Amoxicillin and Clavulanate Potassium (Page 4 of 7)

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.

10 OVERDOSAGE

In case of overdosage, discontinue medication, treat symptomatically, and institute supportive measures as required. A prospective study of 51 pediatric patients at a poison-control center suggested that overdosages of less than 250 mg/kg of amoxicillin are not associated with significant clinical symptoms¹.

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

Crystalluria, in some cases leading to renal failure, has also been reported after amoxicillin/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/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/clavulanate potassium. Amoxicillin/clavulanate potassium may be removed from circulation by hemodialysis. [see Dosage and Administration (2.3)]

11 DESCRIPTION

Amoxicillin and Clavulanate Potassium is an oral antibacterial combination consisting of amoxicillin and the beta‑lactamase inhibitor, clavulanate potassium (the potassium salt of clavulanic acid). Amoxicillin is an analog of ampicillin, derived from the basic penicillin nucleus, 6‑aminopenicillanic acid. The amoxicillin molecular formula is 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:

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 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:

Inactive Ingredients:

• Tablets- Colloidal silicon dioxide, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, sodium starch glycolate, and titanium dioxide. Each tablet of amoxicillin/clavulanate potassium contains 0.63 mEq potassium.

• Powder for Oral Suspension, 125 mg/5mL and 250 mg/5mL — Colloidal silicon dioxide, flavorings, xanthan gum, mannitol, succinic acid, silica gel and sodium saccharin.

• Powder for Oral Suspension, 200 mg/5mL and 400 mg/5mL — Colloidal silicon dioxide, flavorings, xanthan gum, silica gel, hypromellose and aspartame. [see Warnings and Precautions (5.6)]

• Chewable Tablets, 125 mg and 250 mg — Colloidal silicon dioxide, flavorings, magnesium stearate, mannitol, sodium saccharin, glycine, and D&C Yellow No.10.
  • Each 125-mg chewable tablet and each 5 mL of reconstituted 125/5 mL oral suspension of Amoxicillin and Clavulanate Potassium contains 0.16 mEq potassium
  • Each 250-mg chewable tablet and each 5 mL of reconstituted 250/5 mL oral suspension of Amoxicillin and Clavulanate Potassium contains 0.32 mEq potassium
• Chewable Tablets, 200 mg and 400 mg — Colloidal silicon dioxide, flavorings, magnesiumstearate, mannitol, FD&C Red No. 40 and aspartame. [see Warnings and Precautions (5.6)]
  • Each 200-mg chewable tablet and each 5 mL of reconstituted 200/5 mL oral suspension of Amoxicillin and Clavulanate Potassium contains 0.14 mEq potassium
  • Each 400-mg chewable tablet and each 5 mL of reconstituted 400/5 mL oral suspension of Amoxicillin and Clavulanate Potassium contains 0.29 mEq potassium

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Amoxicillin and Clavulanate Potassium is an antibacterial drug. [see Microbiology 12.4 ]

12.3 Pharmacokinetics

Mean amoxicillin and clavulanate potassium pharmacokinetic parameters in normal adults following administration of Amoxicillin and Clavulanate Potassium Tablets are shown in Table 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 Parameters^a,b with Amoxicillin and Clavulanate Potassium Tablets

Dose and Regimen	Cmax (mcg/mL)		AUC0-24 (mcg*h/mL)
Amoxicillin/Clavulanate potassium	Amoxicillin	Clavulanate potassium	Amoxicillin	Clavulanate potassium
250/125 mg every 8 hours	3.3 ± 1.12	1.5 ± 0.70	26.7 ± 4.56	12.6 ± 3.25
500/125 mg every 12 hours	6.5 ± 1.41	1.8 ± 0.61	33.4 ± 6.76	8.6 ± 1.95
500 125 mg every 8 hours	7.2 ± 2.26	2.4 ± 0.83	53.4 ± 8.87	15.7 ± 3.86
875/125 mg every 12 hours	11.6 ± 2.78	2.2 ± 0.99	53.5 ± 12.31	10.2 ± 3.04

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

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

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

Dose	Cmax (mcg/mL)		AUC0-24 (mcg*h/mL)
Amoxicillin/Clavulanate potassium	Amoxicillin	Clavulanate potassium	Amoxicillin	Clavulanate potassium
400/57 mg(5 mL of suspension)	6.94 ± 1.24	1.10 ± 0.42	17.29 ± 2.28	2.34 ± 0.94
400/57 mg(1 chewable tablet)	6.67 ± 1.37	1.03 ± 0.33	17.24 ± 2.64	2.17 ± 0.73

^a Mean (± standard deviation) values of 28 normal adults. Peak concentrations occurred approximately 1 hour after the dose.

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

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

Amoxicillin serum concentrations achieved with Amoxicillin and Clavulanate Potassium 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 250‑mg or 500‑mg tablet of Amoxicillin and Clavulanate Potassium .