AMOXICILLIN AND CLAVULANATE POTASSIUM_- amoxicillin and clavulanate potassium_tablet, film coated

Amoxicillin and clavulanate potassium is an antibacterial drug [see Microbiology (12. 4) Mean amoxicillin and clavulanate potassium pharmacokinetic parameters in normal adults following administration of amoxicillin and clavulanate potassium tablets are shown in Table 6 and following administration of amoxicillin and clavulanate potassium for oral suspension and chewable tablets are shown in Table 7. Table 6: Mean (+/-S. ) Amoxicillin and Clavulanate Potassium Pharmacokinetic Parameters a,b a b Dose and Regimen of Amoxicillin C max AUC 0-24 Amoxicillin and Clavulanate Potassium Amoxicillin Clavulanate Potassium Amoxicillin Clavulanate Potassium 250 mg/125 mg every 8 hours 3. 25 500 mg/125 mg every 12 hours 6. 95 500 mg/125 mg every 8 hours 7. 86 875 mg/125 mg every 12 hours 11. 04 Table 7: Mean (+/-S. ) Amoxicillin and Clavulanate Potassium Pharmacokinetic Parameters a,b a b Dose of Amoxicillin and Clavulanate Potassium C max AUC 0-24 Amoxicillin and Clavulanate Potassium Amoxicillin Clavulanate Potassium Amoxicillin Clavulanate Potassium 400 mg/57 mg (5 mL of suspension) 6. 94 400 mg/57 mg (1 chewable tablet) 6. 73 Oral administration of 5 mL of the 250 mg/62. 5 mg suspension of amoxicillin and clavulanate potassium or the equivalent dose of 10 mL of the 125 mg/31. 25 mg 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 the 250 mg/62. 5 mg suspension of amoxicillin and clavulanate potassium or equivalent dose of 10 mL of the 125 mg/31. 25 mg suspension of amoxicillin and clavulanate potassium were administered to normal adults. One 250 mg/62. 5 mg chewable tablet of amoxicillin and clavulanate potassium or two 125 mg/31. 25 mg chewable tablets of amoxicillin and clavulanate potassium are equivalent to 5 mL of the 250 mg/62. 5 mg suspension of amoxicillin and clavulanate potassium and provide similar serum concentrations of amoxicillin and clavulanic acid. Absorption: Amoxicillin is a semisynthetic antibacterial with in vitro in vitro [see Indications and Usage (1) Gram-positive bacteria Gram-negative bacteria Escherichia coli Haemophilus influenzae Klebsiella Moraxella catarrhalis in vitro but their clinical significance is unknown in vitro has not been Gram-positive bacteria Staphylococcus epidermidis Staphylococcus saprophyticus Streptococcus pneumoniae Streptococcus pyogenes Streptococcus Gram-negative Bacteria Proteus mirabilis Anaerobic Bacteria Bacteroides fragilis Fusobacterium Peptostreptococcus Susceptibility Test Methods https://www.

Amoxicillin and clavulanate potassium tablets are indicated for the treatment of infections in adults and pediatric patients, due to susceptible isolates of the designated bacteria in the conditions listed below: Lower Respiratory Tract Infections - Haemophilus influenzae Moraxella catarrhalis Acute Bacterial Otitis Media - H. influenzae M. catarrhalis Sinusitis - H. catarrhalis Skin and Skin Structure Infections - Staphylococcus aureus, Escherichia coli, Klebsiella. Urinary Tract Infections - E. coli, Klebsiella , Enterobacter Limitations of Use Amoxicillin and clavulanate potassium tablets are a combination of amoxicillin, a penicillin-class antibacterial and clavulanate potassium, a beta-lactamase inhibitor indicated for treatment of the following infections in adults and pediatric patients: ( 1 Lower respiratory tract infections Acute bacterial otitis media Sinusitis Skin and skin structure infections Urinary tract infections Limitations of Use 1 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of amoxicillin and clavulanate potassium tablets and other antibacterial drugs, amoxicillin and clavulanate potassium tablets should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

Adults and Pediatric Patients greater than 40 kg: 500 mg/125 mg or 875 mg/125 mg every 12 hours or 250 mg/125 mg or 500 mg/125 mg every 8 hours, based on amoxicillin component. 3 Pediatric patients aged 12 weeks (3 months) and older: 25 to 45 mg/kg/day every 12 hours or 20 to 40 mg/kg/day every 8 hours, up to the adult dose. 3 Neonates and infants less than 12 weeks of age: 30 mg/kg/day divided every 12 hours, based on the amoxicillin component. Use of the 125 mg/31. 25 mg per 5 mL oral suspension is recommended. 3 Amoxicillin and clavulanate potassium tablets may be taken without regard to meals; however, absorption of clavulanate potassium is enhanced when amoxicillin and clavulanate potassium tablets are administered at the start of a meal. To minimize the potential for gastrointestinal intolerance, amoxicillin and clavulanate potassium tablets should be taken at the start of a meal. See dosing regimens of amoxicillin and clavulanate potassium tablets (based on the amoxicillin component) provided in Table 1 below. Dosing Regimens of Amoxicillin and Clavulanate Potassium Tablets in Adult Patients TYPE OF INFECTION DOSING REGIMEN OF AMOXICILLIN AND CLAVULANATE POTASSIUM TABLETS Severe infections and infections of the respiratory tract one 875 mg/125 mg tablet a b,c Less severe infections one 500 mg/125 mg tablet b,c d a b c NOT [see Dosage and Administration (2. 6) d NOT [see Dosage and Administration (2. 6) Based on the amoxicillin component, amoxicillin and clavulanate potassium tablets should be dosed as follows: Neonates and Infants Aged less than 12 weeks (less than 3 months) Table 2: Dosing Regimens of Amoxicillin and Clavulanate Potassium Tablets in Neonates and Infants Aged Less than 12 Weeks (Less than 3 Months) PATIENT POPULATION DOSING REGIMEN Amoxicillin and clavulanate potassium 125 mg/31. 25 mg per 5 mL for oral suspension a Neonates and Infants aged less than 12 weeks (less than 3 months) 30 mg/kg/day every 12 hours a Patients Aged 12 weeks (3 months) and Older and Weighing Less than 40 kg The every 12 hour regimen is recommended as it is associated with significantly less diarrhea [see Clinical Studies (14. 2) Table 3: Dosing in Patients Aged 12 Weeks (3 Months) and Older and Weighing Less than 40 kg INFECTION DOSING REGIMEN Every 12 hours Every 8 hours Amoxicillin and clavulanate potassium 200 mg/28. 5 mg per 5 mL a Amoxicillin and clavulanate potassium 125 mg/31. 25 mg per 5 a Otitis media b 45 mg/kg/day every 12 hours 40 mg/kg/day every 8 hours Less severe infections 25 mg/kg/day every 12 hours 20 mg/kg/day every 8 hours a b Patients Weighing 40 kg or More The 250 mg/125 mg tablet of amoxicillin and clavulanate potassium should NOT Patients with impaired renal function do not generally require a reduction in dose unless the impairment is severe. Renal impairment patients with a glomerular filtration rate (GFR) of less than 30 mL/min should NOT Table 4. Dosing Regimens of Amoxicillin and Clavulanate Potassium Tablets in Patients with Severe Renal Impairment Patients with Renal Impairment Dosing Regimen GFR 10 mL/min to 30 mL/min 500 mg or 250 mg every 12 hours, depending on the severity of the infection GFR less than 10 mL/min 500 mg or 250 mg every 24 hours, depending on severity of the infection Hemodialysis 500 mg or 250 mg every 24 hours, depending on severity of the infection A moxicillin and Clavulanate Potassium 250 mg/125 mg Tablet is NOT Amoxicillin and Clavulanate Potassium 250 mg/62. 5 mg Chewable Tablet NOT NOT [see Dosage and Administration (2.

Anaphylactic reactions [see Warnings and Precautions (5. 1) Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5. 2) Drug-Induced Enterocolitis Syndrome (DIES) [see Warnings and Precautions (5. 3) Hepatic Dysfunction [see Warnings and Precautions (5. 4) Clostridioides difficile [see Warnings and Precautions (5. 5) The most frequently reported adverse reactions were diarrhea/loose stools (9%), nausea (3%), skin rashes and urticaria (3%), vomiting (1%) and vaginitis (1%). gov/medwatch [see Clinical Studies (14. 2) In addition to adverse reactions reported from clinical trials, the following have been identified during postmarketing use of amoxicillin and clavulanate potassium. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to amoxicillin and clavulanate potassium. Drug-induced enterocolitis syndrome (DIES), indigestion, gastritis, stomatitis, glossitis, black “hairy” tongue, mucocutaneous candidiasis, enterocolitis, and hemorrhagic/pseudomembranous colitis. Onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment [see Warnings and Precautions (5. 5) [see Warnings and Precautions (5. 1 Skin and Appendages: [see Contraindications (4. 2) Warnings and Precautions (5. 4) [see Overdosage (10) [see Drug Interactions (7.

History of a serious hypersensitivity reaction (e. , anaphylaxis or Stevens-Johnson syndrome) to amoxicillin and clavulanate potassium tablets or to other beta-lactams (e. , penicillins or cephalosporins). 1 History of cholestatic jaundice/hepatic dysfunction associated with amoxicillin and clavulanate potassium tablets. 2 Amoxicillin and clavulanate potassium tablets are 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 tablets are contraindicated in patients with a previous history of cholestatic jaundice/hepatic dysfunction associated with amoxicillin and clavulanate potassium tablets.

Pediatric Use: Modify dose in patients 12 weeks or younger. 4) Renal Impairment: Dosage adjustment is recommended for severe renal impairment (GFR less than 30 mL/min). 6) Oral ampicillin-class antibacterials are poorly absorbed during labor. It is not known whether use of amoxicillin and clavulanate potassium in humans during labor or delivery has immediate or delayed adverse effects on the fetus, prolongs the duration of labor, or increases the likelihood of the necessity for an obstetrical intervention. Amoxicillin has been shown to be excreted in human milk. Amoxicillin and clavulanate potassium use by nursing mothers may lead to sensitization of infants. Caution should be exercised when amoxicillin and clavulanate potassium is administered to a nursing woman. The safety and effectiveness of amoxicillin and clavulanate potassium for oral suspension and chewable tablets have been established in pediatric patients. Use of amoxicillin and clavulanate potassium tablets in pediatric patients is supported by evidence from studies of amoxicillin and clavulanate potassium tablets in adults with additional data from a study of amoxicillin and clavulanate potassium for oral suspension in pediatric patients aged 2 months to 12 years with acute otitis media [see Clinical Studies (14. 2) [see Dosage and Administration (2. 3) Of the 3,119 patients in an analysis of clinical studies of amoxicillin and clavulanate potassium, 32% were greater than or equal to 65 years old, and 14% were greater than or equal to 75 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Amoxicillin is primarily eliminated by the kidney and dosage adjustment is usually required in patients with severe renal impairment (GFR less than 30 mL/min). See Patients with Renal Impairment [see Dosage and Administration (2.

Co-administration with probenecid is not recommended. 1) Concomitant use of amoxicillin and clavulanate potassium and oral anticoagulants may increase the prolongation of prothrombin time. 2) Co-administration with allopurinol increases the risk of rash. 3) Amoxicillin and clavulanate potassium may reduce efficacy of oral contraceptives. 4) Probenecid decreases the renal tubular secretion of amoxicillin but does not delay renal excretion of clavulanic acid. Concurrent use with amoxicillin and clavulanate potassium may result in increased and prolonged blood concentrations 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 with amoxicillin and clavulanate potassium. Adjustments in the dose of oral anticoagulants may be necessary to maintain the desired level of anticoagulation. The concurrent administration of allopurinol and amoxicillin 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. Amoxicillin and clavulanate potassium may affect intestinal flora, leading to lower estrogen reabsorption and reduced efficacy of combined oral estrogen/progesterone contraceptives.

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 symptoms 1 [see Dosage and Administration (2.4)
CLINICAL STUDIES
Data from 2 pivotal trials in 1,191 patients treated for either lower respiratory tract infections or complicated urinary tract infections compared a regimen of 875 mg/125 mg tablets of amoxicillin and clavulanate potassium every 12 hours to 500 mg/125 mg tablets of amoxicillin and clavulanate potassium dosed every 8 hours (584 and 607 patients, respectively). Comparable efficacy was demonstrated between the every 12 hours and every 8 hours dosing regimens. There was no significant difference in the percentage of adverse events in each group. The most frequently reported adverse event was diarrhea; incidence rates were similar for the 875 mg/125 mg every 12 hours and 500 mg/125 mg every 8 hours dosing regimens (15% and 14%, respectively); however, there was a statistically significant difference (p less than 0. 05) in rates of severe diarrhea or withdrawals with diarrhea between the regimens: 1% for 875 mg/125 mg every 12 hours regimen versus 2% for the 500 mg/125 mg every 8 hours regimen. Table 8: Bacteriologic Efficacy Rates for Amoxicillin and Clavulanate Potassium Time Post Therapy 875 mg/125 mg every 12 hours % (n) 500 mg/125 mg every 8 hours % (n) 2 to 4 days 81% (58) 80% (54) 5 to 9 days 58% (41) 52% (52) 2 to 4 weeks 52% (101) 55% (104) As noted, before, though there was no significant difference in the percentage of adverse events in each group, there was a statistically significant difference in rates of severe diarrhea or withdrawals with diarrhea between the regimens. /Canadian clinical trial was conducted which compared 45/6. 4 mg/kg/day (divided every 12 hours) of amoxicillin and clavulanate potassium for 10 days versus 40/10 mg/kg/day (divided every 8 hours) of amoxicillin and clavulanate potassium for 10 days in the treatment of acute otitis media. Only the suspension formulations were used in this trial. A total of 575 pediatric patients (aged 2 months to 12 years) were enrolled, with an even distribution among the 2 treatment groups and a comparable number of patients were evaluable (i. , greater than or equal to 84%) per treatment group. Otitis media-specific criteria were required for eligibility and a strong correlation was found at the end of therapy and follow-up between these criteria and physician assessment of clinical response. The clinical efficacy rates at the end of therapy visit (defined as 2 to 4 days after the completion of therapy) and at the follow-up visit (defined as 22 to 28 days post-completion of therapy) were comparable for the 2 treatment groups, with the following cure rates obtained for the evaluable patients: At end of therapy, 87% (n equals 265) and 82% (n equals 260) for 45 mg/kg/day every 12 hours and 40 mg/kg/day every 8 hours, respectively. At follow-up, 67% (n equals 249) and 69% (n equals 243) for 45 mg/kg/day every 12 hours and 40 mg/kg/day every 8 hours, respectively. Diarrhea was defined as either: (a) 3 or more watery or 4 or more loose/watery stools in 1 day; OR (b) 2 watery stools per day or 3 loose/watery stools per day for 2 consecutive days. The incidence of diarrhea was significantly lower in patients who received the every 12 hours regimen compared to patients who received the every 8 hours regimen (14% and 34%, respectively). In addition, the number of patients with either severe diarrhea or who were withdrawn with diarrhea was significantly lower in the every 12 hours treatment group (3% and 8% for the every 12 hours/10 day and every 8 hours/10 day, respectively). In the every 12 hours treatment group, 3 patients (1%) were withdrawn with an allergic reaction, while 1 patient in the every 8 hours group was withdrawn for this reason. The number of patients with a candidal infection of the diaper area was 4% and 6% for the every 12 hours and every 8 hours groups, respectively. It is not known if the finding of a statistically significant reduction in diarrhea with the oral suspensions dosed every 12 hours, versus suspensions dosed every 8 hours of amoxicillin and clavulanate potassium, can be extrapolated to the chewable tablets of amoxicillin and clavulanate potassium. The presence of mannitol in the chewable tablets of amoxicillin and clavulanate potassium may contribute to a different diarrhea profile.
REFERENCES
1. Swanson-Biearman B, Dean BS, Lopez G, Krenzelok EP. The effects of penicillin and cephalosporin ingestions in children less than six years of age. Vet Hum Toxicol. 1988; 30: 66-67.

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AMOXICILLIN AND CLAVULANATE POTASSIUM_- amoxicillin and clavulanate potassium_tablet, film coated Product manual source documgent