【药品名称】
通用名：阿莫西林克拉维酸钾混悬液
英文名：Amoxicillin and Clavulanate Potassium for Suspension
汉语拼音：Amoxilin Kelɑweisuɑnjiɑ Gɑnhunxuɑnji
本品为复方制剂，其组分为阿莫西林和克拉维酸钾，两者之比为2∶1或4∶1。
【性状】
本品为加矫味剂的粉末；气芳香，味甜。
【药理毒理】
本品为阿莫西林和克拉维酸钾的复方制剂。阿莫西林为广谱青霉素类抗生素，克拉维酸钾本身只有微弱的抗菌活性，但具有强大广谱??内酰胺酶抑制作用，两者合用，可保护阿莫西林免遭? 内酰胺酶水解。
本品的抗菌谱与阿莫西林相同，且有所扩大。对产酶金黄色葡萄球菌、表皮葡萄球菌、凝固酶阴性葡萄球菌及肠球菌均具良好作用，对某些产??内酰胺酶的肠肝菌科细菌、流感嗜血杆菌、卡他莫拉菌、脆弱拟杆菌等也有较好抗菌活性。本品对耐甲氧西林葡萄球菌及肠杆菌属等产染色体介导Ⅰ型酶的肠杆菌科细菌和假单胞菌属无作用。
【药代动力学】
本品对胃酸稳定，口服吸收良好，食物对本品的吸收无明显影响。空腹口服本品375mg（阿莫西林250mg，和克拉维酸125mg)，阿莫西林于1.5小时达血药峰浓度（Cmax)，约为5.6mg/L。血消除半衰期（t1/2?)约为1小时。
8小时尿排出率为50%～78%。克拉维酸的药动学参数与单用时相同，正常人口服克拉维酸125g后1小时达血药峰浓度（Cmax)，约为3.4mg/L。蛋白结合率为22%～30%。血消除半衰期（t1/2?)为0.76～1.4小时，8小时尿排出率约为46%。两者口服的生物利用度分别为97%和75%。
【适应症】
本品适用于产酶流感嗜血杆菌和卡他莫拉菌所致的下呼吸道感染、中耳炎、鼻窦炎；产酶金黄色葡萄球菌和产酶肠杆菌科细菌如大肠杆菌、克雷伯菌属所致的呼吸道、尿路和皮肤软组织感染等；亦可用于肠球菌所致的轻中度感染。
本品也可用于敏感不产酶菌所致的上述各种感染。
【用法用量】
口服。
成人 肺炎及其他中重度感染：一次625mg，每8小时1次，疗程7～10日。医学全在.线www.med126.com其他感染：一次375mg ，每8小时1次，疗程7～10日。
小儿 ①新生儿及3个月以内婴儿。按阿莫西林计算，按体重一次15mg/kg，每12小时1次。②体重≤40kg的小儿。按阿莫西林计算，一般感染：按体重一次25mg/kg，每12小时1次；或按体重一次20mg/kg，每8小时1次。较重感染：按体重一次45mg/kg，每12小时1次；或按体重一次40mg/kg，每8小时1次。疗程7～10日。其他感染剂量减半。
40kg以上的儿童可按成人剂量给药。
肾功能减退者 肌酐清除率>30ml/分钟者不需减量；肌酐清除率10～30ml/分钟者每12小时口服本品250～500mg（以阿莫西林计)；肌酐清除率<10ml/分钟者每24小时口服本品250～500mg（以阿莫西林计)。
血液透析患者 根据病情轻重，每24小时口服本品250～500mg（以阿莫西林计)；在血液透析过程中及结束时各加服1次。
【不良反应】
1．常见胃肠道反应如腹泻、恶心和呕吐等。
2．皮疹，尤其易发生于传染性单核细胞增多症者。
3．可见过敏性休克、药物热和哮喘等。
4．偶见血清氨基转移酶升高、嗜酸性粒细胞增多、白细胞降低及念珠菌或耐药菌引起的二重感染。
【禁忌】
青霉素皮试阳性反应者、对本品及其他青霉素类药物过敏者及传染性单核细胞增多症患者禁用。
【注意事项】
1．患者每次开始服用本品前，必须先进行青霉素皮试。
2．对头孢菌素类药物过敏者及有哮喘、湿疹、枯草热、荨麻疹等过敏性疾病史者和严重肝功能障碍者慎用。
3．本品与其他青霉素类和头孢菌素类药物之间有交叉过敏性。执业医师考试若有过敏反应产生，则应立即停用本品，并采取相应措施。
4．本品与氨苄西林有完全交叉耐药性，与其他青霉素类和头孢菌素类有交叉耐药性。
5．肾功能减退者应根据血浆肌酐清除率调整剂量或给药间隔；血液透析可影响本品中阿莫西林的血药浓度，因此在血液透析过程中及结束时应加服本品1次。
6．对怀疑为伴梅毒损害之淋病患者，在使用本品前应进行暗视野检查，并至少在4个月内，每月接受血清试验一次。
7．长期或大剂量服用本品者，应定期检查肝、肾、造血系统功能和检测血清钾或钠。
8．对实验室检查指标的干扰：①硫酸铜法尿糖试验可呈假阳性，但葡萄糖酶试验法不受影响；②可使血清丙氨酸氨基转移酶或门冬氨酸氨基转移酶测定值升高。
【孕妇及哺乳期妇女用药】
1．本品可通过胎盘，脐带血中浓度为母体血药浓度的 ～ ，故孕妇禁用。
2．本品可分泌入母乳中，可能使婴儿致敏并引起腹泻、皮疹、念球菌属感染等，故哺乳期妇女慎用或用药期间暂停哺乳。
【儿童用药】
【老年患者用药】
老年患者应根据肾功能情况调整用药剂量或给药间隔。
【药物相互作用】
1．阿司匹林、吲哚美辛、保泰松、磺胺药可减少本品在肾小管的排泄，因而使本品的血药浓度升高，血消除半衰期（t1/2?)延长，毒性也可能增加。
2．本品与别嘌醇合用时，皮疹发生率显著增高，故应避免合用。
3．本品不宜与双硫仑等乙醛脱氢酶抑制药合用。
4．本品与氯霉素合用于细菌性脑膜炎时，远期后遗症的发生率较两者单用时高。
5．本品可刺激雌激素代谢或减少其肠肝循环，因此可降低口服避孕药的效果。
6．氯霉素、红霉素、四环素类等抗生素和磺胺药等抑菌药可干扰本品的杀菌活性，因此不宜与本品合用，尤其在治疗脑膜炎或急需杀菌药的严重感染时。
7．本品可加强华法林的作用。
8．氨基糖苷类抗生素在亚抑菌浓度时一般可增强本品对粪肠球菌的体外杀菌作用。
9．由于本品在胃肠道的吸收不受食物影响，故可在空腹或餐后服用，并可与牛奶等食物同服；与食物同服可减少胃肠道反应。
【贮藏】
密封，在阴凉干燥处保存。
Augmentin ES
Generic Name: amoxicillin and clavulanate potassium
Dosage Form: powder, for oral suspension
Augmentin ES
(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
Augmentin ES 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, aspartamea, sodium carboxymethylcellulose, and silicon dioxide.
a 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.
Augmentin ES - 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 every 12 hours with a snack or meal. The mean plasma amoxicillin and clavulanate pharmacokinetic parameter values are listed in Table 1.
| Parametera | 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 |
a 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).
| 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.
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.
Streptococcus pneumoniae (including isolates with penicillin MICs ≤ 2 mcg/mL)
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.
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.
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 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.
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.
| 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.
| Quality Control Organism |
Minimum Inhibitory Concentration Range (mcg/mL) |
Disk Diffusion (Zone Diameter Range in mm) |
|
Escherichia coli ATCC®a 35218b (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 |
a ATCC is a trademark of the American Type Culture Collection.
b When using Haemophilus Test Medium (HTM).
Indications and Usage for Augmentin ES
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 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.
Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Augmentin ES-600, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.
C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.
If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
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.
Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as 2 or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.
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 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.
Abnormal prolongation of prothrombin time (increased international normalized ratio [INR]) has been reported rarely 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 ampicillin increases substantially the incidence of rashes in patients receiving both drugs as compared to patients receiving ampicillin alone. It is not known whether this potentiation of ampicillin rashes is due to allopurinol or the hyperuricemia present in these patients. There are no data with AUGMENTIN ES-600 and allopurinol administered concurrently.
In common with other broad-spectrum antibiotics, amoxicillin/clavulanate may reduce the efficacy of oral contraceptives.
Drug/Laboratory Test Interactions
Oral administration of AUGMENTIN will result in high urine concentrations of amoxicillin. High urine concentrations of ampicillin 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 therefore AUGMENTIN ES-600, it is recommended that glucose tests based on enzymatic glucose oxidase reactions (such as CLINISTIX®) be used.
Following administration of ampicillin to pregnant women, a transient decrease in plasma concentration of total conjugated estriol, estriol-glucuronide, conjugated estrone, and estradiol has been noted. This effect may also occur with amoxicillin and therefore AUGMENTIN ES-600.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term studies in animals have not been performed to evaluate carcinogenic potential. The mutagenic potential of AUGMENTIN was investigated in vitro with an Ames test, a human lymphocyte cytogenetic assay, a yeast test, and a mouse lymphoma forward mutation assay, and in vivo with mouse micronucleus tests and a dominant lethal test. All were negative apart from the in vitro mouse lymphoma assay where weak activity was found at very high, cytotoxic concentrations. AUGMENTIN at oral doses of up to 1,200 mg/kg/day (5.7 times the maximum adult human dose based on body surface area) was found to have no effect on fertility and reproductive performance in rats, dosed with a 2:1 ratio formulation of amoxicillin:clavulanate.
Pregnancy
Teratogenic Effects
Pregnancy (Category B). Reproduction studies performed in pregnant rats and mice given AUGMENTIN at oral dosages up to 1,200 mg/kg/day (4.9 and 2.8 times the maximum adult human oral dose based on body surface area, respectively), revealed no evidence of harm to the fetus due to AUGMENTIN. There are, however, 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.
Labor and Delivery
Oral ampicillin-class antibiotics 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 AUGMENTIN 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 AUGMENTIN may be associated with an increased risk of necrotizing enterocolitis in neonates.
Nursing Mothers
Ampicillin-class antibiotics are excreted in human milk; therefore, caution should be exercised when AUGMENTIN is administered to a nursing woman.
Pediatric Use
Safety and efficacy of AUGMENTIN ES-600 in infants younger than 3 months have not been established. Safety and efficacy of AUGMENTIN ES-600 have been demonstrated for treatment of acute otitis media in infants and children 3 months to 12 years (see Description of Clinical Studies).
The safety and effectiveness of AUGMENTIN ES–600 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 AUGMENTIN XR™ Extended Release Tablets in adults with acute bacterial sinusitis, studies of AUGMENTIN ES-600 in pediatric patients with acute otitis media, and by similar pharmacokinetics of amoxicillin and clavulanate in pediatric patients taking Augmentin ES-600 (see CLINICAL PHARMACOLOGY) and adults taking AUGMENTIN XR.
Adverse Reactions
AUGMENTIN ES-600 is generally well tolerated. The majority of side effects observed in pediatric clinical trials of acute otitis media were either mild or moderate, and transient in nature; 4.4% of patients discontinued therapy because of drug-related side effects. The most commonly reported side effects with probable or suspected relationship to AUGMENTIN ES-600 were contact dermatitis, i.e., diaper rash (3.5%), diarrhea (2.9%), vomiting (2.2%), moniliasis (1.4%), and rash (1.1%). The most common adverse experiences leading to withdrawal that were of probable or suspected relationship to AUGMENTIN ES-600 were diarrhea (2.5%) and vomiting (1.4%).
The following adverse reactions have been reported for ampicillin-class antibiotics:
Gastrointestinal
Diarrhea, nausea, vomiting, indigestion, gastritis, stomatitis, glossitis, black “hairy” tongue, mucocutaneous candidiasis, enterocolitis, and hemorrhagic/pseudomembranous colitis. Onset of pseudomembranous colitis symptoms may occur during or after antibiotic treatment. (See WARNINGS.)
Hypersensitivity Reactions
Skin rashes, pruritus, urticaria, angioedema, serum sickness−like reactions (urticaria or skin rash accompanied by arthritis, arthralgia, myalgia, and frequently fever), erythema multiforme (rarely Stevens-Johnson syndrome), acute generalized exanthematous pustulosis, hypersensitivity vasculitis, and an occasional case of exfoliative dermatitis (including toxic epidermal necrolysis) have been reported. These reactions may be controlled with antihistamines and, if necessary, systemic corticosteroids. Whenever such reactions occur, the drug should be discontinued, unless the opinion of the physician dictates otherwise. Serious and occasional fatal hypersensitivity (anaphylactic) reactions can occur with oral penicillin. (See WARNINGS.)
Liver
A moderate rise in AST (SGOT) and/or ALT (SGPT) has been noted in patients treated with ampicillin-class antibiotics, but the significance of these findings is unknown. Hepatic dysfunction, including hepatitis and cholestatic jaundice, (See CONTRAINDICATIONS.) increases in serum transaminases (AST and/or ALT), serum bilirubin, and/or alkaline phosphatase, has been infrequently reported with AUGMENTIN. It has been reported more commonly in the elderly, in males, or in patients on prolonged treatment. The histologic findings on liver biopsy have consisted of predominantly cholestatic, hepatocellular, or mixed cholestatic-hepatocellular changes. The onset of signs/symptoms of hepatic dysfunction may occur during or several weeks after therapy has been discontinued. The hepatic dysfunction, which may be severe, 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.
Renal
Interstitial nephritis and hematuria have been reported rarely. Crystalluria has also been reported (see OVERDOSAGE).
Hemic and Lymphatic Systems
Anemia, including hemolytic anemia, thrombocytopenia, thrombocytopenic purpura, eosinophilia, leukopenia, and agranulocytosis have been reported during therapy with penicillins. These reactions are usually reversible on discontinuation of therapy and are believed to be hypersensitivity phenomena. A slight thrombocytosis was noted in less than 1% of the patients treated with AUGMENTIN. There have been reports of increased prothrombin time in patients receiving AUGMENTIN and anticoagulant therapy concomitantly.
Central Nervous System
Agitation, anxiety, behavioral changes, confusion, convulsions, dizziness, insomnia, and reversible hyperactivity have been reported rarely.
Miscellaneous
Tooth discoloration (brown, yellow, or gray staining) has been rarely reported. Most reports occurred in pediatric patients. Discoloration was reduced or eliminated with brushing or dental cleaning in most cases.
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 AUGMENTIN ES-600, 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.4
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.
Augmentin ES-600 Dosage and Administration
AUGMENTIN ES-600, 600 mg/5 mL, does not contain the same amount of clavulanic acid (as the potassium salt) as any of the other suspensions of AUGMENTIN. AUGMENTIN ES-600 contains 42.9 mg of clavulanic acid per 5 mL, whereas the 200 mg/5 mL suspension of AUGMENTIN contains 28.5 mg of clavulanic acid per 5 mL and the 400 mg/5 mL suspension contains 57 mg of clavulanic acid per 5 mL. Therefore, the 200 mg/5 mL and 400 mg/5 mL suspensions of AUGMENTIN should not be substituted for AUGMENTIN ES-600, as they are not interchangeable.
Dosage
Pediatric patients 3 months and older
Based on the amoxicillin component (600 mg/5 mL), the recommended dose of AUGMENTIN ES-600 is 90 mg/kg/day divided every 12 hours, administered for 10 days (see chart below).
| Body Weight (kg) | Volume of AUGMENTIN ES-600 providing 90 mg/kg/day |
| 8 | 3.0 mL twice daily |
| 12 | 4.5 mL twice daily |
| 16 | 6.0 mL twice daily |
| 20 | 7.5 mL twice daily |
| 24 | 9.0 mL twice daily |
| 28 | 10.5 mL twice daily |
| 32 | 12.0 mL twice daily |
| 36 | 13.5 mL twice daily |
Experience with AUGMENTIN ES-600 (600 mg/5 mL formulation) in this group is not available.
Experience with AUGMENTIN ES-600 (600 mg/5 mL formulation) in adults is not available and adults who have difficulty swallowing should not be given AUGMENTIN ES-600 (600 mg/5 mL) in place of the 500-mg or 875-mg tablet of AUGMENTIN.
Hepatically impaired patients should be dosed with caution and hepatic function monitored at regular intervals. (See WARNINGS.)
Directions for Mixing Oral Suspension
Prepare a suspension at time of dispensing as follows: Tap bottle until all the powder flows freely. Add approximately 2/3 of the total amount of water for reconstitution (see table below) and shake vigorously to suspend powder. Add remainder of the water and again shake vigorously.
| AUGMENTIN ES-600 (600 mg/5 mL Suspension) | |
| Bottle Size |
Amount of Water Required for Reconstitution |
| 75 mL | 70 mL |
| 125 mL | 110 mL |
| 200 mL | 180 mL |
Each teaspoonful (5 mL) will contain 600 mg amoxicillin as the trihydrate and 42.9 mg of clavulanic acid as the potassium salt.
NOTE: SHAKE ORAL SUSPENSION WELL BEFORE USING.
Information for the Pharmacist
For patients who wish to alter the taste of AUGMENTIN ES-600, immediately after reconstitution 1 drop of FLAVORx™ (apple, banana cream, bubble gum, cherry, or watermelon flavor) may be added for every 5 mL of AUGMENTIN ES-600. The resulting suspension is stable for 10 days under refrigeration. Other than the 5 flavors listed above, GlaxoSmithKline has not evaluated the stability of Augmentin ES-600 when mixed with other flavors distributed by FLAVORx.
Administration
To minimize the potential for gastrointestinal intolerance, AUGMENTIN ES-600 should be taken at the start of a meal. Absorption of clavulanate potassium may be enhanced when AUGMENTIN ES-600 is administered at the start of a meal.
How is Augmentin ES Supplied
AUGMENTIN ES-600, 600 mg/5 mL, for Oral Suspension
Each 5 mL of reconstituted strawberry cream-flavored suspension contains 600 mg amoxicillin and 42.9 mg clavulanic acid as the potassium salt.
NDC 0029-6094-40 75 mL bottle
NDC 0029-6094-46 125 mL bottle
NDC 0029-6094-25 200 mL bottle
STORAGE
Store reconstituted suspension under refrigeration. Discard unused suspension after 10 days. Store dry powder for oral suspension at or below 25°C (77°F). Dispense in original container.
Clinical Studies
Two clinical studies were conducted in pediatric patients with acute otitis media.
A non-comparative, open-label study assessed the bacteriologic and clinical efficacy of AUGMENTIN ES-600 (90/6.4 mg/kg/day, divided every 12 hours) for 10 days in 521 pediatric patients (3 to 50 months) with acute otitis media. The primary objective was to assess bacteriological response in children with acute otitis media due to S. pneumoniae with amoxicillin/clavulanic acid MICs of 4 mcg/mL. The study sought the enrollment of patients with the following risk factors: Failure of antibiotic therapy for acute otitis media in the previous 3 months, history of recurrent episodes of acute otitis media, ≤ 2 years, or daycare attendance. Prior to receiving AUGMENTIN ES-600, all patients had tympanocentesis to obtain middle ear fluid for bacteriological evaluation. Patients from whom S. pneumoniae (alone or in combination with other bacteria) was isolated had a second tympanocentesis 4 to 6 days after the start of therapy. Clinical assessments were planned for all patients during treatment (4-6 days after starting therapy), as well as 2-4 days post-treatment and 15-18 days post-treatment. Bacteriological success was defined as the absence of the pretreatment pathogen from the on-therapy tympanocentesis specimen. Clinical success was defined as improvement or resolution of signs and symptoms. Clinical failure was defined as lack of improvement or worsening of signs and/or symptoms at any time following at least 72 hours of AUGMENTN ES-600 (amoxicillin/clavulanate potassium); patients who received an additional systemic antibacterial drug for otitis media after 3 days of therapy were considered clinical failures. Bacteriological eradication on therapy (day 4-6 visit) in the per protocol population is summarized in Table 5.
| Bacteriologic Eradication on Therapy | |||
| Pathogen | n/N | % | 95% CIa |
| All S. pneumoniae | 121/123 | 98.4 | (94.3, 99.8) |
| S. pneumoniae with penicillin MIC = 2 mcg/mL |
19/19 |
100 |
(82.4, 100.0) |
|
S. pneumoniae with penicillin MIC = 4 mcg/mL |
12/14 |
85.7 |
(57.2, 98.2) |
| H. influenzae | 75/81 | 92.6 | (84.6, 97.2) |
| M. catarrhalis | 11/11 | 100 | (71.5, 100.0) |
a CI = confidence intervals; 95% CIs are not adjusted for multiple comparisons.
Clinical assessments were made in the per protocol population 2-4 days post-therapy and 15-18 days post-therapy. Patients who responded to therapy 2-4 days post-therapy were followed for 15-18 days post-therapy to assess them for acute otitis media. Nonresponders at 2-4 days post-therapy were considered failures at the latter timepoint.
| 2-4 Days Post-Therapy (Primary Endpoint) | |||
| Pathogen | n/N | % | 95% CIb |
| All S. pneumoniae | 122/137 | 89.1 | (82.6, 93.7) |
| S. pneumoniae with penicillin MIC = 2 mcg/mL | 17/20 | 85.0 | (62.1, 96.8) |
| S. pneumoniae with penicillin MIC = 4 mcg/mL | 11/14 | 78.6 | (49.2, 95.3) |
| H. influenzae | 141/162 | 87.0 | (80.9, 91.8) |
| M. catarrhalis | 22/26 | 84.6 | (65.1, 95.6) |
| 15-18 Days Post-Therapyc (Secondary Endpoint) | |||
| N/N | % | 95% CI† | |
| All S. pneumoniae | 95/136 | 69.9 | (61.4, 77.4) |
| S. pneumoniae with penicillin MIC = 2 mcg/mL | 11/20 | 55.0 | (31.5, 76.9) |
| S. pneumoniae with penicillin MIC = 4 mcg/mL | 5/14 | 35.7 | (12.8, 64.9) |
| H. influenzae | 106/156 | 67.9 | (60.0, 75.2) |
| M. catarrhalis | 14/25 | 56.0 | (34.9, 75.6) |
a S. pneumoniae strains with penicillin MICs of 2 or 4 mcg/mL are considered resistant to penicillin.
b CI = confidence intervals; 95% CIs are not adjusted for multiple comparisons.
c Clinical assessments at 15-18 days post-therapy may have been confounded by viral infections and new episodes of acute otitis media with time elapsed post-treatment.
In the intent-to-treat analysis, overall clinical outcomes at 2-4 days and 15-18 days post-treatment in patients with S. pneumoniae with penicillin MIC = 2 mcg/mL and 4 mcg/mL were 29/41 (71%) and 17/41 (41.5%), respectively.
In the intent-to-treat population of 521 patients, the most frequently reported adverse events were vomiting (6.9%), fever (6.1%), contact dermatitis (i.e., diaper rash) (6.1%), upper respiratory tract infection (4.0%), and diarrhea (3.8%). Protocol-defined diarrhea (i.e., 3 or more watery stools in one day or 2 watery stools per day for 2 consecutive days as recorded on diary cards) occurred in 12.9% of patients.
A double-blind, randomized, clinical study compared AUGMENTIN ES-600 (90/6.4 mg/kg/day, divided every 12 hours) to AUGMENTIN (45/6.4 mg/kg/day, divided every 12 hours) for 10 days in 450 pediatric patients (3 months to 12 years) with acute otitis media. The primary objective of the study was to compare the safety of AUGMENTIN ES-600 to AUGMENTIN. There was no statistically significant difference between treatments in the proportion of patients with 1 or more adverse events. The most frequently reported adverse events for AUGMENTIN ES-600 and the comparator of AUGMENTIN were coughing (11.9% versus 6.8%), vomiting (6.5% versus 7.7%), contact dermatitis (i.e., diaper rash, 6.0% versus 4.8%), fever (5.5% versus 3.9%), and upper respiratory infection (3.0% versus 9.2%), respectively. The frequencies of protocol-defined diarrhea with AUGMENTIN ES-600 (11.1%) and AUGMENTIN (9.4%) were similar (95% confidence interval on difference: −4.2% to 7.7%). Only 2 patients in the group treated with AUGMENTIN ES-600 and 1 patient in the group treated with AUGMENTIN were withdrawn due to diarrhea.
REFERENCES
- National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically − Sixth Edition; Approved Standard, NCCLS Document M7-A6, Vol. 23, No. 2, NCCLS, Wayne, PA, January 2003.
- National Committee for Clinical Laboratory Standards for Antimicrobial Susceptibility Testing: Fourteenth Informational Supplement; Approved Standard, NCCLS Document 100-S14, Vol. 24, No. 1, NCCLS, Wayne, PA, January 2004.
- National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Disk Susceptibility Tests − Eighth Edition; Approved Standard, NCCLS Document M2-A8, Vol. 23, No. 1, NCCLS, Wayne, PA, January 2003.
- 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.
AUGMENTIN ES-600 is a registered trademark of GlaxoSmithKline.
AUGMENTIN XR is a trademark of GlaxoSmithKline.
CLINITEST is a registered trademark of Miles, Inc.
CLINISTIX is a registered trademark of Bayer Corporation.
FLAVORx is a trademark of FLAVORx, Inc.
GlaxoSmithKline
Research Triangle Park, NC 27709
©2009, GlaxoSmithKline. All rights reserved.
September 2009 AUE:14PI
Principal Display Panel
NDC 0029-6094-40
Augmentin ES-600®
amoxicillin/clavulanate potassium
powder for oral suspension
75 mL (when reconstituted)
600 mg / 5 mL
Rx only
When reconstituted, each 5 mL contains: AMOXICILLIN, 600 MG, as the trihydrate CLAVULANIC ACID, 42.9 MG, as clavulanate potassium
Directions for mixing:
- Tap bottle until all powder flows freely. ADD 70 mL OF WATER IN TWO PARTS.
- Add approximately 2/3 of the water for reconstitution. Shake vigorously.
- Add remaining water. Shake vigorously.
Dosage: Administer every 12 hours. See accompanying prescribing information.
Phenylketonurics: Contains phenylalanine 7 mg per 5 mL.
Keep tightly closed. Shake well before using. Must be refrigerated.
Discard after 10 days.
Use only if inner seal is intact.
Net contents: Equivalent to 9 g amoxicillin and 0.643 g clavulanic acid.
Store dry powder at or below 25oC (77oF).
Augmentin (GSK)
[amoxicilline ;500mg + clavulaanzuur (kaliumzout) 125mg ]
compr. (deelb.)
amoxicilline ;875mg + clavulaanzuur (kaliumzout) 125mg ]
compr. (deelb.)
[amoxicilline (natrium en base) 1g + clavulaanzuur (kaliumzout) 62,5mg ]
compr. Retard (vertraagde vrijst.)
[amoxicilline ;125mg + clavulaanzuur (kaliumzout) 31,25mg / 5ml ]
[amoxicilline ;250mg + clavulaanzuur (kaliumzout) 62,5mg / 5ml ]
80ml
[amoxicilline (natrium) 500mg + clavulaanzuur (kaliumzout) 50mg ]
flacon P i.v. - inf.
[amoxicilline (natrium) 1g + clavulaanzuur (kaliumzout) 100mg ]
flacon P inf.
[amoxicilline (natrium) 1g + clavulaanzuur (kaliumzout) 200mg ]
flacon i.v.
[amoxicilline (natrium) 2g + clavulaanzuur (kaliumzout) 200mg ]
flacon inf.
80ml
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