Date of approval.
Date of revision.
Cefprozil dry suspension instructions
Please read the instructions carefully and use under the guidance of a physician
Drug Name]
Generic name: Cefprozil for Suspension
English name: Cefprozil for Suspension
Hanyu Pinyin: Toubaobingxi Ganhunxuanji
Ingredients
The main ingredient of this product is cefprozil.
Chemical name: (6R,7R)-3-propenyl-7-[(R)-2-amino-2-(4-hydroxyphenyl)acetylamino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid monohydrate.
Chemical structure formula.
and its (Z) isomers
Molecular formula: C18H19N3O5S-H2O
Molecular weight: 407.44
【Properties】.
This product is white to yellow granules or powder; aromatic.
Indications
Used for the following mild and moderate infections caused by sensitive bacteria.
1. Upper respiratory tract infection
(1) Streptococcus pyogenes pharyngitis/tonsillitis.
Note: Intramuscular penicillin should usually be chosen for the treatment and prevention of streptococcal infections (including prevention of rheumatic fever). Although cefprozil is generally effective in clearing septic streptococci from the nasopharynx, there is no available information on the prevention of secondary rheumatic fever with cefprozil.
(2) Streptococcus pneumoniae, Haemophilus influenzae (including β-lactamase-producing strains) and Catamorax (including β-lactamase-producing strains) otitis media and acute sinusitis.
2. Lower respiratory tract infections
Acute bronchitis secondary to bacterial infection caused by Streptococcus pneumoniae, Haemophilus influenzae (including β-lactamase-producing strains) and Catamorax (including β-lactamase-producing strains) and acute episodes of chronic bronchitis.
3. skin and skin soft tissue infections
Uncomplicated skin and skin soft tissue infections caused by Staphylococcus aureus (including penicillinase-producing strains) and Streptococcus pyogenes, but abscesses usually require surgical drainage to drain the pus.
Bacterial culture and drug sensitivity testing should be performed when appropriate to determine the susceptibility of the pathogenic bacteria to cefprozil.
Specification
0.125g (based on C18H19N3O5S)
Dosage and Administration
Take orally.
Dissolution method: Take about 20ml of warm water, shake loose the powder, add the dosing amount of powder slowly to the water, stir while adding, stir well and then take.
For adults (13 years old or above), for upper respiratory tract infection, 0.5g once a day; for lower respiratory tract infection, 0.5g once a day, twice a day; for skin or skin soft tissue infection, 0.5g once a day, divided into 1 or 2 doses; for severe cases, 0.5g once a day, twice a day.
Children from 2 to 12 years old with upper respiratory tract infection: 7.5mg/kg once a day according to body weight, 2 times a day; skin or skin soft tissue infection: 20mg/kg once a day according to body weight, 1 time a day.
Otitis media in children aged 6 months to 12 years: 15mg/kg once by weight, twice a day; acute sinusitis: generally 7.5mg/kg once by weight, twice a day.
In severe cases, 15mg/kg once a day according to body weight, twice a day.
The course of treatment is generally 7-14 days, but the course of treatment for acute tonsillitis and pharyngitis caused by b hemolytic streptococcus is at least 10 days.
Renal insufficiency
The dose of cefprozil in patients with renal insufficiency should be adjusted according to the following table.
Creatinine clearance (ml/min) Dose (mg) Dosing interval 30-120 common dosage regular time 0-29*50% common dosage regular time
* Hemodialysis can remove some cefprozil from the body, so it should be taken after the completion of hemodialysis.
Hepatic impairment
No dose adjustment is needed for patients with hepatic impairment.
Adverse reactions]
Adverse reactions to cefprozil are similar to those of other oral cephalosporins. Cefprozil is usually well tolerated in controlled clinical trials. Approximately 2% of patients discontinued cefprozil treatment due to adverse events.
The most common adverse reactions observed in patients treated with cefprozil are as follows.
Gastrointestinal.
Diarrhea (2.9%), nausea (3.5%), vomiting (1%), and abdominal pain (1%).
Hepatobiliary system.
Elevated AST (glutamic aminotransferase) (2%), elevated ALT (glutamic aminotransferase) (2%), elevated alkaline phosphatase (0.2%) and elevated bilirubin (<0.1%). As with some penicillins and other cephalosporin antibiotics, cholestatic jaundice is rare.
Allergic reactions.
Rash (0.9%), urticaria (0.1%). Allergic reactions are more common in children than in adults. They mostly appear within a few days after starting treatment and disappear a few days after stopping the drug.
Central nervous system.
Dizziness (1%). ADHD, headache, nervousness, insomnia, confusion, and drowsiness were reported less frequently (<1%). All of these reactions are reversible.
Hematopoietic system.
Decreased white blood cell count (0.2%), eosinophilia (2.3%).
Renal.
Elevated serum urea nitrogen (0.1%), elevated serum creatinine (0.1%).
Other.
Diaper rash and secondary infections (1.5%), genital pruritus and vaginitis (1.6%).
Regardless of whether a causal relationship with cefprozil has been established, the following adverse events have been reported rarely in postmarketing surveillance: anaphylactic reactions, angioneurotic edema, colitis (including pseudomembranous colitis), erythema multiforme, fever, serum sickness-like reactions, Stevens-Johnson syndrome, and thrombocytopenia.
Adverse reactions to cephalosporins.
In addition to the adverse reactions occurring with cefprozil listed above, cephalosporins are associated with the following adverse reactions and cause abnormal laboratory tests.
Aplastic anemia, hemolytic anemia, hemorrhage, renal insufficiency, toxic epidermolysis bullosa, toxic nephropathy, prolonged prothrombin time, positive Coombs’ test, elevated LDH, pancytopenia, neutropenia, and granulocyte deficiency.
Several cephalosporin drugs have been associated with seizures, particularly in patients with renal impairment who have not had their dosing reduced (see [DOSAGE]). If seizures are associated with drug therapy, the drug should be discontinued and anticonvulsant therapy should be administered according to clinical manifestations.
Contraindications】It is contraindicated in patients with hypersensitivity to any of the ingredients in this preparation and to cephalosporins.
Precautions】
Before using this product for treatment, patients should be carefully asked whether they have a history of allergy to cefprozil and other cephalosporins, penicillins and other drugs. Caution should be exercised when taking this product in patients with a history of penicillin allergy. This is because cross-sensitivity to β-lactam antibiotics has been well documented and may occur in up to 10% of patients with a history of penicillin allergy. This product should not be used in patients with a previous history of penicillin-induced anaphylaxis or other severe allergic reactions. If an allergic reaction occurs, the drug should be discontinued. Severe anaphylactic reactions require the use of epinephrine and other emergency measures, including administration of oxygen, intravenous fluids, sedation of antihistamines, corticosteroids, antihypertensives, and artificial respiration.
Prescribing cefprozil to patients without proven or strongly suspected bacterial infection or prophylactic indications is unlikely to benefit the patient and may increase the risk of drug-resistant bacteria.
Long-term use of almost all antimicrobial drugs, including cefprozil, can cause overgrowth of nonsusceptible microorganisms, altering the normal intestinal flora and inducing secondary infections, especially pseudomembranous enteritis. Therefore, the reaction of patients on medication should be carefully observed, with special attention to the diagnosis of patients with secondary diarrhea. If a secondary infection occurs during treatment, appropriate measures should be taken. In patients with pseudomembranous enterocolitis, only discontinuation of the drug is required in mild cases, while in moderate to severe cases, depending on clinical symptoms, treatment with regulation of water and electrolyte balance, protein supplementation, and antimicrobial drugs effective against resistant bacteria is indicated.
Patients with confirmed or suspected renal impairment (see Dosage and Administration) should be closely monitored for clinical signs and appropriate laboratory tests prior to and during treatment with this drug. In these patients, the daily dose of this drug should be reduced because of higher blood levels or/and slower excretion at regular doses. Cephalosporins should be used with caution in patients taking concomitant strong diuretic therapy, as these drugs may have deleterious effects on renal function.
Cefprozil should be used with caution in patients with gastrointestinal disorders, especially enteritis.
Clostridium difficile associated diarrhea (CDAD) has been reported with almost all antibiotics, including cefprozil, in applications ranging in severity from mild diarrhea to fatal colitis. Antibacterial drug therapy alters the normal flora of the patient’s colonic site, leading to Clostridium difficile overgrowth.
Toxins A and B produced by C. difficile contribute to the development of C. difficile-associated diarrhea (CDAD). Virulent strains of C. difficile can cause increased morbidity and mortality in CDAD, and because these infections are antimicrobial drug-refractory, colonic resection may be required for such patients. The possibility of CDAD must be considered in any patient who develops diarrhea after antibiotic administration. CDAD has been reported to occur 2 months after the end of antimicrobial therapy, so careful knowledge of the patient’s medical history is required when performing CDAD identification.
Once CDAD is suspected or confirmed in a patient, it may be necessary to discontinue the antibiotic therapy the patient is receiving (except for antibiotics that have a direct inhibitory effect on Clostridium difficile). The patient should also be managed with appropriate fluids and electrolytes, protein supplementation, antibiotics for C. difficile infection, and surgical evaluation, depending on clinical indications.
Positive direct Coomb’s test results have been reported while patients are receiving cephalosporin antibiotics.
This product should not be used if the inner package label is damaged.
[For Pregnant and Lactating Women].
Pregnant women
Oral administration of cefprozil to pregnant rabbits, mice and rats at doses 0.8, 8.5 and 18.5 times the maximum recommended clinical daily dose (1000 mg), respectively (based on body surface area conversion) did not impair fetal development in these animals. There are no adequate and well-controlled clinical studies of the use of this product in pregnant women. During pregnancy, it should be used only if really needed.
Delivery
No studies have been conducted on the use of cefprozil during labor and delivery. It should be used for treatment only when clearly indicated.
Lactating women
A single oral dose of 1 g of cefprozil in a nursing woman may result in a small amount of the drug being measured in breast milk (<0.3% of the dose administered). 24-hour average concentrations range from 0.25 to 3.3 mg/L. Caution should be exercised when administering cefprozil to nursing women as the effects of cefprozil on the infant are not known.
For children
(See
Indications] Uses and [Dosage])
The safety and efficacy of cefprozil in the treatment of otitis media have been established in pediatric patients between the ages of 6 months and 12 years. Evidence obtained from adequate and well-controlled studies in pediatric patients supports the use of cefprozil in the treatment of otitis media.
The safety and efficacy of cefprozil in the treatment of “pharyngitis/tonsillitis” or “uncomplicated skin and skin soft tissue infections” has been established in pediatric patients aged 2 to 12 years. Evidence from adequate and well-controlled studies in pediatric patients supports the use of cefprozil in the treatment of these infections.
The safety and efficacy of cefprozil in the treatment of acute sinusitis has been established in pediatric patients between the ages of 6 months and 12 years. The use of cefprozil in these age groups is supported by the evidence obtained in adequate and well-controlled studies of cefprozil in adults.
No information is available on the safety and efficacy of cefprozil in pediatric patients younger than 6 months of age. However, accumulation of other cephalosporins in neonates (due to the prolonged half-life of the drug in children at this age) has been reported.
Geriatric Use]
Of the more than 4,500 adult patients treated with cefprozil in clinical studies, 14% were over 65 years of age and 5% were over 75 years of age. When elderly patients received the recommended adult usual dose, their clinical efficacy and safety were comparable to those among non-elderly adult patients. Other reported clinical experience has not identified a difference in response between older and younger patients, but it cannot be ruled out that some older adults are more sensitive to the effects of cefprozil.
Cefprozil is known to be excreted primarily through the kidneys, and therefore there is a greater risk of toxic reactions in patients with impaired renal function. Since elderly patients are more likely to have reduced renal function, caution should be exercised in dose selection and it may be useful to monitor renal function at the time of dose selection. For dosing recommendations in patients with impaired renal function, see [DOSAGE AND ADMINISTRATION].
Drug Interactions]
Nephrotoxicity has been reported with the combination of aminoglycoside antibiotics and cephalosporins. Combination with propofol doubles the AUC of cefprozil.
The bioavailability of cefprozil is not affected by antacid administration followed by cefprozil capsules given 5 minutes later.
Drug/laboratory test interactions: Cephalosporin antibiotics can cause false-positive reactions to urine glucose reduction tests [Benedict’s or Feling’s reagents or copper sulfate flake reagents (Clinitestâ tablets)], but urine glucose enzymatic tests (e.g., Tes-Tapeâ urine glucose test strips) do not produce false positives. Such drugs can cause false-negative glucose ferricyanide reactions. Cefprozil in blood does not interfere with the determination of creatinine amounts in blood or urine by the alkaline picrate method.
[Drug overdose].
Single oral doses of up to 5000mg/kg in adult, weaned or neonatal rats and adult mice did not cause death or signs of toxicity, while single oral doses of up to 3000mg/kg in monkeys caused diarrhea and loss of taste sensation, but no death was observed.
Cefprozil is mainly cleared by the kidneys. For severe overdose, especially in patients with renal impairment, hemodialysis helps to clear this product.
Pharmacology and Toxicology
Pharmacological effects
1) Mechanism of action.
Cefprozil inhibits the synthesis of bacterial cell wall by binding to penicillin binding proteins (PBPs) on bacterial cell membranes to achieve bactericidal effect.
2) Antibacterial activity.
Cefprozil has in vitro activity against a wide range of Gram-positive and Gram-negative bacteria.
In vitro and in patients with clinical infections, cefprozil has antibacterial activity against most isolates of the following bacteria (see [Indications])
Aerobic Gram-positive bacteria.
Staphylococcus aureus (including β-lactamase-producing strains)
Note: Cefprozil is inactive against methicillin-resistant staphylococci
Streptococcus pneumoniae
Streptococcus pyogenes
Aerobic gram-negative bacteria.
Haemophilus influenzae (including beta-lactamase-producing strains)
Cataplasma (Cataplasma boulardii) (including β-lactamase-producing strains)
The following in vitro data are available, but their clinical significance is unclear However, the safety and efficacy of cefprozil in the treatment of these bacterial infections has not been established in adequate, well-controlled clinical trials.
Aerobic Gram-positive bacteria.
Enterococcus persistentus
Enterococcus faecalis
Listeria monocytogenes
Staphylococcus epidermidis
Staphylococcus saprophyticus
Staphylococcus volvulus
Streptococcus lactis-free
Streptococci (groups C, D, F and G)
Streptococcus straw green
Note: Cefprozil is inactive against Enterococcus faecalis.
Aerobic Gram-negative bacteria.
Heterobacterium citri
Escherichia coli
Klebsiella pneumoniae
Neisseria gonorrhoeae (including β-lactamase-producing strains)
Aspergillus chimaericus
Salmonella spp.
Shigella spp.
Vibrio spp.
Note: Cefprozil is inactive against most strains of Fusobacterium, Enterobacter, Morgan Morganella, Proteus, Pseudomonas, and Serratia
Anaerobic bacteria.
Melanin-producing Prevotella (melanin-producing-like bacilli)
Clostridium difficile
Clostridium perfringens
Clostridium spp.
Streptococcus pepticus spp.
Propionibacterium acnes
Note: Most strains of the Bacteroides fragilis group are resistant to cefprozil.
3）Susceptibility test
Dilution method: The minimum inhibitory concentration (MIC) of the antibacterial drug is determined using a quantitative method. The susceptibility of bacteria to antimicrobial drugs can be estimated from these MICs. MIC must be determined using a standardized test method. standardized methods are based on dilution methods (broth or agar) or equivalent, and MIC values should be interpreted according to the criteria listed in the table below.
MIC (μg/mL) Interpretation ≤ 8 Sensitive (S) 16 Intermediary (I) ≥ 32 Resistant (R) A reported result of “sensitive” indicates that the pathogen can be suppressed if the antimicrobial substance is present in the blood at a concentration that is normally achievable. A reported “intermediary” indicates that the result is of unknown significance and that the test should be repeated if the microorganism is not fully sensitive to clinically feasible drugs. This classification implies that there may be clinical applicability in body sites where the drug is physiologically concentrated or where high doses of the drug can be used. The classification also serves as a buffer to prevent small uncontrolled technical factors from causing serious bias in outcome judgments. A report of “resistant” indicates that if the antimicrobial drug concentration reaches a concentration normally achievable at the site of infection it is still unlikely to inhibit the growth of the pathogen and other therapies should be used.
Standardized drug sensitivity testing protocols require the use of laboratory control strains to control the technical aspects of the test. The following MIC values should be provided for cefprozil standard powders.
Microbial MIC (μg/mL) Enterococcus faecalis ATCC 292124-16 Escherichia coli ATCC 259221-4 Haemophilus influenzae ATCC 497661-4 Staphylococcus aureus ATCC 292130.25-1 Streptococcus pneumoniae ATCC 496190.25-1
Diffusion method: A quantitative method that requires measurement of the diameter of the inhibition ring can also be used to reproduce the valuation of bacterial susceptibility to antimicrobial drugs. A standard measurement method is also required for the determination of the diameter of the inhibition ring, requiring a standardized inoculum concentration. In this method, paper sheets impregnated with 30 µg of cefprozil were used to determine bacterial susceptibility to cefprozil.
Laboratory reports for susceptibility tests using the standard single-paper method with 30 µg cefprozil paper sheets should be interpreted according to the following criteria.
Diameter of the inhibition circle (mm) Interpretation ≥ 18 Sensitive (S) 15-17 Intermediary (I) ≤ 14 Resistant (R) For results using the dilution method, interpretation should be based on the criteria as described above, including the interpretation of the correlation between diameter and cefprozil MIC obtained in the paper sheet method test.
As with the standard dilution method, the diffusion method requires the use of a laboratory control strain to control the technical aspects of the test operation. For the diffusion method, the diameter of the inhibition circle of 30 μg cefprozil paper tablets in these laboratory quality control strains should be provided.
Microbial inhibition circle diameter (mm) Escherichia coli ATCC 2592221-27 Haemophilus influenzae ATCC 4976620-27 Staphylococcus aureus ATCC 2592327-33 Streptococcus pneumoniae ATCC 4961925-32 Toxicological studies
1) Genotoxicity.
The results of the Ames test for cefprozil, the HGPRT forward gene mutation test in Chinese hamster ovary cells, the extra-programmed DNA synthesis test in rat hepatocytes and the in vivo micronucleus test in rats were all negative.
2) Reproductive toxicity.
The oral administration of cefprozil to female and male rats at doses up to 18.5 times the maximum recommended clinical daily dose (in terms of body surface area) had no effect on the fertility of parental animals.
The oral administration of cefprozil to rabbits, mice and rats was tested for reproductive toxicity at 0.8, 8.5 and 18.5 times the maximum daily dose (1000 mg) for human use, respectively, and no effect on fetuses was observed.
Pharmacokinetics]
Bioequivalence has been demonstrated for oral administration of tablets, capsules and suspensions on an empty stomach. The following data are mainly from capsule studies.
Approximately 95% of the administered dose of cefprozil was absorbed by the subject when taken orally on an empty stomach. The mean plasma half-life in healthy subjects is 1.3 hours and the steady-state volume of distribution is approximately 0.23 L/kg. total clearance and renal clearance are approximately 3 ml/min/kg and 2.3 ml/min/kg, respectively.
The mean peak blood concentrations were 6.1, 10.5 and 18.3 mg/ml for cefprozil 250mg, 500mg or 1g orally on an empty stomach, respectively, and the peak blood concentration was reached within 1.5 hours after dosing, and the urinary recovery rate was about 60% of the dose.
The mean urinary concentrations were 700mg/L, 1000mg/L and 2900mg/L for the first 4 hours after oral administration of 250mg, 500mg and 1g, respectively.
The absorption (AUC) and peak blood concentration of cefprozil were not affected by tablets or suspensions taken with food, but the time to peak was prolonged by 0.25 to 0.75 hours.
The plasma protein binding rate is about 36%. When the blood concentration is in the range of 2~20mg/L, the plasma protein binding rate is not related to the change of blood concentration.
Oral doses of cefprozil up to 1000 mg every 8 hours for 10 days in patients with normal renal function did not show any drug plasma accumulation.
In patients with decompensated renal function, the plasma half-life of cefprozil can be extended to 5.2 hours depending on the degree of renal impairment; in patients with complete loss of renal function, the plasma half-life of cefprozil can be up to 5.9 hours. On hemodialysis, the half-life is shortened. The route of cefprozil excretion in patients with significant renal insufficiency is unclear (see [Precautions] and [Dosage]).
The plasma half-life of cefprozil in patients with hepatic impairment may increase to about 2 hours, but this change does not imply a need for dose adjustment in patients with hepatic impairment.
The mean AUC in the elderly (≥65 years) is approximately 35%-60% higher relative to younger adults, and the AUC in women is 15%-20% higher than the AUC in men. However, the differences in cefprozil pharmacokinetics between age and sex are not sufficient to warrant dose adjustment.
A single oral dose of 1 g of cefprozil in a nursing woman may result in a small amount of the drug being measured in breast milk (<0.3% of the dose taken). 24-hour average concentrations range from 0.25 to 3.3 mg/L. Caution should be exercised in nursing women taking this product because the effects of cefprozil on the infant are not known.
Similar pharmacokinetic parameters were observed in pediatric patients (6 months of age to 12 years of age) and adults after oral administration of the corresponding recommended dose of cefprozil. Maximum blood concentrations were reached 1 to 2 hours after administration, with a plasma elimination half-life of approximately 1.5 hours. Overall, similar blood concentrations were observed in pediatric patients administered cefprozil orally at doses of 7.5, 15 and 30 mg/kg compared to normal adult subjects administered at doses of 250, 500 and 1000 mg over the same time frame.
No information is available on the cerebrospinal fluid pharmacokinetics of cefprozil.
Storage
Store in a cool and dry place (not more than 20℃) under shade and seal.
Package
Package: 4 packs/box, 6 packs/box, 8 packs/box, 12 packs/box, 16 packs/box.
Expiration date】 18 months
【Execution standard
Approval Number】
State Drug Certificate H20041961
[Drug Marketing License Holder
Name: Nanjing Yihua Pharmaceutical Co.
Registered Address: No. 18, Xingang Avenue, Nanjing Economic and Technological Development Zone
Postal Code: 210038
Manufacturer
Company Name: Nanjing Yihua Pharmaceutical Co.
Production Address: No. 18, Xingang Avenue, Nanjing Economic and Technological Development Zone
Zip code: 210038
Contact：025-85804148
Fax: 025-85802103
Website: www.yewin.net