AUGMENTIN ES-600 (amoxicillinclavulanate potassium) Powder for Oral Suspension

NDA 50-755/S-014 Page 3 AE:L12 PRESCRIBING INFORMATION AUGMENTIN ES-600® (amoxicillin/clavulanate potassium) Powder for Oral Suspension To reduce the development of drug-resistant bacteria and maintain the effectiveness of AUGMENTIN ES-600 (amoxicillin/clavulanate potassium) and other antibacterial drugs, AUGMENTIN ES-600 should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. DESCRIPTION AUGMENTIN ES-600 is an oral antibacterial combination consisting of the semisynthetic antibiotic 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 C16H19N3O5S•3H2O, 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 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 C8H8KNO5 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: Powder for Oral Suspension—Colloidal silicon dioxide, strawberry cream flavor, xanthan gum, aspartame•, sodium carboxymethylcellulose, and silicon dioxide. • See PRECAUTIONS–Information for the Patient/Phenylketonurics. Each 5 mL of reconstituted 600 mg/5 mL oral suspension of AUGMENTIN ES-600 contains 0.23 mEq potassium. CLINICAL PHARMACOLOGY The pharmacokinetics of amoxicillin and clavulanate were determined in a study of 19 pediatric patients, 8 months to 11 years, given AUGMENTIN ES-600 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. NDA 50-755/S-014 Page 4 Table 1. Mean (±SD) Plasma Amoxicillin and Clavulanate Pharmacokinetic Parameter Values Following Administration of 45 mg/kg of AUGMENTIN ES-600 Every 12 Hours to Pediatric Patients Parameter* Amoxicillin Clavulanate Cmax (mcg/mL) 15.7 ± 7.7 1.7 ± 0.9 Tmax (hr) 2.0 (1.0 – 4.0) 1.1 (1.0 – 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 *Arithmetic mean ± standard deviation, except Tmax values which are medians (ranges). The effect of food on the oral absorption of AUGMENTIN ES-600 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 AUGMENTIN. Concurrent administration of probenecid delays amoxicillin excretion but does not delay renal excretion of clavulanic acid. Neither component in AUGMENTIN ES-600 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 of AUGMENTIN ES-600 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 AUGMENTIN ES-600 to Pediatric Patients Timepoint Amoxicillin concentration in plasma (mcg/mL) Amoxicillin concentration in MEF (mcg/mL) 1 hour Mean Median range 7.7 9.3 1.5 – 14.0 (n = 5) 3.2 3.5 0.2 – 5.5 (n = 4) 2 hour mean median range 15.7 13.0 11.0 – 25.0 (n = 7) 3.3 2.4 1.9 – 6 (n = 5) 3 hour mean median range 13.0 12.0 5.5 – 21.0 (n = 5) 5.8 6.5 3.9 – 7.4 (n = 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. NDA 50-755/S-014 Page 5 Microbiology: Amoxicillin is a semisynthetic antibiotic 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 AUGMENTIN ES-600 protects amoxicillin from degradation by β-lactamase enzymes and effectively extends the antibiotic spectrum of amoxicillin to include many bacteria normally resistant to amoxicillin and other β-lactam antibiotics. Thus, AUGMENTIN ES-600 possesses the distinctive properties of a broad-spectrum antibiotic 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 as described in the INDICATIONS AND USAGE section. Aerobic Gram-Positive Microorganisms: Streptococcus pneumoniae (including isolates with penicillin MICs ≤2 mcg/mL) Aerobic Gram-Negative Microorganisms: 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. Aerobic Gram-Positive Microorganisms: Staphylococcus aureus (including β-lactamase–producing isolates) NOTE: Staphylococci which are resistant to methicillin/oxacillin must be considered resistant to amoxicillin/clavulanic acid. Streptococcus pyogenes NOTE: 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: When available, the clinical microbiology laboratory should provide cumulative results of in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting the most effective antimicrobial. Dilution Technique: Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure.1,2 Standardized procedures are based on dilution methods (broth for S. pneumoniae and H. influenzae) or equivalent with standardized inoculum concentration and standardized concentrations of amoxicillin/clavulanate potassium powder. The recommended dilution pattern utilizes a constant amoxicillin/clavulanate potassium ratio of 2 to 1 in all tubes with varying amounts of amoxicillin. MICs are expressed in terms of the amoxicillin NDA 50-755/S-014 Page 6 concentration in the presence of clavulanic acid at a constant 2 parts amoxicillin to 1 part clavulanic acid. The MIC values should be interpreted according to criteria provided in Table 3. Diffusion Technique: Quantitative methods that require measurement of zone diameters also provides reproducible estimates of the susceptibility of bacteria to antimicrobials. One such standardized technique requires the use of a standardized inoculum concentration.2,3 This procedure uses paper disks impregnated with 30 mcg amoxicillin/clavulanate potassium (20 mcg amoxicillin plus 10 mcg clavulanate potassium) to test susceptibility of microorganisms to amoxicillin/clavulanate potassium. Disk diffusion zone sizes should be interpreted according to criteria provided in Table 3. Table 3. Susceptibility Test Result Interpretive Criteria for Amoxicillin/Clavulanate Potassium Pathogen Minimum Inhibitory Concentration (mcg/mL) Disk Diffusion (Zone Diameter in mm) S I R S I R Streptococcus pneumoniae ≤2/1 4/2 ≥8/4 Not applicable (NA) Haemophilus influenzae ≤4/2 NA ≥8/4 ≥20 NA ≤19 NOTE: Susceptibility of S. pneumoniae should be determined using a 1-mcg oxacillin disk. Isolates with oxacillin zone sizes of ≥20 mm are susceptible to amoxicillin/clavulanic acid. An amoxicillin/clavulanic acid MIC should be determined on isolates of S. pneumoniae with oxacillin zone sizes of ≤19 mm. NOTE: β-lactamase–negative, ampicillin-resistant H. influenzae isolates must be considered resistant to amoxicillin/clavulanic acid. A report of S (“Susceptible”) indicates that the antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial compound in the blood reaches the concentration usually achievable. A report of I (“Intermediate”) indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible antimicrobials, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high doses of antimicrobial can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of R (“Resistant”) indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial compound in the blood reaches the concentration usually achievable; other therapy should be selected. Standardized susceptibility test procedures require the use of quality control microorganisms to determine the performance of the test procedures.1-3 Standard amoxicillin/clavulanate potassium powder should provide the MIC ranges for the quality control organisms in Table 4. For the disk diffusion technique, the 30 mcg-amoxicillin/clavulanate potassium disk should provide the zone diameter ranges for the quality control organisms in Table 4. NDA 50-755/S-014 Page 7 Table 4. Acceptable Quality Control Ranges for Amoxicillin/Clavulanate Potassium Quality Control Organism Minimum Inhibitory Concentration Range (mcg/mL) Disk Diffusion (Zone Diameter Range in mm) Escherichia coli ATCC®* 35218† (H. influenzae quality control) 4/2 to 16/8 17 to 22 Haemophilus influenzae ATCC 49247 2/1 to 16/8 15 to 23 Streptococcus pneumoniae ATCC 49619 0.03/0.016 to 0.12/0.06 NA *ATCC is a trademark of the American Type Culture Collection. †When using Haemophilus Test Medium (HTM). INDICATIONS AND USAGE AUGMENTIN ES-600 is indicated for the treatment of pediatric patients with recurrent or persistent acute otitis media due to S. pneumoniae (penicillin MICs ≤2 mcg/mL), H. influenzae (including β-lactamase–producing strains), or M. catarrhalis (including β-lactamase–producing strains) characterized by the following risk factors: • antibiotic exposure for acute otitis media within the preceding 3 months, and either of the following: • age ≤2 years • daycare attendance [See CLINICAL PHARMACOLOGY, Microbiology.] NOTE: Acute otitis media due to S. pneumoniae alone can be treated with amoxicillin. AUGMENTIN ES-600 is not indicated for the treatment of acute otitis media due to S. pneumoniae with penicillin MIC ≥4 mcg/mL. Therapy may be instituted prior to obtaining the results from bacteriological studies when there is reason to believe the infection may involve both S. pneumoniae (penicillin MIC ≤2 mcg/mL) and the β-lactamase–producing organisms listed above. To reduce the development of drug-resistant bacteria and maintain the effectiveness of AUGMENTIN ES-600 and other antibacterial drugs, AUGMENTIN ES-600 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. CONTRAINDICATIONS AUGMENTIN ES-600 is contraindicated in patients with a history of allergic reactions to any penicillin. It is also contraindicated in patients with a previous history of cholestatic jaundice/hepatic dysfunction associated with AUGMENTIN. WARNINGS SERIOUS AND OCCASIONALLY FATAL HYPERSENSITIVITY (ANAPHYLACTIC) REACTIONS HAVE BEEN REPORTED IN PATIENTS ON PENICILLIN THERAPY. THESE REACTIONS ARE MORE LIKELY TO OCCUR IN INDIVIDUALS WITH A HISTORY OF PENICILLIN HYPERSENSITIVITY AND/OR A HISTORY OF SENSITIVITY TO MULTIPLE ALLERGENS. THERE HAVE BEEN REPORTS OF INDIVIDUALS WITH A HISTORY OF NDA 50-755/S-014 Page 8 PENICILLIN HYPERSENSITIVITY WHO HAVE EXPERIENCED SEVERE REACTIONS WHEN TREATED WITH CEPHALOSPORINS. BEFORE INITIATING THERAPY WITH AUGMENTIN ES-600, CAREFUL INQUIRY SHOULD BE MADE CONCERNING PREVIOUS HYPERSENSITIVITY REACTIONS TO PENICILLINS, CEPHALOSPORINS, OR OTHER ALLERGENS. IF AN ALLERGIC REACTION OCCURS, AUGMENTIN ES-600 SHOULD BE DISCONTINUED AND THE APPROPRIATE THERAPY INSTITUTED. SERIOUS ANAPHYLACTIC REACTIONS REQUIRE IMMEDIATE EMERGENCY TREATMENT WITH EPINEPHRINE. OXYGEN, INTRAVENOUS STEROIDS, AND AIRWAY MANAGEMENT, INCLUDING INTUBATION, SHOULD ALSO BE ADMINISTERED AS INDICATED. Pseudomembranous colitis has been reported with nearly all antibacterial agents, including amoxicillin/clavulanate potassium, and has ranged in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents. Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is one primary cause of “antibiotic-associated colitis.” After the diagnosis of pseudomembranous colitis has been established, appropriate therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against C. difficile colitis. AUGMENTIN ES-600 should be used with caution in patients with evidence of hepatic dysfunction. Hepatic toxicity associated with the use of amoxicillin/clavulanate potassium is usually reversible. On rare occasions, deaths have been reported (less than 1 death reported per estimated 4 million prescriptions worldwide). These have generally been cases associated with serious underlying diseases or concomitant medications. (See CONTRAINDICATIONS and ADVERSE REACTIONS—Liver.) PRECAUTIONS General: While amoxicillin/clavulanate possesses the characteristic low toxicity of the penicillin group of antibiotics, periodic assessment of organ system functions, including renal, hepatic, and hematopoietic function, is advisable if therapy is for longer than the drug is approved for administration. A high percentage of patients with mononucleosis who receive ampicillin develop an erythematous skin rash. Thus, ampicillin-class antibiotics should not be administered to patients with mononucleosis. The possibility of superinfections with mycotic or bacterial pathogens should be kept in mind during therapy. If superinfections occur (usually involving Pseudomonas or Candida), the drug should be discontinued and/or appropriate therapy instituted. Prescribing AUGMENTIN ES-600 in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. Information for the Patient: AUGMENTIN ES-600 should be taken every 12 hours with a meal or snack to reduce the possibility of gastrointestinal upset. If diarrhea develops and is severe or lasts more than 2 or 3 days, call your doctor. Keep suspension refrigerated. Shake well before using. When dosing a child with the suspension (liquid) of AUGMENTIN ES-600, use a dosing spoon or medicine dropper. Be sure to rinse the spoon or dropper after each use. Bottles of suspension of AUGMENTIN ES-600 may contain NDA 50-755/S-014 Page 9 more liquid than required. Follow your doctor’s instructions about the amount to use and the days of treatment your child requires. Discard any unused medicine. Patients should be counseled that antibacterial drugs, including AUGMENTIN ES-600, should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When AUGMENTIN ES-600 is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may: (1) decrease the effectiveness of the immediate treatment, and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by AUGMENTIN ES-600 or other antibacterial drugs in the future. Phenylketonurics: Each 5 mL of the 600 mg/5 mL suspension of AUGMENTIN ES-600 contains 7 mg phenylalanine. Drug Interactions: Probenecid decreases the renal tubular secretion of amoxicillin. Concurrent use with AUGMENTIN ES-600 may result in increased and prolonged blood levels of amoxicillin. Co-administration of probenecid cannot be recommended. The concurrent administration of allopurinol and ampicillin