets contains a penicillin class drug product that can cause allergic reactions in some individuals.


     

    Severe Cutaneous Adverse Reactions (SCAR)

    Advise patients about the signs and symptoms of serious skin manifestations. Instruct patients to stop taking amoxicillin and clavulanate potassium tablets immediately and promptly report the first signs or symptoms of skin rash, mucosal lesions, or any other sign of hypersensitivity [see Warnings and Precautions ( 5.2)] .


    Diarrhea

    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 as soon as possible.


    Antibacterial Resistance

    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.


    CLINITEST ®is a registered trademark of Miles, Inc.


    Manufactured by:
    Micro Labs Limited
    Bangalore-560 100, INDIA.


    Manufactured for:
    Micro Labs USA, Inc.
    Somerset, NJ 08873


    Rev. 01/2024 

  • Bottle of 20

    227

  • INGREDIENTS AND APPEARANCE
    AMOXICILLIN AND CLAVULANATE POTASSIUM 
    amoxicillin and clavulanate potassium tablet, film coated
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 45865-227(NDC:42571-162)
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    AMOXICILLIN (UNII: 804826J2HU) (AMOXICILLIN ANHYDROUS - UNII:9EM05410Q9) AMOXICILLIN ANHYDROUS875 mg
    CLAVULANATE POTASSIUM (UNII: Q42OMW3AT8) (CLAVULANIC ACID - UNII:23521W1S24) CLAVULANIC ACID125 mg
    Inactive Ingredients
    Ingredient NameStrength
    SILICON DIOXIDE (UNII: ETJ7Z6XBU4)  
    HYPROMELLOSE 2910 (5 MPA.S) (UNII: R75537T0T4)  
    MAGNESIUM STEARATE (UNII: 70097M6I30)  
    MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U)  
    PROPYLENE GLYCOL (UNII: 6DC9Q167V3)  
    SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2)  
    TITANIUM DIOXIDE (UNII: 15FIX9V2JP)  
    ETHYLCELLULOSE (10 MPA.S) (UNII: 3DYK7UYZ62)  
    TALC (UNII: 7SEV7J4R1U)  
    Product Characteristics
    Colorwhite (white to off-white) Score2 pieces
    ShapeCAPSULE (biconvex) Size22mm
    FlavorImprint Code I07
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 45865-227-2020 in 1 BOTTLE; Type 0: Not a Combination Product11/08/2022
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA20475503/01/2017
    Labeler - Medsource Pharmaceuticals (833685915)
    Establishment
    NameAddressID/FEIBusiness Operations
    Micro Labs Limited867064609analysis(45865-227) , label(45865-227) , manufacture(45865-227) , pack(45865-227)
    Establishment
    NameAddressID/FEIBusiness Operations
    Medsource Pharmaceuticals833685915relabel(45865-227)
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