To reduce the development of drug-resistant bacteria and maintain the effectiveness of amoxicillin and clavulanate potassium for oral suspension, USP and other antibacterial drugs, amoxicillin and clavulanate potassium for oral suspension, USP should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.



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

1.1 Lower Respiratory Tract Infections

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

1.2 Acute Bacterial Otitis Media

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

1.3 Sinusitis

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

1.4 Skin and Skin Structure Infections

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

1.5 Urinary Tract Infections

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

1.6 Limitations of Use

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

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

2.1 Adults

The usual adult dose is one amoxicillin and clavulanate potassium 500 mg/125 mg tablet every 12 hours or one amoxicillin and clavulanate potassium 250 mg/125 mg tablet every 8 hours. For more severe infections and infections of the respiratory tract, the dose should be one amoxicillin and clavulanate potassium 875 mg/125 mg tablet every 12 hours or one amoxicillin and clavulanate potassium 500 mg/125 mg tablet every 8 hours. Adults who have difficulty swallowing may be given the 125 mg/31.25 mg per 5 mL or 250 mg/62.5 mg per 5 mL suspension in place of the 500 mg/125 mg tablet. The 200 mg/28.5 mg per 5 mL suspension or the 400 mg/57 mg per 5 mL suspension may be used in place of the 875 mg/125 mg tablet.



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



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

2.2 Pediatric Patients

Based on the amoxicillin component, amoxicillin and clavulanate potassium for oral suspension should be dosed as follows:



Neonates and Infants Aged <12 weeks (<3 months): The recommended dose of amoxicillin and clavulanate potassium for oral suspension is 30 mg/kg/day divided every 12 hours, based on the amoxicillin component. Experience with the 200 mg/28.5 mg per 5 mL formulation in this age group is limited, and thus, use of the 125 mg/31.25 mg per 5 mL oral suspension is recommended.



Patients Aged 12 weeks (3 months) and Older: See dosing regimens provided in Table 1. The every 12 hour regimen is recommended as it is associated with significantly less diarrhea [see CLINICAL STUDIES (14.2)]. However, the every 12 hour suspension (200 mg/28.5 mg per 5 mL and 400 mg/57 mg per 5 mL) and chewable tablets (200 mg/28.5 mg and 400 mg/57 mg) contain aspartame and should not be used by phenylketonurics [see WARNINGS AND PRECAUTIONS (5.6)].

Table 1: Dosing in Patients Aged 12 weeks (3 months) and Older

a Each strength of suspension of amoxicillin and clavulanate potassium 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.

INFECTION

DOSING REGIMEN

Every 12 hours

Every 8 hours

200 mg/28.5 mg per 5 mL or

400 mg/57 mg per 5 mL oral suspensiona

125 mg/31.25 mg per 5 mL or

250 mg/62.5 mg per 5 mL oral suspensiona

Otitis mediab, 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

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



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

2.3 Patients with Renal Impairment

Patients with impaired renal function do not generally require a reduction in dose unless the impairment is severe. Renal impairment patients with a glomerular filtration rate of <30 mL/min should not receive the dose of amoxicillin and clavulanate potassium tablets 875 mg/125 mg. Patients with a glomerular filtration rate of 10 to 30 mL/min should receive amoxicillin and clavulanate potassium tablets 500 mg/125 mg or 250 mg/125 mg every 12 hours, depending on the severity of the infection. Patients with a glomerular filtration rate less than 10 mL/min should receive amoxicillin and clavulanate potassium tablets 500 mg/125 mg or 250 mg/125 mg every 24 hours, depending on severity of the infection.



Hemodialysis patients should receive amoxicillin and clavulanate potassium tablets 500 mg/125 mg or 250 mg/125 mg every 24 hours, depending on severity of the infection. They should receive an additional dose both during and at the end of dialysis.

2.4 Directions for Mixing Oral Suspension

Prepare a suspension at time of dispensing as follows: Tap bottle until all the powder flows freely. Add approximately 2/3 of the total amount of water for reconstitution (see Table 2 below) and shake vigorously to suspend powder. Add remainder of the water and again shake vigorously.

Table 2: Amount of Water for Mixing Oral Suspension

Strength

Bottle Size

Amount of Water for Reconstitution

Contents of Each

Teaspoonful

(5 mL)

200 mg/28.5 mg per 5 mL

50 mL

75 mL

100 mL

52 mL

73 mL

98 mL

200 mg amoxicillin and 28.5 mg of clavulanic acid as the potassium salt

400 mg/57 mg per 5 mL

50 mL

75 mL

100 mL

49 mL

70 mL

94 mL

400 mg amoxicillin and 57 mg of clavulanic acid as the potassium salt

Note: Shake oral suspension well before using. Reconstituted suspension must be stored under refrigeration and discarded after 10 days.

200 mg/28.5 mg per 5 mL: White to off-white granular powder – Each 5 mL of reconstituted white to pale yellow, orange flavored suspension contains 200 mg amoxicillin and 28.5 mg clavulanic acid as the potassium salt.

400 mg/57 mg per 5 mL: White to off-white granular powder – Each 5 mL of reconstituted white to pale yellow, orange flavored suspension contains 400 mg amoxicillin and 57 mg clavulanic acid as the potassium salt.

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



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

4.1 Serious Hypersensitivity Reactions

Amoxicillin and clavulanate potassium for oral suspension is 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 for oral suspension is contraindicated in patients with a previous history of cholestatic jaundice/hepatic dysfunction associated with amoxicillin and clavulanate potassium for oral suspension.

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 for oral suspension. 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 for oral suspension, careful inquiry should be made regarding previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens. If an allergic reaction occurs, amoxicillin and clavulanate potassium for oral suspension should be discontinued and appropriate therapy instituted.

5.2 Hepatic Dysfunction

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

5.3 Clostridium difficile-Associated Diarrhea (CDAD)

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including amoxicillin and clavulanate potassium for oral suspension, 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.

5.4 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 for oral suspension should not be administered to patients with mononucleosis.

5.5 Potential for Microbial Overgrowth

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

5.6 Phenylketonurics

Each 5 mL of the 200 mg/28.5 mg per 5 mL oral suspension contains 4.42 mg phenylalanine and each 5 mL of the 400 mg/57 mg per 5 mL oral suspension contains 6.35 mg phenylalanine.

5.7 Development of Drug-Resistant Bacteria

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

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

Anaphylactic reactions [see WARNINGS AND PRECAUTIONS (5.1)]

Hepatic Dysfunction [see WARNINGS AND PRECAUTIONS (5.2)]

CDAD [see WARNINGS AND PRECAUTIONS (5.3)]

6.1 Clinical Trials Experience

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



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



In pediatric patients (aged 2 months to 12 years), 1 U.S./Canadian clinical trial was conducted which compared 45/6.4 mg/kg/day (divided every 12 hours) of amoxicillin and clavulanate potassium for oral suspension for 10 days versus 40/10 mg/kg/day (divided every 8 hours) of amoxicillin and clavulanate potassium for oral suspension 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 for oral suspension. 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 for oral suspension.



Gastrointestinal: Indigestion, gastritis, stomatitis, glossitis, black “hairy” tongue, mucocutaneous candidiasis, enterocolitis, and hemorrhagic/pseudomembranous colitis. Onset of pseudomembranous colitis symptoms may occur during or after antibiotic treatment [see WARNINGS AND PRECAUTIONS (5.3)].



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



Liver: Hepatic dysfunction, including hepatitis and cholestatic jaundice, increases in serum transaminases (AST and/or ALT), serum bilirubin, and/or alkaline phosphatase, has been reported with amoxicillin and clavulanate potassium for oral suspension. It has been reported more commonly in the elderly, in males, or in patients on prolonged treatment. The histologic findings on liver biopsy have consisted of predominantly cholestatic, hepatocellular, or mixed cholestatic-hepatocellular changes. The onset of signs/symptoms of hepatic dysfunction may occur during or several weeks after therapy has been discontinued. The hepatic dysfunction, which may be severe, is usually reversible. Deaths have been reported [see CONTRAINDICATIONS (4.2), WARNINGS AND PRECAUTIONS (5.2)].



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



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



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



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

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

Anaphylactic reactions [see WARNINGS AND PRECAUTIONS (5.1)]

Hepatic Dysfunction [see WARNINGS AND PRECAUTIONS (5.2)]

CDAD [see WARNINGS AND PRECAUTIONS (5.3)]

6.1 Clinical Trials Experience

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



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



In pediatric patients (aged 2 months to 12 years), 1 U.S./Canadian clinical trial was conducted which compared 45/6.4 mg/kg/day (divided every 12 hours) of amoxicillin and clavulanate potassium for oral suspension for 10 days versus 40/10 mg/kg/day (divided every 8 hours) of amoxicillin and clavulanate potassium for oral suspension 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 for oral suspension. 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 for oral suspension.



Gastrointestinal: Indigestion, gastritis, stomatitis, glossitis, black “hairy” tongue, mucocutaneous candidiasis, enterocolitis, and hemorrhagic/pseudomembranous colitis. Onset of pseudomembranous colitis symptoms may occur during or after antibiotic treatment [see WARNINGS AND PRECAUTIONS (5.3)].



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



Liver: Hepatic dysfunction, including hepatitis and cholestatic jaundice, increases in serum transaminases (AST and/or ALT), serum bilirubin, and/or alkaline phosphatase, has been reported with amoxicillin and clavulanate potassium for oral suspension. It has been reported more commonly in the elderly, in males, or in patients on prolonged treatment. The histologic findings on liver biopsy have consisted of predominantly cholestatic, hepatocellular, or mixed cholestatic-hepatocellular changes. The onset of signs/symptoms of hepatic dysfunction may occur during or several weeks after therapy has been discontinued. The hepatic dysfunction, which may be severe, is usually reversible. Deaths have been reported [see CONTRAINDICATIONS (4.2), WARNINGS AND PRECAUTIONS (5.2)].



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



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



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



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

8.1 Pregnancy

Teratogenic Effects: Pregnancy Category B. Reproduction studies performed in pregnant rats and mice given amoxicillin and clavulanate potassium for oral suspension (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 for oral suspension. 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 antibiotics 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 powder for oral suspension and chewable tablets have been established in pediatric patients. Use of amoxicillin and clavulanate potassium for oral suspension 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 for oral suspension should be modified in pediatric patients aged <12 weeks (<3 months) [see DOSAGE AND ADMINISTRATION (2.2)].

8.5 Geriatric Use

Of the 3,119 patients in an analysis of clinical studies of amoxicillin and clavulanate potassium for oral suspension, 32% were ≥65 years old, and 14% were ≥75 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.



This drug is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

8.6 Dosing in Renal Impairment

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

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 (2.3)].

Amoxicillin and clavulanate potassium for oral suspension, 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 C16H19N3O5S•3H2O, and the molecular weight is 419.46. Chemically, amoxicillin is (2S,5R,6R)-6-[(R)-(-)-2-Amino-2-(p-hydroxyphenyl)acetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid trihydrate and may be represented structurally as:





[Amoxicillin chemical Structure]

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. 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:



[Clavulanic acid chemical structure]



After reconstitution each teaspoonful (5 mL) of suspension will contain 200 mg amoxicillin as the trihydrate and 28.5 mg clavulanic acid as the potassium salt or 400 mg amoxicillin as the trihydrate and 57 mg clavulanic acid as the potassium salt. Each 5 mL of reconstituted amoxicillin and clavulanate potassium for oral suspension USP, 200 mg/28.5 mg per 5 mL contains 0.14 mEq potassium. Each 5 mL of reconstituted amoxicillin and clavulanate potassium for oral suspension USP, 400 mg/57 mg per 5 mL contains 0.29 mEq of potassium.



Amoxicillin and clavulanate potassium for oral suspension, USP is white to off-white granular powder and becomes white to pale yellow with orange flavored suspension after reconstitution.



Inactive Ingredients:



Colloidal silicon dioxide, hypromellose, orange flavour, silicon dioxide, succinic acid, xanthan gum and aspartame [see WARNINGS AND PRECAUTIONS (5.6)].

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 3 and following administration of amoxicillin and clavulanate potassium powder for oral suspension and chewable tablets are shown in Table 4.

Table 3: Mean (±S.D.) Amoxicillin and Clavulanate Potassium Pharmacokinetic Parametersa,b with Amoxicillin and Clavulanate Potassium Tablets

a Mean (± standard deviation) values of 14 normal adults (N=15 for clavulanate potassium in the low-dose regimens). Peak concentrations occurred approximately 1.5 hours after the dose.

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

Dose and Regimen

Cmax (mcg/mL)

AUC0-24 (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 ± 0.7

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

Table 4: Mean (±S.D.) Amoxicillin and Clavulanate Potassium Pharmacokinetic Parametersa,b with Amoxicillin and Clavulanate Potassium Powder for Oral Suspension and Chewable Tablets

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.

Dose

Cmax (mcg/mL)

AUC0-24 (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

1.1 ± 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

Oral administration of 5 mL of amoxicillin and clavulanate potassium 250 mg/62.5 mg per 5 mL suspension or the equivalent dose of 10 mL of amoxicillin and clavulanate potassium 125 mg/31.25 mg per 5 mL suspension 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*hr/mL for amoxicillin and 2.9 mcg•hr/mL for clavulanic acid when 5 mL of amoxicillin and clavulanate potassium 250 mg/62.5 mg per 5 mL suspension or equivalent dose of 10 mL of amoxicillin and clavulanate potassium 125 mg/31.25 mg per 5 mL suspension were administered to normal adults. One amoxicillin and clavulanate potassium 250 mg/62.5 mg chewable tablet or two amoxicillin and clavulanate potassium 125 mg/31.25 mg chewable tablets are equivalent to 5 mL of amoxicillin and clavulanate potassium 250 mg/62.5 mg per 5 mL suspension and provide similar serum concentrations of amoxicillin and clavulanic acid.



Amoxicillin serum concentrations achieved with amoxicillin and clavulanate potassium 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 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 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 was dosed at 30 and 150 minutes after the start of a high-fat breakfast.



Distribution: Neither component in amoxicillin and clavulanate potassium 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 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 amoxicillin and clavulanate potassium 250 mg/125 mg or 500 mg/125 mg tablet.

12.4 Microbiology

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



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



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



Gram-positive Bacteria



Staphylococcus aureus



Gram-negative Bacteria



Enterobacter species

Escherichia coli

Haemophilus influenzae

Klebsiella species

Moraxella catarrhalis



The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for amoxicillin 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 Testing



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.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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



Amoxicillin and clavulanate potassium for oral suspension (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 for oral suspension 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 for oral suspension 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 for oral suspension (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.

14.1 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/125 mg every 12 hours and 500 mg/125 mg every 8 hours dosing regimens (15% and 14%, respectively); however, there was a statistically significant difference (p < 0.05) in rates of severe diarrhea or withdrawals with diarrhea between the regimens: 1% for 875 mg/125 mg every 12 hours regimen versus 2% for the 500 mg/125 mg every 8 hours regimen.



In one of these pivotal trials, patients with either pyelonephritis (n = 361) or a complicated urinary tract infection (i.e., patients with abnormalities of the urinary tract that predispose to relapse of bacteriuria following eradication, n = 268) were randomized (1:1) to receive either 875 mg/125 mg tablets of amoxicillin and clavulanate potassium every 12 hours (n=308) or 500 mg/125 mg tablets of amoxicillin and clavulanate potassium every 8 hours (n=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 7.

Table 7: Bacteriologic efficacy rates for Amoxicillin and Clavulanate Potassium

Time Post Therapy

875 mg/125 mg every 12 hours

% (n)

500 mg/125 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 U.S./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., ≥ 84%) per treatment group. Otitis media-specific criteria were required for eligibility and a strong correlation was found at the end of therapy and follow-up between these criteria and physician assessment of clinical response. The clinical efficacy rates at the end of therapy visit (defined as 2 to 4 days after the completion of therapy) and at the follow-up visit (defined as 22 to 28 days post-completion of therapy) were comparable for the 2 treatment groups, with the following cure rates obtained for the evaluable patients: At end of therapy, 87% (n = 265) and 82% (n = 260) for 45 mg/kg/day every 12 hours and 40 mg/kg/day every 8 hours, respectively. At follow-up, 67% (n = 249) and 69% (n = 243) for 45 mg/kg/day every 12 hours and 40 mg/kg/day every 8 hours, respectively.



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



It is not known if the finding of a statistically significant reduction in diarrhea with the oral suspensions dosed every 12 hours, versus suspensions dosed every 8 hours, can be extrapolated to the chewable tablets. The presence of mannitol in the chewable tablets may contribute to a different diarrhea profile. The every 12 hour oral suspensions (200 mg/28.5 mg per 5 mL and 400 mg/57 mg per 5 mL) are sweetened with aspartame.

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.

Amoxicillin and Clavulanate Potassium for Oral Suspension USP, 200 mg/28.5 mg per 5 mL is a white to off-white granular powder – Each 5 mL of reconstituted white to pale yellow, orange flavored suspension contains 200 mg amoxicillin and 28.5 mg clavulanic acid as the potassium salt.



Bottles of 50 mL NDC 65862-533-50

Bottles of 75 mL NDC 65862-533-75

Bottles of 100 mL NDC 65862-533-01



Amoxicillin and Clavulanate Potassium for Oral Suspension USP, 400 mg/57 mg per 5 mL is a white to off-white granular powder – Each 5 mL of reconstituted white to pale yellow, orange flavored suspension contains 400 mg amoxicillin and 57 mg clavulanic acid as the potassium salt.



Bottles of 50 mL NDC 65862-534-50

Bottles of 75 mL NDC 65862-534-75

Bottles of 100 mL NDC 65862-534-01



Dispense in original container.



Store dry powder at 20º to 25ºC (68º to 77ºF). [See USP Controlled Room Temperature.]



Store reconstituted suspension under refrigeration. Discard unused suspension after 10 days.



Keep out of the reach of children.

17.1 Information for Patients

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



Patients should be counseled that antibacterial drugs, including amoxicillin and clavulanate potassium for oral suspension, should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When amoxicillin and clavulanate potassium for oral suspension is 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 for oral suspension or other antibacterial drugs in the future.



Counsel patients that diarrhea is a common problem caused by antibacterials, and it usually ends when the antibacterial is discontinued. Sometimes after starting treatment with antibacterials, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as 2 or more months after having taken their last dose of the antibacterial. If diarrhea is severe or lasts more than 2 or 3 days, patients should contact their physician.



Patients should be advised to keep suspension refrigerated. Shake well before using. When dosing a child with the suspension (liquid) of amoxicillin and clavulanate potassium for oral suspension, use a dosing spoon or medicine dropper. Be sure to rinse the spoon or dropper after each use. Bottles of suspension of amoxicillin and clavulanate potassium for oral suspension may contain more liquid than required. Follow your doctor’s instructions about the amount to use and the days of treatment your child requires. Discard any unused medicine.



Patients should be aware that amoxicillin and clavulanate potassium for oral suspension contains a penicillin class drug product that can cause allergic reactions in some individuals.



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