AMOXICILLIN AND CLAVULANATE POTASSIUM- amoxicillin and clavulanate potassium_tablet, multilayer, extended release

Amoxicillin and clavulanate potassium extended-release tablets is an antibacterial drug [see Microbiology ( 12. Amoxicillin and clavulanate potassium extended-release tablets is an extended-release formulation which provides sustained plasma concentrations of amoxicillin. Amoxicillin systemic exposure achieved with amoxicillin and clavulanate potassium extended-release tablets is similar to that produced by the oral administration of equivalent doses of amoxicillin alone. Absorption Amoxicillin and clavulanate potassium are well absorbed from the gastrointestinal tract after oral administration of amoxicillin and clavulanate potassium extended-release tablets. In a study of healthy adult volunteers, the pharmacokinetics of amoxicillin and clavulanate potassium extended-release tablets were compared when administered in a fasted state, at the start of a standardized meal (612 kcal, 89. 3 g carb, 24. 9 g fat, and 14 g protein), or 30 minutes after a high‑fat meal. When the systemic exposure to both amoxicillin and clavulanate is taken into consideration, amoxicillin and clavulanate potassium extended-release tablets is optimally administered at the start of a standardized meal. Absorption of amoxicillin is decreased in the fasted state. Amoxicillin and clavulanate potassium extended-release tablets is not recommended to be taken with a high‑fat meal, because clavulanate absorption is decreased. The pharmacokinetics of the components of amoxicillin and clavulanate potassium extended-release tablets following administration of two amoxicillin and clavulanate potassium extended-release tablets at the start of a standardized meal are presented in Table 2 Table 2: Mean (SD) Pharmacokinetic Parameter for Amoxicillin and Clavulanate Following Oral Administration of Two Amoxicillin and Clavulanate Potassium Extended-Release Tablets (2,000 mg/125 mg) to Healthy Adult Volunteers (n = 55) Fed a Standardized Meal Parameter (units) Amoxicillin Clavulanate AUC(0‑inf) (mcghr/mL) 71. 55) C max 17. 80) T max 1. 00) T 1/2 1. 17) * Median (range). The half-life of amoxicillin after the oral administration of amoxicillin and clavulanate potassium extended-release tablets is approximately 1. 3 hours, and that of clavulanate is approximately 1. Distribution Neither component in amoxicillin and clavulanate potassium extended-release tablets is highly protein‑bound; clavulanate has been found to be 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. The results of experiments involving the administration of clavulanic acid to animals suggest that this compound, like amoxicillin, is well distributed in body tissues. Excretion Clearance of amoxicillin is predominantly renal, with approximately 60% to 80% of the dose being excreted unchanged in urine, whereas clearance of clavulanate has both a renal (30% to 50%) and a non‑renal component. Specific Populations Pediatric Patients In a study of pediatric patients with acute bacterial sinusitis, 7 to 15 years of age, and weighing at least 40 kg, the pharmacokinetics of amoxicillin and clavulanate were assessed following administration of amoxicillin and clavulanate potassium extended-release tablets 2000 mg/125 mg (as two 1000 mg/62. 5 mg tablets) every 12 hours with food ( Table 3 Table 3: Mean (SD) Pharmacokinetic Parameters for Amoxicillin and Clavulanate Following Oral Administration of Two Amoxicillin and Clavulanate Potassium Extended-Release Tablets (2,000 mg/125 mg) Every 12 Hours with Food to Pediatric Patients (7 to 15 Years of Age and Weighing greater than or equal to 40kg) With Acute Bacterial Sinusitis Parameter (units) Amoxicillin (n=24) Clavulanate (n=23) AUC(0‑tau) (mcghr/mL) 57. 37) C ma x 11. 67) T m ax 2. 0) T1/2(hours) 3. 21) dagger 0. 13) double dagger * Median (range). dagger n=18. double dagger n=17. Drug Interaction Studies Clinical Studies Concurrent administration of probenecid delays amoxicillin excretion but does not delay renal excretion of clavulanate [see Drug Interactions ( 7. In a study of adults, the pharmacokinetics of amoxicillin and clavulanate were not affected by administration of an antacid (MAALOX registered Mechanism of Action Amoxicillin binds to penicillin-binding proteins within the bacterial cell wall and inhibits bacterial cell wall synthesis. Clavulanic acid is a beta-lactam, structurally related to penicillin, that may inactivate certain beta‑lactamase enzymes. Resistance Resistance to penicillins may be mediated by destruction of the beta-lactam ring by a beta-lactamase, altered affinity of penicillin for target, or decreased penetration of the antibacterial drug to reach the target site. Amoxicillin alone is susceptible to degradation by beta‑lactamases, and therefore its spectrum of activity does not include bacteria that produce these enzymes. Antimicrobial Activity Amoxicillin/clavulanic acid has been shown to be active against most isolates of the following microorganisms, both in vitro [see Indications and Usage ( 1 Gram-positive Bacteria: Staphylococcus aureus Streptococcus pneumoniae Gram-negative Bacteria: Haemophilus influenzae Haemophilus parainfluenzae Klebsiella pneumoniae Moraxella catarrhalis The following in vitro in vitro Gram-positive bacteria: Streptococcus pyogenes 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.

Amoxicillin and clavulanate potassium extended-release tablets is indicated for the treatment of infections in adults and pediatric patients weighing greater than or equal to 40 kg who are able to swallow tablets with: due to confirmed, or suspected beta-lactamase-producing pathogens (i. influenzae, M. catarrhalis, H. parainfluenzae, K. pneumoniae S. pneumoniae Limitations of Use Amoxicillin and clavulanate potassium extended-release tablets is not indicated for the treatment of infections due to S. pneumoniae [see Clinical Studies ( 14 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of amoxicillin and clavulanate potassium extended-release tablets and other antibacterial drugs, amoxicillin and clavulanate potassium extended-release tablets should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. In patients with community-acquired pneumonia in whom penicillin-resistant S. pneumoniae Acute bacterial sinusitis or community-acquired pneumonia due to a penicillin-susceptible strain of S. pneumoniae Amoxicillin and clavulanate potassium extended-release tablets is a combination of amoxicillin, a penicillin-class antibacterial and clavulanate potassium, a beta-lactamase inhibitor, indicated for treatment of adults and pediatric patients weighing greater than or equal to 40 kg who are able to swallow tablets with: H. pneumoniae 1 Limitations of Use Amoxicillin and clavulanate potassium extended-release tablets is not indicated for the treatment of infections due to S. pneumoniae 1 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of amoxicillin and clavulanate potassium extended-release tablets and other antibacterial drugs, amoxicillin and clavulanate potassium extended-release tablets should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

2 Indication Dose Duration Acute bacterial sinusitis Two (1,000 mg/62. 5 mg) tablets every 12 hours 10 days Community-acquired pneumonia Two (1,000 mg/62. 5 mg) tablets every 12 hours 7 to 10 days Amoxicillin and clavulanate potassium extended-release tablets should be taken at the start of a meal to enhance the absorption of amoxicillin and to minimize the potential for gastrointestinal intolerance. Amoxicillin and clavulanate potassium extended-release tablets is not recommended to be taken with a high-fat meal because clavulanate absorption is decreased [see Clinical Pharmacology ( 12. 3 The recommended dosage of amoxicillin and clavulanate potassium extended-release tablets is 4,000 mg/250 mg daily in divided doses according to the following table: Table 1: Recommended Dosage of Amoxicillin and Clavulanate Potassium Extended-Release Tablets in Adult Patients Indication Dose Duration Acute bacterial sinusitis Two (1,000 mg/62. 5 mg) tablets every 12 hours 7 to 10 days Amoxicillin and clavulanate potassium extended-release tablets can be split in half along the score line for patients with difficulty swallowing the tablets whole. Both halves of the tablet must be taken immediately. Pediatric patients who weigh 40 kg or more and can swallow tablets should receive the adult dose [see Dosage and Administration ( 2. 4 Hepatically impaired patients should be dosed with caution and hepatic function monitored at regular intervals [see Warnings and Precautions ( 5. Amoxicillin and clavulanate potassium extended-release tablet is NOT.

The following clinically significant adverse reactions are described elsewhere in the labeling: [se e Warnings and Precautions ( 5. 1 [see Warnings and Precautions ( 5. 2 [see Warnings and Precautions ( 5. 3 [see Warnings and Precautions ( 5. 4 Clostridioides difficile [se e Warnings and Precautions ( 5. 5 )] [see Warnings and Precautions ( 5. 6 The most frequently reported adverse reactions were (incidence > 2%), diarrhea, vaginal mycosis, nausea, and loose stools. 1 To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www. gov/medwatch. 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. In clinical trials, 5,643 patients have been treated with amoxicillin and clavulanate potassium extended-release tablets. The most frequently reported adverse reactions which were suspected or probably drug- related were diarrhea (15%), vaginal mycosis (3%), nausea (2%), and loose stools (2%). Amoxicillin and clavulanate potassium extended-release tablets had a higher rate of diarrhea which required corrective therapy (4% versus 3% for amoxicillin and clavulanate potassium extended-release tablets and all comparators, respectively). Two percent of patients discontinued therapy because of drug-related adverse reactions. The following adverse reactions have been identified during post-marketing use of amoxicillin and clavulanate potassium products, including amoxicillin and clavulanate potassium extended-release tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal see Warnings and Precautions ( 5. 5 Immune: [see Warnings and Precautions ( 5. 1 Skin and Appendages: [see Warnings and Precautions ( 5. 6 Liver [see Contraindications ( 4. 2 )], [see Contraindications ( 4. 2 ), Warnings and Precautions ( 5. 4 Renal [see Overdosage ( 10 Hemic and Lymphatic Systems Central Nervous System Miscellaneous.

3 Amoxicillin and clavulanate potassium extended-release tablets is contraindicated in patients with a history of serious hypersensitivity reactions (e. , anaphylaxis or Stevens-Johnson syndrome) to amoxicillin, clavulanate or to other beta-lactam antibacterial drugs (e. , penicillins and cephalosporins). Amoxicillin and clavulanate potassium extended-release tablets is contraindicated in patients with a previous history of cholestatic jaundice/hepatic dysfunction associated with treatment with amoxicillin/clavulanate potassium. Amoxicillin and clavulanate potassium extended-release tablets is contraindicated in patients with severe renal impairment (creatinine clearance less than 30 mL/min) and in hemodialysis patients.

6 Risk Summary Available data from published epidemiologic studies and pharmacovigilance case reports over several decades of use with amoxicillin and clavulanate during pregnancy have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal outcomes. A study in women with preterm prelabor rupture of membranes (PPROM) reported that prophylactic treatment with amoxicillin and clavulanate may be associated with an increased risk of necrotizing enterocolitis in neonates (see Data). Reproduction studies performed in pregnant rodents, given oral doses up to approximately 1. 6 times the amount of amoxicillin and 13 times the amount of clavulanate in the Maximum Human Recommended Dose (MHRD) of amoxicillin and clavulanate potassium extended-release tablets, revealed no evidence of harm to the fetus (see Data). The background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Human Data One randomized, controlled trial included 4,826 pregnant women with premature rupture of fetal membranes who were randomly assigned to 250 mg erythromycin (n=1,197), 250 mg amoxicillin and 125 mg clavulanic acid (amoxicillin and clavulanate, n=1,212), amoxicillin and clavulanate and erythromycin (n=1,192), or placebo (n=1,225) four times daily for 10 days or until delivery. Amoxicillin and clavulanate was associated with a significantly increased rate of proven neonatal necrotizing enterocolitis: 1. 9% (n = 24) in the amoxicillin and clavulanate only group versus 0. 5% (n = 6) in the placebo group (p = 0. 001), and 1. 8% (n = 44) in the any amoxicillin and clavulanate group versus 0. 7% (n =17) in the no amoxicillin and clavulanate group (p = 0. Animal Data Reproduction studies performed in pregnant rats and mice given amoxicillin and clavulanate (2:1 ratio formulation) at oral doses up to 1,200 mg/kg/day revealed no evidence of harm to the fetus due to amoxicillin and clavulanate. In terms of body surface area, the doses in rats were 1. 6 times the Maximum Human Recommended Dose (MHRD) of amoxicillin and 13 times the MHRD for clavulanate in amoxicillin and clavulanate potassium extended-release tablets. For mice, these doses were 0. 4 times the MHRD of amoxicillin and clavulanate, respectively. Risk Summary Data from a published clinical lactation study report that amoxicillin is present in human milk. There are reports of diarrhea, irritability, and rash in infants exposed to amoxicillin and clavulanate through breast milk; therefore, infants exposed to amoxicillin and clavulanate potassium extended-release tablets should be monitored for these symptoms. There are no data on the effects of amoxicillin and clavulanate on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for amoxicillin and clavulanate potassium extended-release tablets and any potential adverse effects on the breastfed child from amoxicillin and clavulanate potassium extended-release tablets or from the underlying maternal condition. The safety and effectiveness of amoxicillin and clavulanate potassium extended-release tablets have been established for pediatric patients weighing greater than or equal to 40 kg who are able to swallow tablets. Use of amoxicillin and clavulanate potassium extended-release tablets in these pediatric patients is supported by evidence from adequate and well-controlled trials of adults with acute bacterial sinusitis and community-acquired pneumonia with additional data from a pediatric pharmacokinetic study. A pharmacokinetic study in pediatric patients (7 to 15 years of age and weighing greater than or equal to 40 kg) was conducted [see Clinical Pharmacology ( 12. 3 Of the total number of subjects in clinical studies of amoxicillin and clavulanate potassium extended-release tablets, 18% were 65 years or older and 7% were 75 years or older. No overall differences in safety and effectiveness were observed between these subjects and younger subjects, and other clinical experience has not reported differences in responses between the elderly and younger patients, but a greater sensitivity of some older individuals cannot be ruled out. Amoxicillin and clavulanate potassium extended-release tablets drug is known to be substantially excreted by the kidney, and the risk of dose dependent toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function. The pharmacokinetics of amoxicillin and clavulanate potassium extended-release tablets have not been studied in patients with renal impairment. Amoxicillin and clavulanate potassium extended-release tablets is contraindicated in patients with a creatinine clearance of less than 30 mL/min and in hemodialysis patients [see Contraindications ( 4. 3 Hepatically impaired patients should be dosed with caution and hepatic function monitored at regular intervals [see Contraindications ( 4. 2 ), Warnings and Precautions ( 5.

4 Probenecid decreases the renal tubular secretion of amoxicillin. Concurrent use with amoxicillin and clavulanate potassium extended-release tablets may result in increased and prolonged blood levels of amoxicillin. Co-administration of probenecid is not recommended. 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. The concurrent administration of allopurinol and amoxicillin substantially increases the incidence of rashes in patients receiving both drugs as compared to patients receiving amoxicillin alone. It is not known whether this potentiation of amoxicillin rashes is due to allopurinol or the hyperuricemia present in these patients. In controlled clinical trials of amoxicillin and clavulanate potassium extended-release tablets, 25 patients received concomitant allopurinol and amoxicillin and clavulanate potassium extended-release tablets. No rashes were reported in these patients. However, this sample size is too small to allow for any conclusions to be drawn regarding the risk of rashes with concomitant amoxicillin and clavulanate potassium extended-release tablets and allopurinol use. Amoxicillin and clavulanate potassium extended-release tablets may affect intestinal flora, leading to lower estrogen reabsorption and reduced efficacy of combined oral estrogen/progesterone contraceptives. High urine concentrations of amoxicillin may result in false-positive reactions when testing for the presence of glucose in urine using CLINITEST registered 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.

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 the case of overdosage, discontinue amoxicillin and clavulanate potassium extended-release tablets, 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 the 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.
NONCLINICAL TOXICOLOGY
Long-term studies in animals have not been performed to evaluate carcinogenic potential. Amoxicillin and clavulanate (4:1 ratio formulation of amoxicillin:clavulanate) was nonmutagenic in the Ames bacterial mutation assay, and the yeast gene conversion assay. Amoxicillin and clavulanate was weakly positive in the mouse lymphoma assay, but the trend toward increased mutation frequencies in this assay occurred at concentrations that were also associated with decreased cell survival. Amoxicillin and clavulanate 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 (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 1.6 times the Maximum Human Recommended Dose (MHRD) in amoxicillin and clavulanate potassium extended-release tablets and the clavulanate dose multiple is approximately 13 times higher than the MHRD.
CLINICAL STUDIES
Adults with a diagnosis of acute bacterial sinusitis (ABS) were evaluated in 3 clinical studies. In one study, 363 patients were randomized to receive either amoxicillin and clavulanate potassium extended-release tablets 2,000 mg/125 mg orally every 12 hours or levofloxacin 500 mg orally daily for 10 days in a double‑blind, multicenter, prospective trial. These patients were clinically and radiologically evaluated at the test of cure (day 17 to 28) visit. The combined clinical and radiological responses were 84% for amoxicillin and clavulanate potassium extended-release tablets and 84% for levofloxacin at the test of cure visit in clinically evaluable patients (95% CI for the treatment difference equals ‑9. The clinical response rates at the test of cure were 87% and 89%, respectively. The other 2 trials were non‑comparative, multicenter studies designed to assess the bacteriological and clinical efficacy of amoxicillin and clavulanate potassium extended-release tablets (2,000 mg/125 mg orally every 12 hours for 10 days) in the treatment of 2,288 patients with ABS. Evaluation timepoints were the same as in the prior study. Patients underwent maxillary sinus puncture for culture prior to receiving study medication. Patients with acute bacterial sinusitis due to S. pneumoniae Table 4 Table 4: Clinical Outcome for ABS Penicillin MICs of S. pneumoniae Intent-To-Treat Clinically Evaluable n/N % 95% CI dagger n/N % 95% CI dagger All S. pneumoniae 344/370 93 em dash 318/326 98 em dash MIC greater than or equal to 2. 0 mcg/mL double dagger 35/36 97 85. 9 30/31 96 83. 0 mcg/mL 23/24 96 78. 9 19/20 95 75. 9 MIC greater than or equal to 4. 0 mcg/mL section 12/12 100 73. 5, 100 11/11 100 71. influenzae 265/305 87 em dash 242/259 93 em dash M. catarrhalis 94/105 90 em dash 86/90 96 em dash * n/N = patients with pathogen eradicated or presumed eradicated/total number of patients. dagger double dagger S. pneumoniae section S. pneumoniae Four randomized, controlled, double‑blind clinical studies and one non‑comparative study were conducted in adults with community-acquired pneumonia (CAP). In comparative studies, 904 patients received amoxicillin and clavulanate potassium extended-release tablets at a dose of 2,000 mg/125 mg orally every 12 hours for 7 or 10 days. In the non-comparative study to assess both clinical and bacteriological efficacy, 1,122 patients received amoxicillin and clavulanate potassium extended-release tablets 2,000 mg/125 mg orally every 12 hours for 7 days. In the 4 comparative studies, the combined clinical success rate at test of cure ranged from 86% to 95% in clinically evaluable patients who received amoxicillin and clavulanate potassium extended-release tablets. Data on the efficacy of amoxicillin and clavulanate potassium extended-release tablets in the treatment of community‑ acquired pneumonia due to S. pneumoniae Table 5 Table 5: Clinical Outcome for CAP due to S. pneumoniae Penicillin MICs of S. pneumoniae 318/367 87 ____ 275/297 93 _____ MIC greater than or equal to 2. 0 mcg/mL double dagger 30/35 86 69. 2 24/25 96 79. 0 mcg/mL 22/24 92 73. 0 18/18 100 81. 5, 100 MIC greater than or equal to 4. 0 mcg/mL section 8/11 73 39. 0 6/7 86 42. 6 * n/N = patients with pathogen eradicated or presumed eradicated/total number of patients.
REFERENCES
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Sandoz Inc

AMOXICILLIN AND CLAVULANATE POTASSIUM- amoxicillin and clavulanate potassium_tablet, multilayer, extended release Product manual source documgent