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amox-clav 500-125 mg tablet

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Uses

Amoxicillin and clavulanate potassium is used orally for the treatment of lower respiratory tract infections, otitis media, sinusitis, skin and skin structure infections, and urinary tract infections caused by susceptible organisms. Amoxicillin and clavulanate potassium also has been used orally for the treatment of chancroid and gonorrhea caused by susceptible organisms.

Amoxicillin and clavulanate potassium is used principally for the treatment of infections caused by susceptible β-lactamase-producing strains of Moraxella catarrhalis (formerly Branhamella catarrhalis), Escherichia coli, Haemophilus influenzae, Klebsiella, and Staphylococcus aureus. Although amoxicillin and clavulanate potassium also may be effective in the treatment of infections caused by non-β-lactamase-producing organisms susceptible to amoxicillin alone, most clinicians state that an aminopenicillin used alone is preferred to the combination drug for the treatment of these infections and that amoxicillin and clavulanate potassium should be reserved for use in the treatment of infections caused by, or suspected of being caused by, β-lactamase-producing organisms when an aminopenicillin alone would be ineffective.

Prior to initiation of therapy with amoxicillin and clavulanate potassium, appropriate specimens should be obtained for identification of the causative organism and in vitro susceptibility tests. Amoxicillin and clavulanate potassium therapy may be started pending results of susceptibility tests if the infection is believed to be caused by β-lactamase-producing bacteria susceptible to the drug, but should be discontinued if the organism is found to be resistant to the drug.(See Spectrum: In Vitro Susceptibility Testing.) If the infection is found to be caused by non-β-lactamase-producing organisms susceptible to aminopenicillins, some clinicians suggest that therapy generally should be changed to an aminopenicillin alone, unless this is impractical.

Gram-positive Aerobic Bacterial Infections

Amoxicillin and clavulanate potassium has been effective when used orally in adults and children for the treatment of abscesses, cellulitis, and impetigo caused by susceptible penicillinase-producing and nonpenicillinase-producing Staphylococcus aureus and S. epidermidis, Streptococcus pyogenes (group A β-hemolytic streptococci), or Corynebacterium. Results of several controlled studies indicate that amoxicillin and clavulanate potassium is as effective as cefaclor in the treatment of these infections. However, natural penicillins are generally the drugs of choice for the treatment of infections caused by nonpenicillinase-producing staphylococci or group A β-hemolytic streptococci and penicillinase-resistant penicillins are generally the drugs of choice for the treatment of infections caused by susceptible penicillinase-producing staphylococci.

Amoxicillin and clavulanate potassium should not be used in the treatment of infections caused by methicillin-resistant staphylococci, even though results of in vitro susceptibility tests may indicate that the organism is susceptible to the drug.

Gram-negative Aerobic Bacterial Infections

Haemophilus Infections

Amoxicillin and clavulanate potassium generally has been effective when used in adults or children for the treatment of otitis media or upper and lower respiratory tract infections such as bronchopneumonia, sinusitis, and acute exacerbations of chronic bronchitis caused by susceptible H. influenzae. Amoxicillin and clavulanate potassium usually is the drug of choice for empiric anti-infective therapy of otitis media and sinusitis in communities with a high incidence of ampicillin-resistant H. influenzae or M. catarrhalis and for infections that fail to respond to other regimens.(See Uses: Acute Otitis Media.)

Chancroid

Oral amoxicillin and clavulanate potassium (500 mg of amoxicillin and 125 or 250 mg of clavulanic acid every 8 hours for 7 days) has been effective when used in the treatment of chancroid (genital ulcers caused by H. ducreyi); the mean time to complete healing of ulcers with amoxicillin and clavulanate potassium therapy has been 6.5-11.4 days and buboes have generally resolved within 4 weeks. However, amoxicillin and clavulanate potassium is not included in current US Centers for Disease Control and Prevention (CDC) guidelines for the treatment of chancroid; the CDC states that a single oral dose of azithromycin, a single IM dose of ceftriaxone, a 3-day regimen of oral ciprofloxacin, or a 7-day regimen of oral erythromycin are the regimens of choice for the treatment of chancroid.

Moraxella catarrhalis Infections

Infections caused by β-lactamase-producing M. catarrhalis have been reported with increasing frequency. This organism recently has been recognized as a common cause of otitis media and maxillary sinusitis in children and of bronchitis and pneumonia in adults, especially those with chronic lung disease. Rarely, septicemia, endocarditis, urethritis, meningitis, neonatal ophthalmia, and conjunctivitis caused by M. catarrhalis have been reported. Amoxicillin and clavulanate potassium generally has been effective when used in the treatment of upper and lower respiratory tract infections caused by M. catarrhalis, and many clinicians consider it a drug of choice for infections caused by the organism.

Amoxicillin and clavulanate potassium generally has been effective when used for the treatment of acute otitis media or acute maxillary sinusitis caused by M. catarrhalis. In several controlled studies, amoxicillin and clavulanate potassium was more effective than cefaclor for the empiric treatment of acute otitis media in children 2 months to 12 years of age. Although adverse GI effects occurred more frequently with amoxicillin and clavulanate potassium than with cefaclor, amoxicillin and clavulanate potassium appears to be more active than cefaclor against β-lactamase-producing M. catarrhalis. Some clinicians suggest that amoxicillin and clavulanate potassium is a drug of choice for the empiric treatment of otitis media and sinusitis in communities with a high incidence of β-lactamase-producing M. catarrhalis.

Gonorrhea

Amoxicillin and clavulanate potassium has been used orally with some success for the treatment of uncomplicated gonorrhea caused by penicillinase-producing strains of N. gonorrhoeae (PPNG) or nonpenicillinase-producing strains of the organism. Regimens consisting of a single oral dose of amoxicillin (3 g) and clavulanic acid (125-500 mg) with or without oral probenecid (1 g) have been effective in some cases for the treatment of uncomplicated gonorrhea caused by PPNG or nonpenicillinase-producing N. gonorrhoeae. However, treatment failures have been reported when these single-dose regimens were used in the treatment of infections caused by PPNG, although, in some cases, in vitro tests indicated that the organism was susceptible to the drug. Penicillins, including amoxicillin and clavulanate potassium, are not included in current CDC recommendations for the treatment of gonorrhea.

Urinary Tract Infections

Amoxicillin and clavulanate potassium has generally been effective when used orally in adults or children for the treatment of uncomplicated or complicated urinary tract infections (UTIs) caused by susceptible organisms including E. coli, Klebsiella, Enterobacter, or P. mirabilis. Although most strains of Enterobacter are resistant to amoxicillin and clavulanate potassium in vitro, the drug has been effective in some cases when used in the treatment of UTIs caused by this organism. Because amoxicillin and clavulanate potassium is active in vitro against many urinary pathogens resistant to aminopenicillins, some clinicians suggest that the combination drug may be preferred over ampicillin or amoxicillin alone for the initial treatment of UTIs; however, further studies are needed to evaluate the relative efficacy of amoxicillin and clavulanate potassium and other anti-infectives (e.g., co-trimoxazole) in the treatment of UTIs.

Other Gram-negative Aerobic Bacterial Infections

Amoxicillin and clavulanate potassium has been used in the treatment of infections caused by Eikenella corrodens or Pasteurella multocida.

Anaerobic and Mixed Aerobic-Anaerobic Bacterial Infections

Amoxicillin and clavulanate potassium has been used orally with some success in a limited number of patients for the treatment of anaerobic and mixed aerobic-anaerobic bacterial infections including intra-abdominal and gynecologic infections such as endometritis, salpingitis, pelvic cellulitis, and acute pelvic inflammatory disease. Although oral amoxicillin and clavulanate potassium has been effective in the treatment of these infections, including infections caused by Bacteroides fragilis, some clinicians suggest that further study is needed to evaluate efficacy of the drug in the treatment of anaerobic and mixed aerobic-anaerobic bacterial infections and to determine if serum and tissue concentrations of amoxicillin and clavulanic acid obtained following oral administration of the drug are adequate for the treatment of these infections.

Acute Otitis Media

Amoxicillin and clavulanate potassium is used for the treatment of acute otitis media (AOM) caused by S. pneumoniae, H. influenzae (including β-lactamase-producing strains), or M. catarrhalis (including β-lactamase-producing strains). Amoxicillin usually is considered the drug of first choice for initial treatment of AOM, unless the patient has severe illness (moderate to severe otalgia or fever 39°C or higher) or the infection is suspected of being caused by β-lactamase-producing bacteria resistant to the drug, in which case amoxicillin and clavulanate potassium is recommended for initial treatment. The American Academy of Pediatrics (AAP), American Academy of Family Physicians (AAFP), CDC, and others state that, despite the increasing prevalence of multidrug-resistant S. pneumoniae and presence of β-lactamase-producing H. influenzae or M. catarrhalis in many communities, amoxicillin remains the anti-infective of first choice for treatment of uncomplicated AOM since it is highly effective, has a narrow spectrum of activity, is well distributed into middle ear fluid, is well tolerated, has an acceptable taste, and is inexpensive. Amoxicillin (when given in a dosage of 80-90 mg/kg daily) usually is effective in the treatment of AOM caused by S. pneumoniae, including infections involving strains with intermediate resistance to penicillins, and also usually is effective in the treatment of AOM caused by most strains of H. influenzae.

Alternatives for initial treatment of AOM in patients with a history of non-type I hypersensitivity reactions to penicillins include oral cephalosporins (cefdinir, cefpodoxime, cefuroxime axetil) or parenteral ceftriaxone. Alternatives for patients with type I penicillin hypersensitivity include oral macrolides (azithromycin, clarithromycin, fixed combination of erythromycin and sulfisoxazole), oral co-trimoxazole, or oral clindamycin (especially in those with infections known or presumed to be caused by penicillin-resistant S. pneumoniae).

Amoxicillin and clavulanate potassium (given in a dosage of 80-90 mg/kg of amoxicillin and 6.4 mg/kg of clavulanate daily) is the drug of choice for retreatment in patients who fail to respond to an initial amoxicillin regimen (given in a dosage of 80-90 mg/kg daily). The AAP and AAFP recommend that amoxicillin and clavulanate be substituted if there has been no response to amoxicillin within 48-72 hours. A 3-day regimen of IM or IV ceftriaxone also is recommended for retreatment, especially in those who have severe illness (moderate to severe otalgia or fever 39°C or higher) and in those who are vomiting or cannot otherwise tolerate an oral regimen.

For additional information regarding treatment of AOM, including information on diagnosis and management strategies, anti-infectives for initial treatment, duration of initial treatment, and anti-infectives for retreatment and for information on current recommendations regarding management of otitis media with effusion (OME), .

Pharyngitis and Tonsillitis

Although not considered a drug of choice for the treatment of pharyngitis and tonsillitis caused by S. pyogenes (group A β-hemolytic streptococci), amoxicillin and clavulanate potassium is recommended as one of several possible alternatives for the treatment of symptomatic patients who have multiple, recurrent episodes of pharyngitis known to caused by S. pyogenes. Natural penicillins (i.e., 10 days of oral penicillin V or a single IM dose of penicillin G benzathine) is the treatment of choice for streptococcal pharyngitis and tonsillitis, although oral amoxicillin often is used instead of penicillin V in small children because of a more acceptable taste.

If there is recurrence of signs and symptoms of pharyngitis shortly after the initial recommended regimen is completed (i.e., within a few weeks) and presence of S. pyogenes is detected, retreatment with the original regimen or another regimen of choice is indicated; if compliance with a 10-day oral regimen is a concern, IM penicillin G benzathine should be used for retreatment. Some clinicians suggest use of an alternative agent (e.g., amoxicillin and clavulanate, clindamycin, macrolide) for retreatment. However, if there are multiple, recurrent episodes of symptomatic pharyngitis within a period of months to years, it may be difficult to determine whether these are true episodes of S. pyogenes infection or whether the patient is a long-term streptococcal pharyngeal carrier who is experiencing repeated episodes of nonstreptococcal pharyngitis (e.g., viral pharyngitis) in whom treatment is not usually indicated. Continuous anti-infective prophylaxis (secondary prophylaxis) to prevent the recurrence of streptococcal pharyngitis is not recommended in these circumstances, unless the patient has a history of rheumatic fever. Instead, use of an alternative regimen is recommended by some clinicians. Although there are no controlled clinical studies evaluating efficacy, the IDSA suggests that symptomatic individuals with multiple, recurrent episodes of documented S. pyogenes pharyngitis receive a regimen of oral amoxicillin clavulanate, oral clindamycin, or IM penicillin G benzathine (with or without oral rifampin).

For additional information on treatment ofS. pyogenespharyngitis, see Pharyngitis and Tonsillitis under Gram-positive Aerobic Bacterial Infections: Streptococcus pyogenes Infections in Uses in the Natural Penicillins General Statement 8:12.16.04.

Dosage and Administration

Reconstitution and Administration

Amoxicillin and clavulanate potassium is administered orally. Chewable tablets should be thoroughly chewed before swallowing. Amoxicillin and clavulanate potassium has also been given IV, but a parenteral dosage form of the drug is not currently available in the US.

Because GI absorption of amoxicillin and clavulanate potassium is not affected by food following oral administration of conventional preparations of the drug, these preparations may be administered orally without regard to meals. However, administration of oral amoxicillin and clavulanate potassium with meals reportedly may minimize adverse GI effects. Extended-release tablets of the combination should be administered at the beginning of a meal to enhance GI absorption of amoxicillin and clavulanate and to minimize adverse GI effects; amoxicillin absorption from extended-release tablets is decreased when administered in a fasting state, and clavulanate absorption is decreased when these tablets are administered with a high-fat meal.

Amoxicillin and clavulanate potassium powder for oral suspension should be reconstituted at the time of dispensing by adding the amount of water specified on the bottle to provide a suspension containing 125 mg of amoxicillin and 31.25 mg of clavulanic acid per 5 mL, 200 mg of amoxicillin and 28.5 mg of clavulanic acid per 5 mL, 250 mg of amoxicillin and 62.5 mg of clavulanic acid per 5 mL, or 600 mg of amoxicillin and 42.9 mg of clavulanic acid per 5 mL. After tapping the bottle to thoroughly loosen the powder for oral suspension, the water should be added to the powder in 2 portions and the suspension agitated well after each addition. The suspension should be agitated well just prior to administration of each dose.

Dosage

Dosage of amoxicillin and clavulanate potassium generally is expressed in terms of the amoxicillin content of the fixed combination. Although commercially available amoxicillin and clavulanate potassium contains amoxicillin as the trihydrate and/or the sodium salt and clavulanic acid as the potassium salt, potency of amoxicillin is calculated on the anhydrous basis and potency of clavulanate potassium is expressed in terms of clavulanic acid.

Amoxicillin and clavulanate potassium is commercially available for oral administration as a powder for oral suspension containing a 4:1, 7:1, or 14:1 ratio of amoxicillin to clavulanic acid; as chewable tablets containing a 4:1 or 7:1 ratio of the drugs; as film-coated tablets containing a 2:1 or 4:1 ratio of the drugs; as scored tablets containing a 7:1 ratio of the drugs; and as extended-release tablets containing a 16:1 ratio of the drugs.

Commercially available amoxicillin and clavulanate potassium powders for oral suspension should not be considered interchangeable since they contain different amounts of clavulanic acid. The powder for oral suspension containing 600 mg of amoxicillin and 42.9 mg of clavulanic acid per 5 mL (Augmentin ES-600) is indicated only for the treatment of persistent or recurrent acute otitis media (AOM) in certain pediatric patients 3 months to 12 years of age; safety and efficacy of this preparation in younger children or in adolescents or adults have not been established. Because commercially available amoxicillin and clavulanate potassium film-coated tablets containing 250 mg of amoxicillin contain 125 mg of clavulanic acid and commercially available chewable tablets containing 250 mg of amoxicillin contain 62.5 mg of clavulanic acid, these preparations should not be considered interchangeable. In addition, since the 250- and 500-mg film-coated tablets of the drug both contain the same amount of clavulanic acid, two 250-mg film-coated tablets are not equivalent to one 500-mg film-coated tablet. Because extended-release tablets of amoxicillin and clavulanate potassium contain different ratios of the drugs, the extended-release tablets are not equivalent to conventional or chewable tablets of the drug.

Children weighing less than 40 kg should not receive the 250-mg film-coated tablets since this formulation contains a higher dose of clavulanic acid.(See Dosage: Pediatric Dosage, under Dosage and Administration.) Safety and efficacy of the extended-release tablets have not been established in pediatric patients younger than 16 years of age.

Adult Dosage

The usual adult oral dosage of amoxicillin and clavulanate potassium is one 250-mg film-coated tablet (containing 250 mg of amoxicillin and 125 mg of clavulanic acid) every 8 hours or one 500-mg film-coated tablet (containing 500 mg of amoxicillin and 125 mg of clavulanic acid) every 12 hours. For more severe infections and infections of the respiratory tract, the usual adult oral dosage is one 500-mg film-coated tablet (containing 500 mg of amoxicillin and 125 mg of clavulanic acid) every 8 hours or one 875-mg scored tablet (containing 875 mg of amoxicillin and 125 mg of clavulanic acid) every 12 hours. Alternatively, adults who have difficulty swallowing tablets may receive the oral suspension containing 125 or 250 mg of amoxicillin/5 mL instead of the 500-mg film-coated tablet or may receive the oral suspension containing 200 or 400 mg of amoxicillin/5 mL instead of the 875-mg scored tablet.

The usual oral dosage of amoxicillin and clavulanate potassium extended-release tablets for the treatment of acute bacterial sinusitis in patients 16 years of age and older is 2 tablets (containing 1 g of amoxicillin and 62.5 mg of clavulanic acid in each tablet) every 12 hours for 10 days. The usual oral dosage of the extended-release tablets for the treatment of community-acquired pneumonia (CAP) in patients 16 years of age and older is 2 tablets (containing 1 g of amoxicillin and 62.5 mg of clavulanic acid in each tablet) every 12 hours for 7-10 days. Dosage adjustment for extended-release tablets of the combination based solely on age is not necessary in geriatric patients.

Pediatric Dosage

Children weighing 40 kg or more may receive the usual adult oral dosage of amoxicillin and clavulanate potassium.

The usual dosage of amoxicillin and clavulanate potassium in neonates and infants younger than 12 weeks of age is 30 mg/kg of amoxicillin daily given in divided doses every 12 hours. Because experience with the oral suspension containing 200 mg of amoxicillin/5 mL is limited in this age group, the manufacturer recommends that the oral suspension containing 125 mg of amoxicillin/5 mL be used in neonates and infants younger than 12 weeks of age.

For the treatment of sinusitis, lower respiratory tract infections, and more severe infections in pediatric patients 12 weeks of age and older, the usual dosage of amoxicillin and clavulanate potassium is 45 mg/kg of amoxicillin daily in divided doses every 12 hours administered as the oral suspension containing 200 or 400 mg of amoxicillin/5 mL or as chewable tablets containing 200 or 400 mg of amoxicillin. Alternatively, these infections in this age group can be treated with a dosage of 40 mg/kg of amoxicillin daily in divided doses every 8 hours administered as the oral suspension containing 125 or 250 mg of amoxicillin/5 mL or as chewable tablets containing 125 or 250 mg of amoxicillin.

For the treatment of less severe infections in pediatric patients 12 weeks of age or older, the usual dosage of amoxicillin and clavulanate potassium is 25 mg/kg of amoxicillin daily in divided doses every 12 hours administered as the oral suspension containing 200 or 400 mg of amoxicillin/5 mL or as chewable tablets containing 200 or 400 mg of amoxicillin. Alternatively, less severe infections in this age group can be treated with a dosage of 20 mg/kg of amoxicillin daily in divided doses every 8 hours administered as the oral suspension containing 125 or 250 mg of amoxicillin/5 mL or as chewable tablets containing 125 or 250 mg of amoxicillin.

Acute Otitis Media

For the treatment of acute otitis media (AOM) in pediatric patients, the recommended dosage of amoxicillin and clavulanate potassium is 90 mg/kg of amoxicillin and 6.4 mg/kg of clavulanate daily given in 2 divided doses. The drug usually is given for 10 days, but the optimal duration of therapy is uncertain. The American Academy of Pediatrics (AAP) and American Academy of Family Physicians (AAFP) recommend that a 10-day regimen be used for treatment of AOM in children younger than 6 years of age and in those with severe disease, but that a duration of 5-7 days may be appropriate in those 6 years of age or older with mild to moderate AOM.

Although amoxicillin and clavulanate potassium can be administered in a dosage of 40-45 mg/kg of amoxicillin daily given in 2 or 3 divided doses for 10 days for the treatment of AOM, the AAP, AAFP, US Centers for Disease Control and Prevention (CDC), and others recommend use of the higher dosage. The higher dosage is especially important in patients with AOM known or suspected of being caused by Streptococcus pneumoniae with reduced susceptibility to penicillins, patients with primary treatment failure or persistent or recurrent AOM after treatment with amoxicillin, and in patients who have received anti-infective therapy within the previous few months.

When amoxicillin and clavulanate potassium is administered in the higher dosage for the treatment of AOM in pediatric patients, commercially available formulations containing a 7:1 or 14:1 ratio of amoxicillin to clavulanic acid should be used since these formulations provide a lower daily dosage of clavulanate potassium and minimize the risk of adverse GI effects associated with the clavulanate potassium component. When the oral suspension containing 600 mg of amoxicillin and 42.9 mg of clavulanic acid per 5 mL is used for the treatment of persistent or recurrent AOM in pediatric patients weighing less than 40 kg, the usual dosage is 90 mg/kg of amoxicillin daily given in divided doses every 12 hours for 10 days.

Pharyngitis and Tonsillitis

If amoxicillin and clavulanate potassium is used for the treatment of symptomatic patients who have multiple, recurrent episodes of pharyngitis known to be caused by Streptococcus pyogenes (group A β-hemolytic streptococci) (see Uses: Pharyngitis and Tonsillitis), the Infectious Diseases Society of America (IDSA) recommends that children receive 40 mg/kg of amoxicillin daily (maximum 750 mg daily) given in 3 equally divided doses for 10 days. Adults should receive amoxicillin and clavulanate potassium in a dosage of 500 mg of amoxicillin twice daily for 10 days; the IDSA states that this dosage has not been specifically studied in adults and was extrapolated from the pediatric dosage.

Dosage in Renal and Hepatic Impairment

In patients with renal impairment, doses and/or frequency of administration of amoxicillin and clavulanate potassium should be modified in response to the degree of renal impairment. Some clinicians suggest that modification of usual dosage is unnecessary in adults with creatinine clearances greater than 30 mL/minute. These clinicians recommend that adults with creatinine clearances of 15-30 mL/minute receive the usual dose of conventional preparations of the drug every 12-18 hours, adults with creatinine clearances of 5-15 mL/minute receive the usual dose every 20-36 hours, and adults with creatinine clearances less than 5 mL/minute receive the usual dose every 48 hours. However, other clinicians suggest that use of amoxicillin and clavulanate potassium should be avoided in patients with creatinine clearances less than 30 mL/minute until more data are available on use of the drug in these patients.

Some clinicians suggest that adults undergoing hemodialysis receive a 500-mg tablet containing 500 mg of amoxicillin and 125 mg of clavulanic acid halfway through each dialysis period and an additional 500-mg tablet after each dialysis period.

The pharmacokinetics of extended-release tablets of amoxicillin and clavulanate potassium have not been studied in patients with renal impairment, and the manufacturer states that this preparation is contraindicated in patients with severe impairment (creatinine clearance less than 30 mL/minute and those undergoing hemodialysis). The extended-release tablets should be dosed cautiously in patients with hepatic impairment and liver function should be monitored at frequent intervals.

Cautions

Adverse Effects

Adverse effects reported with amoxicillin and clavulanate potassium are generally dose related and are similar to those reported with amoxicillin alone. For information on adverse effects reported with amoxicillin and other aminopenicillins, .

With the exception of adverse GI effects, which have been reported more frequently with amoxicillin and clavulanate potassium than with amoxicillin alone, the frequency and severity of adverse effects reported with the fixed-combination preparations are generally similar to those reported with amoxicillin alone. The manufacturers state that adverse effects reported with oral amoxicillin and clavulanate potassium are generally mild and transient and have required discontinuance of therapy in less than 3% of patients receiving the drug.

GI effects are the most frequent adverse reactions to oral amoxicillin and clavulanate potassium. Diarrhea or loose stools has been reported in about 9% of patients receiving the drug, and nausea and vomiting have been reported in 1-5% of patients. Abdominal discomfort, anorexia, and flatulence, dyspepsia, gastritis, stomatitis, glossitis, black or hairy tongue, and enterocolitis also have been reported. The frequency of nausea and vomiting appears to be related to the dose of clavulanic acid since these effects have been reported in up to 40% of patients when a 250-mg dose of clavulanic acid rather than a 125-mg dose was used in conjunction with amoxicillin. Administration of oral amoxicillin and clavulanate potassium with meals reportedly decreases the frequency and severity of adverse GI effects, and therefore patients should be advised to take the drug with a meal or snack.

Clostridium difficile-associated diarrhea and colitis (also known as antibiotic-associated pseudomembranous colitis) caused by toxin-producing clostridia may occur during or following discontinuance of amoxicillin and clavulanate potassium. Colitis may range in severity from mild to life-threatening. Mild cases of colitis may respond to discontinuance of the drug alone, but diagnosis and management of moderate to severe cases should include appropriate bacteriologic studies and treatment with fluid, electrolyte, and protein supplementation as indicated; rarely, cautious use of sigmoidoscopy (or other appropriate endoscopic examination) may be considered necessary. If colitis is severe or is not relieved by discontinuance of the drug, appropriate anti-infective therapy (e.g., oral metronidazole or vancomycin) should be administered.

Rash and urticaria have been reported in approximately 3% of patients receiving amoxicillin and clavulanate potassium. Other adverse effects that have been reported in 1% or less of patients receiving the drug include candidal vaginitis, dizziness, headache, fever, and slight thrombocytosis.

Moderate increases in serum concentrations of AST (SGOT) and/or ALT (SGPT), alkaline phosphatase, and/or bilirubin have been reported in patients receiving amoxicillin and clavulanate potassium. Hepatic dysfunction has been reported most frequently in geriatric patients, males, or in patients receiving prolonged therapy with the drug. Histologic findings on liver biopsies have consisted of predominantly cholestatic, hepatocellular, or mixed cholestatic-hepatocellular changes. The onset of manifestations of hepatic dysfunction may occur during or several weeks following discontinuance of amoxicillin and clavulanate potassium therapy and usually is reversible. However, fatal cholestatic hepatitis has been reported rarely; these generally have been cases associated with serious underlying diseases or concomitant drug therapy.

Although not reported to date with amoxicillin and clavulanate potassium, positive direct antiglobulin (Coombs') test results have been reported in patients who received therapy with ticarcillin and clavulanic acid. In one study in immunocompromised patients, positive direct antiglobulin test results occurred during 44% of the courses of therapy with ticarcillin and clavulanic acid and concomitant tobramycin. Positive reactions occurred within 48 hours after initiation of therapy and reverted to negative within 2-4 months after completion of therapy. These reactions appear to result from nonimmunologic adsorption of proteins onto erythrocytes in the presence of clavulanic acid; this nonimmunologic mechanism is similar to that observed with cephalosporins. Nonimmunologic adsorption of proteins onto erythrocyte membranes and positive direct antiglobulin test results also occurred in vitro when erythrocytes obtained from healthy individuals were exposed to clavulanic acid; however, exposure of erythrocytes to ticarcillin alone under various conditions did not result in a positive reaction.

Precautions and Contraindications

Amoxicillin and clavulanate potassium shares the toxic potentials of the penicillins, including the risk of hypersensitivity reactions, and the usual precautions of penicillin therapy should be observed. Prior to initiation of therapy with amoxicillin and clavulanate potassium, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, or other drugs. There is clinical and laboratory evidence of partial cross-allergenicity among penicillins and other β-lactam antibiotics including cephalosporins and cephamycins.

Renal, hepatic, and hematologic function should be evaluated periodically during prolonged therapy with amoxicillin and clavulanate potassium. Because C. difficile-associated diarrhea and colitis has been reported with the use of anti-infective agents including amoxicillin and clavulanate potassium, it should be considered in the differential diagnosis of patients who develop diarrhea during amoxicillin and clavulanate potassium therapy.

Because a high percentage of patients with infectious mononucleosis have developed rash during therapy with aminopenicillins, amoxicillin and clavulanate potassium should not be used in patients with the disease. Amoxicillin and clavulanate potassium is contraindicated in patients who are hypersensitive to any penicillin.

Commercially available amoxicillin and clavulanate potassium chewable tablets containing 200 or 400 mg of amoxicillin and amoxicillin and clavulanate potassium oral suspension containing 200, 400, or 600 mg of amoxicillin per 5 mL contain aspartame, which is metabolized in the GI tract to phenylalanine following oral administration. Individuals with phenylketonuria (i.e., homozygous genetic deficiency of phenylalanine hydroxylase) and other individuals who must restrict their intake of phenylalanine should be warned that each 200- or 400-mg chewable tablet of amoxicillin and clavulanate potassium provides 2.1 or 4.2 mg of phenylalanine, respectively, and each 5 mL of amoxicillin and clavulanate potassium oral suspension containing 200, 400, or 600 mg of amoxicillin provides 7 mg of phenylalanine. While these preparations should not be used in patients with phenylketonuria, other commercially available preparations of amoxicillin and clavulanate potassium do not contain aspartame.

For information on the potassium and sodium content of various amoxicillin and clavulanate potassium preparations, see Chemistry and Stability: Chemistry.

For a more complete discussion of these and other precautions associated with the use of amoxicillin, .

Pediatric Precautions

Adverse effects reported in pediatric patients receiving amoxicillin and clavulanate potassium are similar to those reported in adults. In a clinical study in pediatric patients 2 months to 12 years of age with acute otitis media who received amoxicillin and clavulanate potassium oral suspension, the incidence of diarrhea was lower in those who received the drug in a dosage of 45 mg/kg of amoxicillin daily in divided doses every 12 hours than in those who received the drug in a dosage of 40 mg/kg of amoxicillin daily in divided doses every 8 hours. Diarrhea occurred in 14.3% of those receiving the twice-daily regimen and 34.3% of those receiving the 3-times-daily regimen, and 3.1% of those receiving the twice-daily regimen and 7.6% of those receiving the 3-times-daily regimen had severe diarrhea or were withdrawn from the study with diarrhea. It is not known whether a similar difference in the incidence of diarrhea occurs when amoxicillin and clavulanate potassium chewable tablets are administered in a twice-daily or 3-times-daily regimen.

Safety and efficacy of the extended-release tablets of amoxicillin and clavulanate potassium have not been established in pediatric patients younger than 16 years of age.

Mutagenicity and Carcinogenicity

Studies have not been performed to date to evaluate the mutagenic or carcinogenic potential of amoxicillin and clavulanate potassium.

Pregnancy, Fertility, and Lactation

Pregnancy

Safe use of amoxicillin and clavulanate potassium during pregnancy has not been definitely established. However, oral amoxicillin and clavulanate potassium has been used in a limited number of pregnant women for the treatment of urinary tract infections or acute pelvic inflammatory disease (PID) without evidence of adverse effects to the fetus. There are no adequate or controlled studies using amoxicillin and clavulanate potassium in pregnant women, and the drug should be used during pregnancy only when clearly needed.

Aminopenicillins are generally poorly absorbed when given orally during labor. Although the mechanism is unclear and the clinical importance has not been determined to date, studies using oral ampicillin indicate that, when administered during pregnancy, the drug interferes with metabolism and enterohepatic circulation of steroids resulting in decreased urinary concentrations of estrogen metabolites. The manufacturers state that this effect could also occur with amoxicillin and clavulanate potassium. IV administration of ampicillin to guinea pigs has decreased uterine tone and decreased the frequency, height, and duration of uterine contractions; however, it is not known whether use of amoxicillin and clavulanate potassium in humans during labor or delivery could have any immediate or delayed adverse effects on the fetus, prolong the duration of labor, or increase the likelihood of forceps delivery, other obstetrical intervention, or resuscitation of the neonate.

Fertility

Reproduction studies in mice and rats using doses up to 10 times the usual human dose have not revealed evidence of impaired fertility or harm to the fetus.

Lactation

Because amoxicillin and clavulanic acid are distributed into milk, amoxicillin and clavulanate potassium should be used with caution in nursing women.

Drug Interactions

Probenecid

Oral probenecid administered shortly before or concomitantly with amoxicillin and clavulanate potassium slows the rate of renal tubular secretion of amoxicillin and produces higher and prolonged serum concentrations of amoxicillin. However, concomitant administration of probenecid with amoxicillin and clavulanate potassium does not affect the area under the serum concentration-time curve (AUC), half-life, or peak serum concentration of clavulanic acid.

Allopurinol

Because an increased incidence of rash reportedly occurs in patients with hyperuricemia who are receiving allopurinol and concomitant amoxicillin or ampicillin compared with those receiving amoxicillin, ampicillin, or allopurinol alone, some clinicians suggest that concomitant use of the drugs should be avoided if possible. The manufacturers state that there are no data to date on concomitant administration of allopurinol and amoxicillin and clavulanate potassium.

Disulfiram

Although the rationale is unclear, the US Food and Drug Administration has required the manufacturers to state in their labeling that amoxicillin and clavulanate potassium should not be used in patients receiving disulfiram. However, there is no evidence to date that concomitant use of the drugs would result in a disulfiram-like reaction, and the need for precaution when concomitant use of the drugs is considered has been questioned.

Pharmacokinetics

Crossover studies using fixed combinations of amoxicillin and clavulanate potassium, amoxicillin alone, and clavulanate potassium alone indicate that concomitant administration of clavulanate potassium does not affect the pharmacokinetics of amoxicillin; however, concomitant administration of amoxicillin reportedly may increase GI absorption and renal elimination of clavulanate potassium compared with administration of clavulanate potassium alone.

For additional information on absorption, distribution, and elimination of amoxicillin, and in .

Absorption

Amoxicillin trihydrate and clavulanate potassium are both generally stable in the presence of acidic gastric secretions and are well absorbed following oral administration of amoxicillin and clavulanate potassium. Peak serum concentrations of amoxicillin and of clavulanic acid are generally attained within 1-2.5 hours following oral administration of a single dose of conventional preparations of amoxicillin and clavulanate potassium in fasting adults or a single dose of extended-release tablets in adults fed a standardized meal.

Following oral administration of a single conventional tablet containing 250 mg of amoxicillin and 125 mg of clavulanic acid in healthy, fasting adults, peak serum concentrations of amoxicillin and of clavulanic acid average 3.7-4.8 mcg/mL and 2.2-3.5 mcg/mL, respectively. Following oral administration of a single conventional tablet containing 500 mg of amoxicillin and 125 mg of clavulanic acid in healthy, fasting adults, peak serum concentrations of amoxicillin average 6.5-9.7 mcg/mL and peak serum concentrations of clavulanic acid average 2.1-3.9 mcg/mL. The manufacturer states that serum concentrations of the drugs achieved following oral administration of a single chewable tablet containing 250 mg of amoxicillin and 62.5 mg of clavulanic acid or 2 chewable tablets each containing 125 and 31.25 mg of the drugs, respectively, are similar to those achieved following oral administration of a single equivalent dose of the oral suspension. The manufacturer also states that serum concentrations of amoxicillin achieved following oral administration of conventional preparations or extended-release tablets of amoxicillin and clavulanate potassium are similar to those achieved following oral administration of equivalent doses of amoxicillin alone.

Following oral administration of a single dose of 250 mg of amoxicillin and 62.5 mg of clavulanic acid as an oral suspension, peak serum concentrations of amoxicillin average 6.9 mcg/mL and peak concentrations of clavulanic acid average 1.6 mcg/mL. In one study in children 2-5 years of age with urinary tract infections, oral administration of a single dose of 125 mg of amoxicillin and 31.75 mg of clavulanic acid as an oral suspension resulted in serum concentrations of amoxicillin that averaged 9.4, 9.7, and 6.5 mcg/mL and serum concentrations of clavulanic acid that averaged 2.1, 4.4, and 2.5 mcg/mL at 30, 60, and 90 minutes, respectively, after the dose.

Studies in healthy adults using conventional preparations of amoxicillin and clavulanate potassium indicate that presence of food in the GI tract does not affect oral absorption of either amoxicillin or clavulanic acid following administration of fixed-combination preparations of the drugs. However, amoxicillin and clavulanate are optimally absorbed from extended-release tablets of the combination when administered orally at the beginning of a standardized meal (612 kcal, 89.3 g carbohydrate, 24.9 g fat, and 14 g protein); administration of the extended-release tablets with a high-fat meal is not recommended because clavulanate absorption is decreased, and administration of these tablets in the fasting state is not recommended because amoxicillin absorption is decreased. GI absorption of the drugs from extended-release tablets is not affected by administration simultaneously with or 2 hours before a magnesium and aluminum-containing antacid (Maalox).

Distribution

Following administration of amoxicillin and clavulanate potassium, amoxicillin and clavulanic acid are both distributed into the lungs, pleural fluid, and peritoneal fluid. Low concentrations (i.e., less than 1 mcg/mL) of each drug are attained in sputum and saliva.

In one study in fasting children who received a single amoxicillin dose of 35 mg/kg given as amoxicillin and clavulanate potassium oral suspension, concentrations of amoxicillin and of clavulanic acid in middle ear effusions averaged 3 and 0.5 mcg/mL, respectively, 2 hours after the dose.

Only minimal concentrations of amoxicillin or clavulanic acid are attained in CSF following oral administration of amoxicillin and clavulanate potassium in patients with uninflamed meninges; higher concentrations may be attained when meninges are inflamed. In one study in patients with uninflamed meninges who received a single 250-mg oral dose of clavulanic acid as the sodium salt, concentrations of clavulanic acid in CSF obtained 1-6 hours after the dose ranged from 0-0.2 mcg/mL. In 2 patients with continuous CSF drainage after neurosurgical procedures who received a similar oral dose of the drug, peak CSF concentrations of clavulanic acid were 2.4 and 0.4 mcg/mL, respectively, and occurred approximately 4 hours after the dose; concurrent serum concentrations of clavulanic acid were 2.3 and 0.3 mcg/mL, respectively.

Amoxicillin is 17-20% bound to serum proteins. In vitro or in vivo following oral administration, clavulanic acid is reportedly 22-30% bound to serum proteins at a concentration of 1-100 mcg/mL.

Amoxicillin and clavulanic acid readily cross the placenta. Amoxicillin and clavulanic acid are distributed into milk in low concentrations.

Elimination

Serum concentrations of amoxicillin and clavulanic acid both decline in a biphasic manner and half-lives of the drugs are similar. Following oral administration of conventional preparations or extended-release tablets of amoxicillin and clavulanate potassium in adults with normal renal function, amoxicillin has an elimination half-life of 1-1.3 hours and clavulanic acid has a distribution half-life of 0.28 hours and an elimination half-life of 0.78-1.2 hours. In one study in children 2-15 years of age, the elimination half-lives of amoxicillin and of clavulanic acid averaged 1.2 and 0.8 hours, respectively.

The metabolic fate of clavulanate potassium has not been fully elucidated; however, the drug appears to be extensively metabolized. In rats and dogs, the major metabolite of clavulanic acid is 1-amino-4-hydroxybutan-2-one; this metabolite has also been found in human urine following administration of clavulanic acid. Clavulanic acid is excreted in urine principally by glomerular filtration. Studies in dogs and rats using radiolabeled clavulanic acid indicate that 34-52, 25-27, and 16-33% of a dose of the drug is excreted in urine, feces, and respired air, respectively.

Following oral administration of a single oral dose of amoxicillin and clavulanate potassium in adults with normal renal function, approximately 50-73 and 25-45% of the amoxicillin and clavulanic acid doses, respectively, are excreted unchanged in urine within 6-8 hours. In one study in healthy adults who received a single oral dose of 250 mg of amoxicillin and 125 mg of clavulanic acid, urinary concentrations of amoxicillin and of clavulanic acid averaged 381 and 118 mcg/mL, respectively, in urine collected over the first 2 hours after the dose.

Serum concentrations of amoxicillin and of clavulanic acid are higher and the serum half-lives prolonged in patients with renal impairment. In one study in patients with creatinine clearances of 9 mL/minute, the serum half-lives of amoxicillin and of clavulanic acid were 7.5 and 4.3 hours, respectively.

Oral probenecid administered shortly before or with amoxicillin and clavulanate potassium competitively inhibits renal tubular secretion of amoxicillin and produces higher and prolonged serum concentrations of the drug; however, probenecid does not appreciably affect the pharmacokinetics of clavulanic acid.(See Drug Interactions: Probenecid.)

Amoxicillin and clavulanic acid are both removed by hemodialysis. The manufacturers state that clavulanic acid is also removed by peritoneal dialysis. Only minimal amounts of amoxicillin appear to be removed by peritoneal dialysis.

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