Amoxicillin and Clavulanate Potassium (amoxicillin 250 mg clavulanate potassium 125 mg) Dailymed
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Recent Major Changes
Warnings and Precautions, Drug-Induced Enterocolitis Syndrome (DIES) (5.3 ) 5/2024
1
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 uled below:
- Lower Respiratory Tract Infections - caused by beta-lactamase–producing isolates of Haemophilus influenzae and Moraxella catarrhalis.
- Acute Bacterial Otitis Media - caused by beta-lactamase–producing isolates of H. influenzae and M. catarrhalis.
- Sinusitis - caused by beta-lactamase–producing isolates of H. influenzae and M. catarrhalis.
Skin and Skin Structure Infections - caused by beta-lactamase–producing isolates of Staphylococcus aureus, Escherichia coli, and Klebsiella species. - Urinary Tract Infections - caused by beta-lactamase–producing isolates of E. coli, Klebsiella species, and Enterobacter species.
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.
Amoxicillin and clavulanate potassium tablets are a combination of amoxicillin, a penicillin-class antibacterial and clavulanate potassium, a beta-lactamase inhibitor indicated for treatment of the following infections in adults and pediatric patients (1 ):
- Lower respiratory tract infections
- Acute bacterial otitis media
- Sinusitis
- Skin and skin structure infections
- Urinary tract infections
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. (1 )
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 bacteria. (1 )
Dosage & Administration Section
Amoxicillin and clavulanate potassium tablets may be taken without regard to meals; however, absorption of clavulanate potassium is enhanced when amoxicillin and clavulanate potassium tablets, USP are administered at the start of a meal. To minimize the potential for gastrointestinal intolerance, amoxicillin and clavulanate potassium tablets should be taken at the start of a meal.
Adults and Pediatric Patients greater than 40 kg: 500 or 875 mg every 12 hours or 250 or 500 mg every 8 hours, based on amoxicillin component. (2.2 ,2.3 )
Pediatric patients aged 12 weeks (3 months) and older: 25 to 45 mg/kg/day every 12 hours or 20 to 40 mg/kg/day every 8 hours, up to the adult dose. (2.3 )
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
See dosing regiments of amoxicillin and clavulanate potassium tablets (based on the amoxicillin component) provided in Table 1 below.
Table 1. Dosing Regimens of Amoxicillin and Clavulanate Potassium Tablets in Adult Patients
TYPE OF INFECTION DOSING REGIMEN OF AMOXICILLIN AND CLAVULANATE POTASSIUM TABLETS Severe infections and infections of the respiratory tract One 875 mg tableta of amoxicillin and clavulanate every 12 hours or One 500 mg tabletb,c of amoxicillin and clavulanate every 8 hours Less severe infections One 500 mg tabletb,c of amoxicillin and clavulanate every 12 hours or one 250 mg tabletd of amoxicillin and clavulanate every 8 hours
aAdults 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.
bAdults who have difficulty swallowing may be given the amoxicillin and clavulanate potassium 125 mg/31.25 mg per 5 mL or amoxicillin and clavulanate potassium 250 mg/62.5 mg per 5 mL suspension in place of the 500 mg/125 mg tablet.
cTwo 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)].
2.3Pediatric Patients
Based on the amoxicillin component, amoxicillin and clavulanate potassium tablets 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 tablets provided in Table 2 below:
Table 2: Dosing Regimens of Amoxicillin and Clavulanate Potassium Tablets in Neonates and Infants Aged Less than 12 Weeks (Less than 3 Months)
PATIENT POPULATION DOSING REGIMEN Amoxicillin and Clavulanate Potassium Tablets 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
aExperience with amoxicillin and clavulanate potassium tablets 200 mg/28.5 mg per 5 mL formulation in this age group is limited, and thus, use of the amoxicillin and clavulanate potassium tablets 125 mg/31.25 mg per 5 mL for oral suspension is recommended.
Patients Weighing 40 kg or More
Pediatric patients weighing 40 kg or more should be dosed according to adult recommendations.
The 250-mg/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 tablets. See dosing regimens in patients with severe renal impairment provided in Table 4.
Table 4. Dosing Regimens of Amoxicillin and Clavulanate Potassium Tablets 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 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 tablet of amoxicillin and clavulanate potassium and the 250 mg chewable tablet of amoxicillin and clavulanate potassium do not contain the same amount of clavulanic acid. The 250 mg tablet of amoxicillin and clavulanate potassium contains 125 mg of clavulanic acid whereas the 250 mg chewable tablet of amoxicillin and clavulanate potassium contains 62.5 mg of clavulanic acid.
Two Amoxicillin and Clavulanate Potassium 250 mg/125 mg Tablets areNOT 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 and 500 mg tablets of amoxicillin and clavulanate potassium contain the same amount of clavulanic acid (125 mg, as the potassium salt), two 250 mg tablets of amoxicillin and clavulanate potassium are not equivalent to one 500 mg tablet of amoxicillin and clavulanate potassium.
3 Dosage Forms And Strengths
- 250-mg/125-mg Tablets: white, oval, biconvex, film-coated tablets, engraved “APO” on one side, “250-125” on the other, contains 250 mg of amoxicillin as the trihydrate and 125 mg of clavulanic acid as the potassium salt.
- 500-mg/125-mg Tablets: white, oval, biconvex, film-coated tablets, engraved “APO” on one side, “500-125” on the other, contains 500 mg of amoxicillin as the trihydrate and 125 mg of clavulanic acid as the potassium salt.
- 875-mg/125-mg Tablets: white, capsule-shaped, biconvex, film-coated tablets, engraved “APO” on one side, engraved “A” bisect “C” on the other, contains 875 mg of amoxicillin as the trihydrate and 125 mg of clavulanic acid as the potassium salt.
Tablets: 250 mg/125 mg, 500 mg/125 mg and 875 mg/125 mg tablets are scored (3 ).
4 Contraindications
History of a serious hypersensitivity reaction (e.g., anaphylaxis or Stevens-Johnson syndrome) to amoxicillin and clavulanate potassium tablets or to other beta-lactams (e.g., penicillins or cephalosporins) (4.1 )
History of cholestatic jaundice/hepatic dysfunction associated with amoxicillin and clavulanate potassium tablets. (4.2 )
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).
4.2Cholestatic 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 tablets.
5 Warnings And Precautions
- Serious (including fatal) hypersensitivity reactions: Discontinue amoxicillin and clavulanate potassium tablets if a reaction occurs. (
5.1 )- Severe Cutaneous Adverse Reactions (SCAR): Monitor closely. Discontinue if rash progresses. (
5.2 )- Drug-induced enterocolitis syndrome (DIES) has been reported with amoxicillin, a component of amoxicillin and clavulanate potassium tablets. If this occurs, discontinue amoxicillin and clavulanate potassium tablets and institute appropriate therapy. (
5.3 )- Hepatic dysfunction and cholestatic jaundice: Discontinue if signs/symptoms of hepatitis occur. Monitor liver function tests in patients with hepatic impairment. (
5.4 )- Clostridioides difficile-associated diarrhea (CDAD): Evaluate patients if diarrhea occurs. (
5.5 )- Patients with mononucleosis who receive amoxicillin and clavulanate potassium tablets develop skin rash. Avoid amoxicillin and clavulanate potassium tablets use in these patients. (
5.6 )- Overgrowth: The possibility of superinfections with fungal or bacterial pathogens should be considered during therapy. (
5.7 )5.1Hypersensitivity Reactions
Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving beta-lactam antibacterials, including amoxicillin and clavulanate potassium tablets. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and/or a history of sensitivity to multiple allergens. Before initiating therapy with amoxicillin and clavulanate potassium tablets, careful inquiry should be made regarding previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens. If an allergic reaction occurs, amoxicillin and clavulanate potassium tablets should be discontinued and appropriate therapy instituted.
5.2
Amoxicillin and clavulanate potassium tablets 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 tablets discontinued if lesions progress.
5.3 Drug-Induced Enterocolitis Syndrome (DIES)
Drug-induced enterocolitis syndrome (DIES) has been reported with use of amoxicillin, a component of amoxicillin and clavuklanate potassium tablets [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 absemce of skin or respiratory symptoms. DIES may be associated with pallor, lethargy, hypotension, shock, diarrhea within 24 hours of ingesting amoxicillin, and leukocytosis with neutrophilia. If DIES occurs, discontinue amoxicillin and clavulanate potassium tablets and institute appropriate therapy.
5.4 HepaticDysfunction
Hepatic dysfunction, including hepatitis and cholestatic jaundice has been associated with the use of amoxicillin and clavulanate potassium tablets. Hepatic toxicity is usually reversible; however, deaths have been reported. Hepatic function should be monitored at regular intervals in patients with hepatic impairment.
5.5
Clostridioides difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including amoxicillin and clavulanate potassium tablets, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.
C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin -producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary since CDAD has been reported to occur over 2 months after the administration of antibacterial agents.
If CDAD is suspected or confirmed, ongoing antibacterial use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
5.6 SkinRashinPatients withMononucleosis
A high percentage of patients with mononucleosis who receive amoxicillin develop an erythematous skin rash. Thus, amoxicillin and clavulanate potassium tablets should not be administered to patients with mononucleosis.
5.7 Potentialfor 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.
5.9 Development of Drug-Resistant Bacteria
Prescribing amoxicillin and clavulanate potassium tablets in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
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 difficile Associated Diarrhea (CDAD) [see Warnings and Precautions (5.5)]
The most frequently reported adverse reactions were diarrhea/loose stools (9%), nausea (3%), skin rashes and urticaria (3%), vomiting (1%) and vaginitis (1%) (6.1 )
To report SUSPECTED ADVERSE REACTIONS, contact Apotex Corp. at 1-800-706-5575 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1Clinical 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 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.
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 tablets. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to amoxicillin and clavulanate potassium tablets.
Gastrointestinal
Drug-induced enterocolitis syndrome (DIES), indigestion, gastritis, stomatitis, glossitis, 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 tablets. It has been reported more commonly in the elderly, in males, or in patients on prolonged treatment. The histologic findings on liver biopsy have consisted of predominantly cholestatic, hepatocellular, or mixed cholestatic-hepatocellular changes. The onset of signs/symptoms of hepatic dysfunction may occur during or several weeks after therapy has been discontinued. The hepatic dysfunction, which may be severe, is usually reversible. Deaths have been reported [see Contraindications (4.2 ), Warnings and Precuations (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 has been reported. These reactions are usually reversible on discontinuation of therapy and are believed to be hypersensitivity phenomena. Thrombocytosis was noted in less than 1% of the patients treated with amoxicillin and clavulanate potassium tablets. There have been reports of increased prothrombin time in patients receiving amoxicillin and clavulanate potassium tablets and anticoagulant therapy concomitantly [see Drug Interactions (7.2)].
Central Nervous System
Agitation, anxiety, behavioral changes, 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
- Co-administration with probenecid is not recommended. (
7.1 )- Concomitant use of amoxicillin and clavulanate potassium tablets and oral anticoagulants may increase the prolongation of prothrombin time. (
7.2 )- Coadministration with allopurinol increases the risk of rash. (
7.3) - Amoxicillin and clavulanate potassium tablets may reduce efficacy of oral contraceptives. (
7.4 )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 tablets 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
Pediatric Use: Modify dose in patients 12 weeks or younger. (8.4 )
Renal Impairment: Dosage adjustment is recommended for severe renal impairment (GFR less than 30mL/min). (2.4 ,8.6 )
8.1 Pregnancy
Teratogenic effects: Pregnancy Category B.
Reproduction studies performed in pregnant rats and mice given amoxicillin and clavulanate potassium tablets (2:1 ratio formulation of amoxicillin: clavulanate) at oral doses up to 1200 mg/kg/day revealed no evidence of harm to the fetus due to amoxicillin and clavulanate potassium tablets. The amoxicillin doses in rats and mice (based on body surface area) were approximately 4 and 2 times the maximum recommended adult human oral dose (875 mg every 12 hours). For clavulanate, these dose multiples were approximately 9 and 4 times the maximum recommended adult human oral dose (125 mg every 8 hours). There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
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.
8.4Pediatric Use
The safety and effectiveness of amoxicillin and clavulanate potassium 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 powder for oral suspension in pediatric patients aged 2 months to 12 years with acute otitis media [see Clinical Studies (14.2)].
Because of incompletely developed renal function in neonates and young infants, the elimination of amoxicillin may be delayed; clavulanate elimination is unaltered in this age group. Dosing of amoxicillin and clavulanate potassium 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 tablets, 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 symptoms1.
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 are 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 C16H19N3O5S•3H2O, and the molecular weight is 419.46 g/mol. 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 is C8H8KNO5, and the molecular weight is 237.25 g/mol. Chemically, clavulanate potassium is potassium (Z)-(2R,5R)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo[3.2.0]-heptane-2-carboxylate, and may be represented structurally as:
Amoxicillin and Clavulanate Potassium Tablets, USP:
250 mg/125 mg: Each film coated tablet contains 250 mg of amoxicillin as the trihydrate and 125 mg of clavulanic acid as clavulanate potassium. The potassium content is 0.63 mEq.
500 mg/125 mg: Each film coated tablet contains 500 mg of amoxicillin as the trihydrate and 125 mg of clavulanic acid as clavulanate potassium. The potassium content is 0.63 mEq.
875 mg/125 mg: Each film coated tablet contains 875 mg of amoxicillin as the trihydrate and 125 mg of clavulanic acid as clavulanate potassium. The potassium content is 0.63 mEq.
Inactive Ingredients
Colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, hydroxypropyl cellulose, methanol, polyethylene glycol, and titanium dioxide
Amoxicillin and clavulanate potassium tablets meet USP Dissolution Test # 2
12 Clinical Pharmacology
12.1 Mechanism of Action
Amoxicillin and clavulanate potassium tablets are 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
T able 6: Mean (±S.D.) Amoxicillin and Clavulanate Potassium Pharmacokinetic Parameters a,b with Amoxicillin and Clavulanate Potassium Tablets
Dose and Regimen Cmax (mcg/mL) Cmax (mcg/mL) AUC0 to 24 (mcg * hr/mL) AUC0 to 24 (mcg * hr/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 equals15 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.
Amoxicillin serum concentrations achieved with amoxicillin and clavulanate potassium tablets are similar to those produced by the oral administration of equivalent doses of amoxicillin alone. Time above the minimum inhibitory concentration of 1 mcg/mL for amoxicillin has been shown to be similar after corresponding every 12 hour and every 8-hour dosing regimens of amoxicillin and clavulanate potassium tablets in adults and children.
Absorption
Dosing in the fasted or fed state has minimal effect on the pharmacokinetics of amoxicillin. While amoxicillin and clavulanate potassium tablets can be given without regard to meals, absorption of clavulanate potassium when taken with food is greater relative to the fasted state. In one study, the relative bioavailability of clavulanate was reduced when amoxicillin and clavulanate potassium tablets was dosed at 30 and 150 minutes after the start of a high-fat breakfast.
Distribution
Neither component in amoxicillin and clavulanate potassium tablets is highly protein-bound; clavulanic acid is approximately 25% bound to human serum and amoxicillin approximately 18% bound. Amoxicillin diffuses readily into most body tissues and fluids with the exception of the brain and spinal fluid.
Metabolism and Excretion
The half-life of amoxicillin after the oral administration of amoxicillin and clavulanate potassium tablets is 1.3 hours and that of clavulanic acid is 1 hour.
Approximately 50% to 70% of the amoxicillin and approximately 25% to 40% of the clavulanic acid are excreted unchanged in urine during the first 6 hours after administration of a single 250 mg/125 mg or 500 mg/125 mg tablet of amoxicillin and clavulanate potassium tablets.
12.4 Microbiology
Amoxicillin is a semisynthetic antibacterial with in vitro bactericidal activity against Gram- positive and Gram-negative bacteria. Amoxicillin is, however, susceptible to degradation by beta-lactamases, and therefore, the spectrum of activity does not include organisms which produce these enzymes. Clavulanic acid is a beta-lactam, structurally related to the penicillins, which possesses the ability to inactivate some beta-lactamase enzymes commonly found in microorganisms resistant to penicillins and cephalosporins. In particular, it has good activity against the clinically important plasmid-mediated beta-lactamases frequently responsible for transferred drug resistance.
The formulation of amoxicillin and clavulanic acid in amoxicillin and clavulanate potassium tablets protects amoxicillin from degradation by some beta-lactamase enzymes and extends the 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 vitro and in clinical infections [see Indications and Usage (1)].
Gram-positive bacteria
Staphylococcus aureus
Gram-negative bacteria
Enterobacter species
Escherichia coli
Haemophilus influenzae
Klebsiella species
Moraxella catarrhalis
The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for amoxicillin and clavulanic acid. However, the efficacy of amoxicillin and clavulanic acid in treating clinical infections due to these bacteria has not been established in adequate and well-controlled clinical trials.
Gram-positive bacteria
Enterococcus faecalis
Staphylococcus epidermidis
Staphylococcus saprophyticus
Streptococcus pneumoniae
Streptococcus pyogenes
Viridans group Streptococcus
Gram-negative Bacteria
Eikenella corrodens
Proteus mirabilis
Anaerobic Bacteria
Bacteroides species including Bacteroides fragilis
Fusobacterium species
Peptostreptococcus species
Susceptibility Test Methods
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 tablets (4:1 ratio formulation of amoxicillin:clavulanate) were non-mutagenic in the Ames bacterial mutation assay, and the yeast gene conversion assay. Amoxicillin and clavulanate potassium tablets was weakly positive in the mouse lymphoma assay, but the trend toward increased mutation frequencies in this assay occurred at doses that were also associated with decreased cell survival. Amoxicillin and clavulanate potassium tablets were negative in the mouse micronucleus test, and in the dominant lethal assay in mice. Potassium clavulanate alone was tested in the Ames bacterial mutation assay and in the mouse micronucleus test, and was negative in each of these assays.
Amoxicillin and clavulanate potassium tablets (2:1 ratio formulation of amoxicillin:clavulanate) at oral doses of up to 1,200 mg/kg/day were 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 tablets every 12 hours to 500 mg/125 mg tablets of amoxicillin and clavulanate potassium tablets dosed every 8 hours (584 and 607 patients, respectively). Comparable efficacy was demonstrated between the every 12 hours and every 8 hours dosing regimens. There was no significant difference in the percentage of adverse events in each group. The most frequently reported adverse event was diarrhea; incidence rates were similar for the 875-mg every 12 hours and 500-mg every 8 hours dosing regimens (15% and 14%, respectively); however, there was a statistically significant difference (p 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 = 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 tablets every 12 hours (n equals 308) or 500 mg/125 mg tablets of amoxicillin and clavulanate potassium tablets every 8 hours (n equals 321).
The number of bacteriologically evaluable patients was comparable between the two dosing regimens. Amoxicillin and clavulanate potassium tablets produced comparable bacteriological success rates in patients assessed 2 to 4 days immediately following end of therapy. The bacteriologic efficacy rates were comparable at one of the follow-up visits (5 to 9 days post-therapy) and at a late post-therapy visit (in the majority of cases, this was 2 to 4 weeks post-therapy), as seen in Table 8.
T able 8: Bacteriologic Efficacy Rates for Amoxicillin and Clavulanate Potassium Tablets
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 tablets for 10 days versus 40/10 mg/kg/day (divided every 8 hours) of amoxicillin and clavulanate potassium tablets for 10 days in the treatment of acute otitis media. Only the suspension formulations were used in this trial. A total of 575 pediatric patients (aged 2 months to 12 years) were enrolled, with an even distribution among the 2 treatment groups and a comparable number of patients were evaluable (i.e., 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.
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: Each white, oval, biconvex, film-coated tablets, engraved “APO” on one side, “250-125” on the other. 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 20 (NDC 60505-2539-2)
Bottles of 30 (NDC 60505-2539-3)
Bottles of 500 (NDC 60505-2539-5)
500 mg/125 mg Tablets: Each white, oval, biconvex, film-coated tablets, engraved “APO” on one side, “500-125” on the other. 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 60505-2540-2)
Bottles of 30 (NDC 60505-2540-3)
Bottles of 500 (NDC 60505-2540-5)
875 mg/125 mg Tablets: Each white, capsule-shaped, biconvex, film-coated tablets, engraved “APO” on one side, engraved “A” bisect “C” on the other. 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 60505-2541-2)
Bottles of 30 (NDC 60505-2541-3)
Bottles of 500 (NDC 60505-2541-5)
Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Dispense in a tight container.
Keep out of the reach of children.
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 contain 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.
Manufactured by: Manufactured for: Apotex Inc. Apotex Corp. Toronto, Ontario Weston, Florida Canada M9L 1T9 33326
Revised: May 2024
Rev. 16
CLINITEST is a registered trademark of Miles, Inc.
Package Label.principal Display Panel
PRINCIPAL DISPLAY PANEL - 250 mg/125 mg BOTTLE
APOTEX CORP. NDC 60505-2539-3
AMOXICILLIN AND CLAVULANATE POTASSIUM TABLETS, USP
250 mg/125 mg *
Rx only
30 bottle count
Package Label.principal Display Panel
PRINCIPAL DISPLAY PANEL - 500 mg/125 mg BOTTLE
APOTEX CORP. NDC 60505-2540-3
AMOXICILLIN AND CLAVULANATE POTASSIUM TABLETS, USP
500 mg/125 mg *
Rx only
30 bottle count
Package Label.principal Display Panel
PRINCIPAL DISPLAY PANEL - 875 mg/125 mg BOTTLE
APOTEX CORP. NDC 60505-2541-3
AMOXICILLIN AND CLAVULANATE POTASSIUM TABLETS , USP
875 mg/125 mg *
Rx only
30 bottle count
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