AMOXICILLIN AND CLAVULANATE POTASSIUM: Package Insert and Label Information (Page 2 of 4)

7 DRUG INTERACTIONS

7.1 Probenecid

Probenecid decreases the renal tubular secretion of amoxicillin. Concurrent use with Amoxicillin and Clavulanate Potassium for oral suspension may result in increased and prolonged blood levels of amoxicillin. Co-administration of probenecid is not recommended.

7.2 Oral Anticoagulants

Abnormal prolongation of prothrombin time (increased international normalized ratio [INR]) has been reported in patients receiving amoxicillin and oral anticoagulants. Appropriate monitoring should be undertaken when anticoagulants are prescribed concurrently. Adjustments in the dose of oral anticoagulants may be necessary to maintain the desired level of anticoagulation.

7.3 Allopurinol

The concurrent administration of allopurinol and amoxicillin increases substantially the incidence of rashes in patients receiving both drugs as compared to patients receiving amoxicillin alone. It is not known whether this potentiation of amoxicillin rashes is due to allopurinol or the hyperuricemia present in these patients. There are no data with Amoxicillin and Clavulanate Potassium for oral suspension and allopurinol administered concurrently.

7.4 Oral Contraceptives

Amoxicillin and Clavulanate Potassium for oral suspension may affect intestinal flora, leading to lower estrogen reabsorption and reduced efficacy of combined oral estrogen/progesterone contraceptives.

7.5 Effects on Laboratory Tests

High urine concentrations of amoxicillin may result in false-positive reactions when testing for the presence of glucose in urine using CLINITEST® , Benedict’s Solution, or Fehling’s Solution. Since this effect may also occur with Amoxicillin and Clavulanate Potassium for oral suspension, it is recommended that glucose tests based on enzymatic glucose oxidase reactions be used.

Following administration of amoxicillin to pregnant women, a transient decrease in plasma concentration of total conjugated estriol, estriol-glucuronide, conjugated estrone, and estradiol has been noted.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B.

There are 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.

Reproduction studies performed in pregnant rats and mice given Amoxicillin and Clavulanate Potassium (2:1 ratio formulation of amoxicillin:clavulanate) at oral dosages up to 1200 mg/kg/day revealed no evidence of harm to the fetus due to Amoxicillin and Clavulanate Potassium. The amoxicillin doses in rodents (based on body surface area and assuming a 20 kg child) were approximately 2 times (rats) or equal to (mice) the recommended clinical Amoxicillin and Clavulanate Potassium for oral suspension dose of 90/6.4 mg/kg/day. For clavulanate, these dose multiples were approximately 15 times and 7.5 times the recommended daily dose of Amoxicillin and Clavulanate Potassium for oral suspension.

8.2 Labor and Delivery

Oral ampicillin-class antibacterial drugs are generally poorly absorbed during labor. Studies in guinea pigs have shown that intravenous administration of ampicillin decreased the uterine tone, frequency of contractions, height of contractions, and duration of contractions. However, it is not known whether the 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 that forceps delivery or other obstetrical intervention or resuscitation of the newborn will be necessary. In a single study in women with premature rupture of fetal membranes, it was reported that prophylactic treatment with Amoxicillin and Clavulanate Potassium may be associated with an increased risk of necrotizing enterocolitis in neonates.

8.3 Nursing Mothers

Ampicillin-class antibacterial drugs are excreted in human milk; therefore, caution should be exercised when Amoxicillin and Clavulanate Potassium is administered to a nursing woman.

8.4 Pediatric Use

Safety and efficacy of Amoxicillin and Clavulanate Potassium for oral suspension in infants younger than 3 months have not been established. Safety and efficacy of Amoxicillin and Clavulanate Potassium for oral suspension have been demonstrated for treatment of acute otitis media in infants and children 3 months to 12 years [see Clinical Studies (14)].

The safety and effectiveness of Amoxicillin and Clavulanate Potassium for oral suspension have been established for the treatment of pediatric patients (3 months to 12 years) with acute bacterial sinusitis. This use is supported by evidence from adequate and well-controlled studies of Amoxicillin and Clavulanate Potassium Extended Release Tablets in adults with acute bacterial sinusitis, studies of Amoxicillin and Clavulanate Potassium for oral suspension in pediatric patients with acute otitis media, and by similar pharmacokinetics of amoxicillin and clavulanate in pediatric patients taking Amoxicillin and Clavulanate Potassium for oral suspension [see Clinical Pharmacology (12)] and adults taking Amoxicillin and Clavulanate Potassium Extended Release Tablets.

10 OVERDOSAGE

Following overdosage, patients have experienced primarily gastrointestinal symptoms including stomach and abdominal pain, vomiting, and diarrhea. Rash, hyperactivity, or drowsiness have also been observed in a small number of patients.

In case of overdosage, discontinue Amoxicillin and Clavulanate Potassium for oral suspension, treat symptomatically, and institute supportive measures as required. If the overdosage is very recent and there is no contraindication, an attempt at emesis or other means of removal of drug from the stomach may be performed. A prospective study of 51 pediatric patients at a poison control center suggested that overdosages of less than 250 mg/kg of amoxicillin are not associated with significant clinical symptoms and do not require gastric emptying.1

Interstitial nephritis resulting in oliguric renal failure has been reported in a small number of patients after overdosage with amoxicillin.

Crystalluria, in some cases leading to renal failure, has also been reported after amoxicillin overdosage in adult and pediatric patients. In case of overdosage, adequate fluid intake and diuresis should be maintained to reduce the risk of amoxicillin 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 both amoxicillin and clavulanate. Both amoxicillin and clavulanate are removed from the circulation by hemodialysis [see Dosage and Administration (2)].

11 DESCRIPTION

Amoxicillin and Clavulanate Potassium for oral suspension, USP, is an oral antibacterial combination consisting of the semisynthetic antibacterial amoxicillin and the β-lactamase inhibitor, clavulanate potassium (the potassium salt of clavulanic acid). Amoxicillin is an analog of ampicillin, derived from the basic penicillin nucleus, 6-aminopenicillanic acid. The amoxicillin molecular formula is C16 H19 N3 O5 S•3H2 O, 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:

Figure
(click image for full-size original)

Clavulanic acid is produced by the fermentation of Streptomyces clavuligerus . It is a β-lactam structurally related to the penicillins and possesses the ability to inactivate a wide variety of β-lactamases by blocking the active sites of these enzymes. Clavulanic acid is particularly active against the clinically important plasmid-mediated β-lactamases frequently responsible for transferred drug resistance to penicillins and cephalosporins. The clavulanate potassium molecular formula is C8 H8 KNO5 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:

Figure

Following constitution, each 5 mL of oral suspension contains 600 mg of amoxicillin as the trihydrate and 42.9 mg of clavulanic acid (equivalent to 51.1 mg of clavulanate potassium).

Inactive Ingredients: Aspartame, colloidal silicon dioxide, strawberry cream flavor, xanthan gum, sodium carboxymethylcellulose, and silicon dioxide. [see Warnings and Precautions (5.7)].

Each 5 mL of reconstituted Amoxicillin and Clavulanate Potassium contains 0.23 mEq potassium.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Amoxicillin and Clavulanate Potassium for oral suspension is an antibacterial drug [see Microbiology (12.4)].

12.3 Pharmacokinetics

The pharmacokinetics of amoxicillin and clavulanate were determined in a study of 19 pediatric patients, 8 months to 11 years, given Amoxicillin and Clavulanate Potassium for oral suspension at an amoxicillin dose of 45 mg/kg q12h with a snack or meal. The mean plasma amoxicillin and clavulanate pharmacokinetic parameter values are listed in the following table.

Table 1. Mean (±SD) Plasma Amoxicillin and Clavulanate Pharmacokinetic Parameter Values Following Administration of 45 mg/kg of Amoxicillin and Clavulanate Potassium for oral suspension Every 12 Hours to Pediatric Patients

* Arithmetic mean ± standard deviation, except Tmax values which are medians (ranges).

PARAMETER AMOXICILLIN CLAVULANATE
Cmax (mcg/mL) 15.7 ± 7.7 1.7 ± 0.9
Tmax (hr) 2.0 (1.0 to 4.0) 1.1 (1.0 to 4.0)
AUC0-T (mcg*hr/mL) 59.8 ± 20.0 4.0 ± 1.9
T½ (hr) 1.4 ± 0.3 1.1 ± 0.3
CL/F (L/hr/kg) 0.9 ± 0.4 1.1 ± 1.1

The effect of food on the oral absorption of Amoxicillin and Clavulanate Potassium for oral suspension has not been studied.

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 10 mL of 250 mg/5 mL suspension of Amoxicillin and Clavulanate Potassium.

Concurrent administration of probenecid delays amoxicillin excretion but does not delay renal excretion of clavulanic acid.

Neither component in Amoxicillin and Clavulanate Potassium for oral suspension is highly protein-bound; clavulanic acid has been found to be approximately 25% bound to human serum and amoxicillin approximately 18% bound.

Oral administration of a single dose ofAmoxicillin and Clavulanate Potassium for oral suspension at 45 mg/kg (based on the amoxicillin component) to pediatric patients, 9 months to 8 years, yielded the following pharmacokinetic data for amoxicillin in plasma and middle ear fluid (MEF):

Table 2. Amoxicillin Concentrations in Plasma and Middle Ear Fluid Following Administration of 45 mg/kg of Amoxicillin and Clavulanate Potassium for oral suspension to Pediatric Patients

Timepoint Amoxicillin concentration in plasma (mcg/mL) Amoxicillin concentration in MEF (mcg/mL)
1 hour meanmedianrange 7.79.31.5 to 14.0(n equals 5) 3.23.50.2 to 5.5(n equals 4)
2 hour meanmedianrange 15.713.011.0 to 25.0(n equals 7) 3.32.41.9 to 6(n equals 5)
3 hour meanmedianrange 13.012.05.5 to 21.0(n equals 5) 5.86.53.9 to 7.4(n equals 5)

Dose administered immediately prior to eating.

Amoxicillin diffuses readily into most body tissues and fluids, with the exception of the brain and spinal fluid. The results of experiments involving the administration of clavulanic acid to animals suggest that this compound, like amoxicillin, is well distributed in body tissues.

12.4 Microbiology

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

The clavulanic acid component of Amoxicillin and Clavulanate Potassium for oral suspension protects amoxicillin from degradation by β-lactamase enzymes and effectively extends the antibacterial spectrum of amoxicillin to include many bacteria normally resistant to amoxicillin and other β-lactam antibacterials. Thus, Amoxicillin and Clavulanate Potassium for oral suspension possesses the distinctive properties of a broad spectrum antibacterial and a β-lactamase inhibitor.

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

Gram-Positive bacteria:

Streptococcus pneumoniae (including isolates with penicillin MICs less than or equal to 2 mcg/mL)

Gram-Negative bacteria:

Haemophilus influenzae (including β-lactamase-producing isolates)

Moraxella catarrhalis (including β-lactamase-producing isolates)

The following in vitro data are available, but their clinical significance is unknown. At least 90% of the following microorganisms exhibit in vitro minimum inhibitory concentrations (MICs) less than or equal to the susceptible breakpoint for amoxicillin/clavulanic acid. However, the safety and efficacy of amoxicillin/clavulanic acid in treating infections due to these microorganisms have not been established in adequate and well-controlled trials.

Gram-Positive bacteria:

Staphylococcus aureus (including β-lactamase-producing isolates)

Staphylococci which are resistant to methicillin/oxacillin must be considered resistant to amoxicillin/clavulanic acid.

Streptococcus pyogenes

S. pyogenes do not produce β-lactamase, and therefore, are susceptible to amoxicillin alone. Adequate and well-controlled clinical trials have established the effectiveness of amoxicillin alone in treating certain clinical infections due to S. pyogenes.

Susceptibility Test Methods:

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

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