Approved on.
Revision Date.
Amoxicillin Clavulanate Potassium Tablets Instructions
Please read the instruction manual carefully and use under the guidance of your physician.
[Medication Name].
Generic Name: Amoxicillin Clavulanate Potassium Tablets
Trade Name: Ampicillin Tablets
Hanyu Pinyin: Amoxilin Kelaweisuanjia Pian
English Name: Amoxicillin and Clavulanate Potassium Tablets
[Ingredients].
This product is a compound formulation, the components of which are amoxicillin and potassium clavulanate. Each 0.375g of this product contains 0.25g of amoxicillin and 0.125g of clavulanic acid.
[Properties].
This product is a film-coated tablet, which appears off-white to light yellow after removing the coating.
[Indications].
This product is for the short-term treatment of infections suspected to be caused by β-lactamase-producing amoxicillin-resistant bacteria, and amoxicillin alone should be considered in other cases :.
Lower respiratory tract infections:
Caused by β-lactamase-producing Haemophilus influenzae and Catamorax.
Upper respiratory tract infections (including ear, nose, and throat):
Caused by β-lactamase-producing Haemophilus influenzae and Catamorax.
Skin and soft tissue infections:caused by β-lactamase-producing Staphylococcus aureus, Escherichia coli, and Klebsiella spp. strains.
Urinary tract infections:
Caused by β-lactamase-producing Escherichia coli and Klebsiella and Enterobacteriaceae.
*Some strains of the causative genus of the above disease produce β -lactamases, making them insensitive to amoxicillin alone.
Use with reference to official clinical guidelines for the use of antimicrobial drugs.
[Specifications].
0.375g (C16H19N305S 0.25g with C8H9 NO5 0.125g)
[Dosage and Administration].
Dosage is always expressed as amoxicillin/clavulanic acid content, unless the dosage is prescribed in individual components.
The dose of this product selected for the treatment of different infections should consider.
– the intended pathogen and its possible susceptibility to antimicrobial drugs
– Severity and site of infection
The patient’s age, weight and renal function are shown below.
Alternative preparations of this product should be considered if necessary (e.g., provide a higher dose of amoxicillin and/or a different ratio of amoxicillin to clavulanic acid).
For adults and children weighing ≥40 kg, this product provides a total daily dose of 0.75 g amoxicillin/0.375 g clavulanic acid (three times daily) when administered as recommended below (one tablet each). If a higher daily dose of amoxicillin is deemed necessary, it is recommended that the appropriate formulation be selected to avoid giving unnecessarily high daily doses of clavulanic acid.
No more than 14 consecutive days of treatment without re-examination.
Adults and children weighing ≥40 kg
One tablet three times daily.
Children weighing <40 kg
This film-coated tablet is not recommended for use in children weighing <40 kg.
Elderly
Dose adjustment may be considered unnecessary. However, caution should be exercised in dose selection because of the greater likelihood of reduced renal function in the elderly.
Renal impairment
Dose adjustment based on the maximum recommended level of amoxicillin.
Patients with creatinine clearance (CrCl) greater than 30 ml/min do not require dose adjustment.
Adults and children weighing ≥40 kg
CrCl:10-30 ml/min1 tablet, 2 times dailyCrCl﹤10 ml/min 1 tablet, 1 time dailyHemodialysis1 tablet every 24 hours; 1 additional tablet at the end of dialysis (due to reduced serum concentrations of both amoxicillin and clavulanic acid)Children weighing <40 kg
For children <40 kg with creatinine clearance below 30 ml/min, the use of amoxicillin to clavulanic acid in a ratio of 2:1 is not recommended. An alternative formulation with a 4:1 ratio of amoxicillin to clavulanic acid is recommended.
Hepatic impairment
Be careful with dosing and monitor liver function regularly; there are insufficient data to support the use of the recommended dose in patients with hepatic impairment (see [Contraindications] and [Precautions]).
Dosing method
Orally. It should be taken with meals and not chewed to minimize potential gastrointestinal intolerance and to achieve optimal absorption.
[Adverse Reactions].
1. Skin and adnexal damage: rash, pruritus, urticaria, flushing, erythema multiforme, Stevens-Johnson syndrome, toxic epidermolysis bullosa, exfoliative erythrodermatitis (erythroderma) and acute generalized eruptive pustulosis and drug reactions with systemic symptoms (DRESS).
2. Gastrointestinal damage: nausea, vomiting, dyspepsia, bloating, diarrhea, gastritis, stomatitis, tongue inflammation, black hairy tongue, pseudomembranous enterocolitis, colitis, hemorrhagic colitis.
3. Immune disorders and infections: angioedema, candidiasis of the skin and mucous membranes, secondary infections, serum sickness-like syndrome (urticaria with arthritis, arthralgia, myalgia, and fever) , asthma, severe allergic-like reactions, cough, anaphylaxis, anaphylactic vasculitis.
4. Neurological damage: dizziness, headache, vertigo, insomnia, agitation, anxiety, irritability, behavioral changes, confusion, convulsions and reversible hyperfunction, convulsions, aseptic meningitis.
5. Hematologic damage: leukopenia (including neutropenia) and thrombocytopenia, thrombocytopenic purpura, eosinophilia, thrombocytosis prolonged prothrombin time, granulocyte deficiency, and hemolytic anemia.
6. Urinary tract damage: hematuria, crystalluria, interstitial nephritis, acute kidney injury (including acute renal failure, elevated creatinine), vaginal pruritus, ulcers and abnormal secretions.
7. Hepatobiliary damage: elevated transaminases, hepatitis and cholestatic jaundice, elevated blood bilirubin and or alkaline phosphatase.
8. Other impairments: dyspnea, palpitations, cyanosis, chest tightness, chills, drug fever.
9. Other Medication-Related Events: Very rare tooth surface staining after medication in children, mostly in patients taking suspensions. Brushing may prevent and remove tooth surface staining.
[Contraindication].
1. Contraindicated in patients with positive skin test reaction to penicillin, hypersensitivity to this product and other penicillins, and in patients with infectious mononucleosis.
2. Contraindicated in patients with previous amoxicillin (sodium) clavulanic acid potassium-associated cholestasis or hepatic impairment.
[Caution].
Patients must have a penicillin skin test before starting each dose of this product.
1. Use with caution in patients with hypersensitivity to cephalosporins and a history of allergic diseases such as asthma, allergic rhinitis, eczema, kwashiorkor fever, and urticaria.
2. There is cross-sensitivity between this product and other penicillins and cephalosporins. If an allergic reaction develops, the product should be discontinued immediately and appropriate measures should be taken. Severe and occasionally fatal allergic reactions (anaphylaxis) have been reported in patients treated with penicillin, and this reaction is more likely to occur in patients with a history of penicillin allergy. If an allergic reaction occurs, amoxicillin-clavulanic acid should be discontinued and appropriate replacement therapy administered. Severe allergic reactions require immediate emergency treatment with epinephrine. Oxygen administration, intravenous steroid infusion, and airway management, including intubation, may also be required.
3. There is cross-resistance between this product and other penicillins and cephalosporins such as ampicillin.
4. Use with caution if estimated glomerular filtration rate is less than 30 ml/min. Dose or dosing interval should be adjusted according to glomerular filtration rate in patients with decreased renal function; hemodialysis may affect the concentration of amoxicillin in this product. The blood concentration of amoxicillin in this product can be affected by hemodialysis, so one additional dose of this product should be given after hemodialysis.
5. With high doses of amoxicillin, patients are advised to consume adequate fluid and ensure adequate urinary output to reduce the likelihood of amoxicillin crystalluria.
6. Use with caution in patients with hepatic insufficiency. There have been isolated cases of altered liver function in patients taking this product. Because the clinical significance of such changes has not been determined, caution must be exercised in the use of this product in patients with hepatic insufficiency. Severe reversible cholestatic jaundice has been reported, and this sign and symptom may also occur six weeks after discontinuation of the drug.
7. For long-term or high-dose use of this product, liver, renal, and hematopoietic system function and serum potassium or sodium testing should be performed periodically.
8. When combined with warfarin, appropriate monitoring must be performed and the dose of oral anticoagulant may need to be adjusted to maintain the desired anticoagulation level.
9. This drug is a time-dependent antibiotic and should be used strictly as directed, with no less than 6 hours between doses.
10. To reduce gastrointestinal reactions, the oral formulation should be taken with a meal.
11. Prolonged use of this product may occasionally cause overgrowth of non-susceptible bacteria. Pseudomembranous colitis has been reported with antibiotics. If a patient develops persistent or severe diarrhea, or develops abdominal cramps, treatment should be discontinued immediately and the patient further examined.
12. To ensure the effectiveness of treatment and to avoid development of bacterial resistance, medications should be administered regularly as prescribed, avoiding missed or early discontinuation.
13. For patients with suspected gonorrhea with syphilis damage, dark-field testing should be performed prior to the use of this product and serologic testing should be performed once a month for at least 4 months.
14. Interference with laboratory test indices.
(1) The copper sulfate method of urine glucose testing can be false positive, but the glucose enzyme test method is not affected, and the application of a urine glucose test based on the glucose oxidase reaction is recommended when taking this product.
(2) May affect serum alanine aminotransferase or menthyltransferase assay values.
15. Compound preparations of amoxicillin and potassium clavulanate in different ratios are not interchangeable.
16. Carefully open the aluminum foil of each tablet.
17. Please open the moisture-proof pouch only before use and consume within 30 days after opening the moisture-proof pouch.
Effect on mechanical operability: Unknown.
[For Pregnant and Lactating Women].
Pregnancy
Reproductive toxicity tests in animals (rats and mice) showed no teratogenic effects when given orally or parenterally. In a separate study of premature rupture of membranes (pPROM), prophylactic treatment with this product was reported to increase the risk of neonatal necrotizing small bowel colitis. The use of this product in pregnant cases is limited and, as with all drugs, should be avoided in pregnant women, especially in the third trimester, unless deemed necessary by the physician.
Lactation
Both substances are excreted into breast milk (the effect of clavulanic acid on breastfed infants is not known). Therefore, breastfed infants may develop diarrhea and mucosal fungal infections and may have to be terminated from breastfeeding. The possibility of sensitization should be considered. Amoxicillin/clavulanic acid should be used during breastfeeding only after a benefit/risk assessment by a competent physician.
[Pediatric Use]See [Dosage].
[Drug Interactions]
Probenecid
The combination of this product with probenecid is not recommended. Probenecid decreases renal tubular secretion of amoxicillin. Co-administration may result in increased blood levels and prolonged half-life of amoxicillin, but does not affect blood levels of clavulanic acid.
Oral anticoagulants
The literature reports rare cases of increased international normalized ratio (INR) in patients on maintenance vinblastine or warfarin in combination with a course of amoxicillin. If a combination is necessary, prothrombin time (PT) and international normalized ratio (INR) should be carefully monitored as amoxicillin is added and discontinued. In addition, the dose of oral anticoagulant may need to be adjusted (see [Precautions] and [Adverse Reactions]).
Mortimefloxyprost
Patients receiving morte-mescaline have been reported to have approximately 50% lower preadministration concentrations of the active metabolite mycophenolic acid (MPA) after initiation of oral amoxicillin plus clavulanic acid. Changes in preadministration levels may not accurately reflect changes in total MPA exposure. Therefore, in the absence of clinical evidence of graft deactivation, a change in the dose of mycophenolate mofetil is not usually necessary. However, close clinical monitoring should be performed during combination therapy and shortly after antibiotic therapy.
Although there is no information on the combination of this product with allopurinol, the combination of amoxicillin and allopurinol may increase the likelihood of allergic skin reactions.
As with other antibiotics, this product may affect intestinal flora, leading to decreased estrogen reabsorption and reduced efficacy of combined oral contraceptive use.
[Drug overdose].
Signs and symptoms of overdose
Gastrointestinal symptoms and disturbances in water and electrolyte balance may be evident. Amoxicillin crystalluria has been observed to cause renal failure in some cases. (See [Precautions])
Convulsions may occur in patients with impaired renal function or those receiving high doses.
Amoxicillin has been reported to precipitate in the bladder catheter, especially after high-dose intravenous administration. Patency should be checked periodically.
Treatment of toxicity
Gastrointestinal symptoms can be treated symptomatically with attention to water/electrolyte balance.
Amoxicillin/clavulanic acid can be cleared from the circulation by hemodialysis.
[Pharmacokinetics].
Absorption
Amoxicillin and clavulanic acid are completely dissociated in aqueous physiological pH solutions. Both components are rapidly and fully absorbed under the oral route of administration. After oral administration, the bioavailability of amoxicillin and clavulanic acid was approximately 70%. The plasma distribution of both components was similar, and the time to peak plasma concentration (Tmax) was approximately 1 hour in each case.
In a pharmacokinetic study, amoxicillin/clavulanic acid (250 mg/125 mg tablets three times daily) was given to a healthy volunteer group on an empty stomach, and the results of the study are shown below.
mean (±SD) pharmacokinetic parametersActivesDoseCmaxTmax*AUC (0-24h)T 1/2(mg)(μg/ml)(h)(μg.h/ml)(h)AmoxicillinAMX/CA
250 mg/125 mg2503.3±1.121.5
(1.0-2.0)26.7±4.561.36±0.56Clavulanic acidAMX/CA
250 mg/125 mg1251.5±0.701.2
(1.0-2.0)12.6±3.251.01±0.11AMX-amoxicillin, CA-clavulanic acid
* Median value (range) Serum concentrations of amoxicillin and clavulanic acid obtained with amoxicillin/clavulanic acid are similar to those produced by oral equivalents of amoxicillin or clavulanic acid alone.
Distribution
About 25% of total plasma clavulanic acid and 18% of total plasma amoxicillin are protein bound. The apparent volume of distribution was approximately 0.3-0.4 l/kg for amoxicillin and 0.2 l/kg for clavulanic acid.
After intravenous administration, amoxicillin and clavulanic acid were found in the gallbladder, abdominal tissue, skin, fat, muscle tissue, synovial and peritoneal fluid, bile, and pus. Amoxicillin was not adequately distributed to the cerebrospinal fluid.
Animal tests showed no accumulation of the components in organs. As with most penicillin antibiotics, amoxicillin can be detected in breast milk. Trace amounts of clavulanic acid can also be detected in breast milk (see [Medication for Pregnant and Lactating Women]).
Both amoxicillin and clavulanic acid have been shown to cross the placental barrier (see [Medications for Pregnant and Lactating Women]).
Biotransformation
Part of amoxicillin is excreted in the urine as inactive penicillic acid, corresponding to 10% to 25% of the initial dose. Clavulanic acid is extensively metabolized in the body and is excreted in the urine and feces and as carbon dioxide in exhalation.
Clearance
Amoxicillin is primarily cleared by the kidneys, whereas clavulanic acid is cleared by both renal and non-renal mechanisms.
In healthy subjects, the mean clearance half-life of amoxicillin/clavulanic acid was approximately 1 h and the mean total clearance was approximately 25 L/h. Single administration of this product 250 mg/125 mg or 500 mg/125 mg tablet, approximately 60-70% of amoxicillin and approximately 40-65% of clavulanic acid is excreted in the urine as a prototype within the first 6 h after administration. Several studies have shown that 50-85% of amoxicillin and 27-60% of clavulanic acid are excreted in the urine during the 24-h cycle. Clavulanic acid, on the other hand, is excreted in the first 2 hours after administration in the largest quantity.
The combined use of probenecid delays the excretion of amoxicillin, but not the renal excretion of clavulanic acid (see [Drug Interactions]).
Age
For children 3 months to 2 years of age, older children, and adults, the elimination half-life of amoxicillin is similar. In very young children (including premature neonates), dosing intervals should not exceed twice daily during the first week of life due to immature renal elimination pathways. Because of the greater potential for decreased renal function in older patients, care should be taken in dose selection and possibly monitoring of renal function.
Gender
There was no significant effect of gender on the pharmacokinetics of amoxicillin or clavulanic acid after oral administration of amoxicillin/clavulanic acid in healthy male and female subjects.
Renal impairment
Total serum clearance of amoxicillin/clavulanic acid decreases proportionally with decreased renal function. Amoxicillin drug clearance is significantly more reduced than clavulanic acid because a higher proportion of amoxicillin is excreted via the renal route. Therefore, dosing in patients with renal impairment must prevent excessive accumulation of amoxicillin while maintaining adequate levels of clavulanic acid (see [DOSAGE]).
Hepatic impairment
Patients with hepatic impairment should take with caution and monitor liver function regularly.
[Storage] not to exceed 25C. .
[Packaging]
Aluminum-plastic blister plate, 6 tablets per plate, 1 plate per box; 8 tablets per plate, 1 plate per box; 9 tablets per plate, 1 plate per box; 10 tablets per plate, 1 plate per box; 6 tablets per plate, 2 plates per box.
[Expiration Date] 12 months
[Execution Standard]
[Approval Number] State Drug Certificate H10920034
[Pharmaceutical Marketing Licensee]
Drug Marketing Authorization Holder: North China Pharmaceutical Co.
Registered office: No. 388, Heping East Road, Shijiazhuang, China
[Manufacturer].
Manufacturer: North China Pharmaceutical Co.
Production Address: No. 388 Heping East Road, Shijiazhuang
Customer Service Phone: 4006128588 4006128585
Zip Code: 050015
Website: www.ncpc.com.cn