Imipenem and Cilastatin Sodium for Injection

Indication

This product is a broad-spectrum antibiotic that is suitable for mixed infections caused by various pathogens and aerobic/anaerobic bacteria, as well as early treatment before pathogens are determined. This product is suitable for the following infections caused by sensitive bacteria: • Intra-abdominal infections • Lower respiratory tract infections • Gynecological infections • Sepsis • Genitourinary tract infections • Osteoarticular infections • Skin and soft tissue infections • Endocarditis This product is suitable for treatment Mixed infection caused by sensitive aerobic/anaerobic strains. These mixed infections are primarily associated with bacterial contamination of the feces, vagina, skin and mouth. Bacteroides fragilis is the most common anaerobic bacteria in these mixed infections. They are usually resistant to aminoglycosides, cephalosporins and penicillin antibiotics and are sensitive to this product. This product has been shown to have potent antibacterial activity against many cephalosporin-resistant bacteria, including aerobic and anaerobic Gram-positive and Gram-negative bacteria; these bacterial resistant cephalosporins Antibiotics include cefazolin, cefoperazone, cefotaxime, cefoxitin, cefotaxime, oxycarboxamide, ceftime, ceftazidime and ceftriaxone. Similarly, many are resistant to aminoglycoside antibiotics (such as gentamicin, amikacin, tobramycin) and/or penicillins (ampicillin, carbenicillin, penicillin, ticarcillin, piperacillin, a The infection caused by bacteria of loscillin or mezlocillin is still effective in using this product. This product is not suitable for the treatment of meningitis.

Clinical pharmacology

This product (imipenem cilastatin sodium for injection) is a broad-spectrum β-lactam antibiotic supplied in an intravenous drip form. This product contains two components: (1) imipenem, a new type of β-lactam antibiotic-imipenem, which is characterized by a broader spectrum of bactericidal spectrum than any other antibiotics studied. (2) cilastatin sodium, a specific enzyme inhibitor that blocks the metabolism of imipenem in the kidney, thereby increasing the concentration of the imipenem prodrug in the urinary tract. In this product, the weight ratio of imipenem to cilastatin is 1:1. The broad-spectrum bactericidal effect of this product is due to its strong ability to inhibit bacterial cell wall synthesis. It can kill most of the gram-positive and gram-negative aerobic and anaerobic pathogens.

Dosage

This product is supplied in the form of intravenous drip. After the product is compatible with clinical infusion, the instillation should be completed within 4 hours. The recommended dose of this product is expressed in terms of the amount of imipenem used, and also represents the same dose of cilastatin. The total daily dose of this product depends on the type and severity of the infection; and according to the sensitivity of the pathogen, the renal function and weight of the patient, consider giving the total dose of the day to the patient in equal parts (Details) See instructions)

Formulation

Powder needle

specification

(1) 1.0 g (C12H17N3O4S 0.5 g and C16H26N2O5S 0.5 g); (2) 0.5 g (C12H17N3O4S 0.25 g and C16H26N2O5S 0.25 g).

Instruction manual

Approval date: April 09, 2009

Date of revision: August 15, 2013

December 17, 2013

August 29, 2016

Instructions for imipenem cilastatin sodium for injection

Please read the instructions carefully and use them under the guidance of a physician.

【Drug Name】

Generic name: imipenem cilastatin sodium for injection

English name: Imipenem and Cilastatin Sodium for Injection

Pinyin: Zhusheyong Yaanpeinan Xisitadingna

【ingredients】

This product is a compound preparation, the components of which are imipenem and cilastatin sodium.

(1) 1.0 g per bottle (containing imipenem 0.5 g and cilastatin 0.5 g);

(2) 0.5 g per bottle (containing 0.25 mg of imipenem and 0.25 g of cilastatin).

The excipient is sodium bicarbonate.

【Properties】 This product is white or off-white powder.

【indications】

treatment

This product is a broad-spectrum antibiotic that is suitable for mixed infections caused by various pathogens and aerobic/anaerobic bacteria, as well as early treatment before pathogens are determined. This product is suitable for the following infections caused by sensitive bacteria:

· Intraperitoneal infection

· Lower respiratory tract infection

· Gynecological infection

· Septicemia

· Genitourinary tract infection

· Osteoarticular infection

· Skin and soft tissue infections

· Endocarditis

This product is suitable for the treatment of mixed infections caused by sensitive aerobic / anaerobic strains. These mixed infections are primarily associated with bacterial contamination of the feces, vagina, skin and mouth. Bacteroides fragilis is the most common anaerobic bacteria in these mixed infections. They are usually resistant to aminoglycosides, cephalosporins and penicillin antibiotics and are sensitive to this product.

This product has been shown to have potent antibacterial activity against many cephalosporin-resistant bacteria, including aerobic and anaerobic Gram-positive and Gram-negative bacteria; these bacterial resistant cephalosporins Antibiotics include cefazolin, cefoperazone, cefotaxime, cefoxitin, cefotaxime, oxycarboxamide, ceftime, ceftazidime and ceftriaxone. Similarly, many are resistant to aminoglycoside antibiotics (such as gentamicin, amikacin, tobramycin) and/or penicillins (ampicillin, carbenicillin, penicillin, ticarcillin, piperacillin, a The infection caused by bacteria of loscillin or mezlocillin is still effective in using this product.

This product is not suitable for the treatment of meningitis.

prevention

This product is suitable for the prevention of such postoperative infections in patients who are already contaminated or have potentially contaminating surgery or if the postoperative infection is particularly severe.

【specification】

(1) 1.0 g (C12H17N3O4S 0.5g and C16H26N2O5S 0.5g);

(2) 0.5 g (C12H17N3O4S 0.25 g and C16H26N2O5S 0.25 g).

【Dosage】

This product is supplied in the form of intravenous drip. After the product is compatible with clinical infusion, the instillation should be completed within 4 hours.

The recommended dose of this product is expressed in terms of the amount of imipenem used, and also represents the same dose of cilastatin.

The total daily dose of this product depends on the type and severity of the infection; and according to the sensitivity of the pathogen, the renal function and weight of the patient, it is considered to give the patient the same amount of the day.

Treatment: Dosing schedule for adult patients with normal renal function

The doses listed in Table (1) are based on normal renal function (creatinine clearance > 70 ml/min (min) / 1.73 m2) and body weight ≥ 70 kg. Patients with creatinine clearance ≤70 ml/min (min)/1.73 m2 (see Table 2) and/or weight <70 kg must reduce the dose. For patients with very low body weight and/or moderate to severe renal insufficiency, it is especially important to reduce the dose of this product.

The recommended therapeutic dose for most infections is 1 to 2 grams per day, divided into 3 to 4 infusions. For moderate infections, you can also use 1 gram each time, 2 times a day. For infections caused by insensitive pathogens, the dose of this product can be increased up to 4 grams per day, or 50 mg / kg body weight / day, whichever is lower.

When the dose of intravenous infusion of this product is less than or equal to 500 mg, the intravenous infusion time should be no less than 20 to 30 minutes. If the dose is greater than 500 mg, the intravenous infusion time should be no less than 40 to 60 minutes. . If the patient has nausea during the instillation, the drip rate can be slowed down.

Table (1) Dosage schedule for intravenous infusion of this product in adult patients with normal renal function and body weight ≥ 70 kg*

* For patients weighing <70 kg, the dose should be further reduced proportionally.

+ Commonly used in transplant patients with low immunity. Mild infections in patients with cancer chemotherapy and in elderly patients with body failure.

Due to the high antibacterial effect of this product, the recommended maximum daily total dose is no more than 50 mg / kg body weight / day or 4 g / day, and the lower dose is used. However, in the case of patients with cystic fibrosis who have normal renal function, the dose of this product can be used up to 90 mg / kg body weight / day, divided doses, but not more than 4 grams per day.

As a single drug, this product has successfully treated cancer patients with low or low-determined confirmed or suspected infections such as sepsis.

Treatment: dose scheduling for adult patients with impaired renal function

For adult patients with impaired renal function, the following steps can be used to determine the reduced dose of this product.

1. According to the characteristics of the infection, the total daily dose is selected from Table (1).

2. According to the total daily dose of Table (1) and the range of creatinine clearance rate of patients, select the appropriate dose from Table (2) (see the above treatment for the infusion time: dose schedule for adult patients with normal renal function) ").

Table (2) Renal dysfunction and weight loss ≥70kg* adult patients using this product intravenous drip dose reduction arrangement

* For patients weighing <70 kg, the dose should be further reduced proportionally.

When the patient's creatinine clearance is 6-20 ml/min/1.73 m2, the risk of epilepsy may increase with a 500 mg dose.

If the patient's creatinine clearance rate is ≤ 5ml / min / 1.73m2, unless the patient performs hemodialysis within 48 hours, this product should not be given intravenous drip.

Hemodialysis

For patients with creatinine clearance ≤5ml/min/1.73m2 and undergoing hemodialysis, the recommended dose for patients with creatinine clearance of 6-20ml/min/1.73m2 can be used. (See "Treatment: Dose Arrangement for Adult Patients with Impaired Renal Function")

Imipenem and cilastatin are removed from the circulation during hemodialysis. The patient should be given an IV infusion after hemodialysis and once every 12 hours after hemodialysis. In particular, dialysis patients with central nervous system diseases should pay attention to monitoring; for patients undergoing hemodialysis, it is recommended only when the benefit of intravenous infusion of this product is greater than the risk of inducing seizures. (See "Precautions")

There is currently not enough information to recommend intravenous infusion of this product for peritoneal dialysis patients.

Since the renal function of elderly patients cannot be accurately determined by serum urea nitrogen or creatinine concentration alone, creatinine clearance can be measured as a guide for the doses administered by these patients.

Prevention: Adult dose schedule

In order to prevent post-operative infection in adults, 1000 mg of this product can be administered intravenously during induction of anesthesia, and 1000 mg after 3 hours. For the prevention of infections in high-risk (such as colorectal) surgery, an additional 500 mg of intravenous drip can be given at 8 and 16 hours after induction.

There is insufficient data on the recommended preventive dose for patients with creatinine clearance ≤70ml/min/1.73m2.

Treatment: Arrangement of pediatric dose (3 months or larger)

The recommended dosage arrangements for children and babies are as follows:

(1) Children weighing ≥ 40 kg can be given in adult doses.

(2) For children and infants weighing <40 kg, they can be administered once every 6 hours at 15 mg/kg. The total daily dose is no more than 2 grams.

For pediatric patients (serum creatinine > 2 mg/dl) with infant or renal impairment within 3 months, there is insufficient clinical data as a recommended basis.

This product is not recommended for the treatment of meningitis. If you suspect that you have meningitis, you should use other suitable antibiotics.

For children with sepsis, as long as the possibility of meningitis can be ruled out, this product can still be used.

Preparation of intravenous drip solution

The product for intravenous drip is sodium bicarbonate as a buffer, so that the pH of the solution is between 6.5 and 8.5. If formulated and used as indicated, there is no significant change in pH. Intravenous infusion of 250 mg of this product contains 18.8 mg of sodium (0.8 mEq); and 500 mg of this product for intravenous infusion contains 37.5 mg of sodium (1.6 mEq).

This product for intravenous drip is a bottled sterile powder in two sizes, one in a 100 ml glass bottle (infusion bottle), each containing 0.5 g of imipenem and 0.5 g of cilastatin; The seeds were 10 ml glass bottles (non-infusion bottles) containing 0.25 g of imipenem and 0.25 g of cilastatin.

Preparation method of this product in 100 ml glass bottle (infusion bottle) (specification: 1.0g):

The sterile powder in the 100 ml glass bottle (infusion bottle) of this product should be prepared according to the method shown in Table (3) and shaken until the solution is clarified. The color change from colorless to yellow does not affect the efficacy of this product.

Table (3) Preparation of infusion solution for intravenous infusion

Preparation method of this product in 10 ml glass bottle (non-infusion bottle) (specification 0.5g):

The sterile powder in the 10 ml glass bottle (non-infusion bottle) package should be prepared as follows: the contents of the bottle must be prepared into a suspension and transferred to a suitable 50 ml infusion container.

The recommended procedure is to take 5 ml from the infusion container containing 50 ml of the diluent (see the stability of the infusion solution), add to the 10 ml bottle of this product, and shake well. Transfer the suspension to the infusion container.

Note: The suspension cannot be used directly for infusion.

Repeat the above steps once to ensure that the contents of the 10 ml glass vial are completely transferred to the infusion container. Shake the infusion container well until the solution is clear.

The stability of the infusion solution

Dry powders should be stored below 25 °C.

Table (4) is the use of different instillation solutions to prepare the intravenous infusion of cost products, respectively, at room temperature or under refrigeration conditions.

Table (4) Stability of intravenous infusion of this product after infusion

Note: The chemical characteristics of this product for intravenous drip are incompatible with lactate, so the diluent used should not contain lactate; however, it can be administered via an intravenous infusion system that is undergoing lactate infusion.

Intravenous infusion of this product can not be mixed with other antibiotics or directly added to other antibiotics.

【Adverse reactions】

In general, this product is well tolerated. Clinical control studies have shown that this product is as well tolerant as cefazolin, cefotaxime and cefotaxime. Most of the adverse reactions were mild and transient, and it was rarely necessary to stop the drug, and very few serious adverse reactions occurred. The most common adverse reactions are some local reactions.

Local reaction

Erythema, local pain and induration, thrombophlebitis.

Allergic reaction / skin

Rash, itching, urticaria, erythema multiforme, Johnson syndrome, angioedema, toxic epidermal necrosis (rare), epidermal dermatitis (rare), candidiasis, including drug fever and allergic reactions.

Gastrointestinal reaction

Nausea, vomiting, diarrhea, teeth and/or tongue spots. It has been reported that the use of all other broad-spectrum antibiotics can cause pseudomembranous colitis.

blood

Eosinophilia, leukopenia, neutropenia, including agranulocytosis, thrombocytopenia, thrombocytopenia, and hemoglobin reduction, as well as prolonged prothrombin time have been reported. Some patients may have a positive positive Coombs test.

liver function

Elevated serum aminotransferase, bilirubin and/or serum alkaline phosphatase; hepatitis (rare).

Renal function

Oliguria / no urine, polyuria, acute renal failure (rare). Since these patients usually have factors that cause prerenal azotemia or impaired renal function, it is difficult to assess the effect of this product on renal function changes.

It has been observed that this product can cause elevated serum creatinine and blood urinary nitrogen; the discoloration of urine is harmless and should not be confused with hematuria.

Nervous system / mental illness

Like other β-lactam antibiotics, it has been reported that intravenous infusion of this product can cause adverse reactions in the central nervous system, such as myoclonus, mental disorders, including hallucinations, disorders or seizures, and paresthesia is also reported.

Special feeling

Loss of hearing and abnormal taste.

Patients with neutropenia

Intravenous instillation of this product in patients with neutropenia is more often associated with drug-related nausea and/or vomiting than in patients with no agranulocytopenia.

【taboo】

This product is contraindicated in patients who are allergic to any of the ingredients in this product.

【Precautions】

General use

Some clinical and laboratory data indicate that this product has partial cross-allergic reactions with other β-lactam antibiotics, penicillins and cephalosporins. It has been reported that most β-lactam antibiotics can cause severe reactions (including allergic reactions). Therefore, before using this product, you should ask the patient in detail whether there has been a history of allergies to β-lactam antibiotics in the past. If an allergic reaction occurs during the use of this product, the drug should be discontinued immediately and treated accordingly.

In fact, it has been reported that almost all antibiotics can cause pseudomembranous colitis, ranging from mild to life-threatening. Therefore, patients who have had gastrointestinal diseases, especially colitis, need to be careful to use antibiotics. The diagnosis of pseudomembranous colitis should be considered in patients with diarrhea during the use of antibiotics. Studies have shown that the toxin produced by Clostridium is the main cause of colitis during the use of antibiotics, but other reasons should also be considered.

Like other antibiotics, prolonged use of this product may result in excessive growth of resistant bacteria. It is necessary to repeat the assessment of the patient's condition. If a double infection occurs during treatment, appropriate measures should be taken.

It is not possible to benefit patients with unproven or strongly suspected bacterial infections or prophylactic medications, and it increases the risk of bacterial resistance.

Central Nervous System

This product is the same as other β-lactam antibiotics. Intravenous infusion preparations can produce adverse reactions in the central nervous system, such as muscle cramps, insanity or seizures, especially when the dosage exceeds the recommended body weight and renal function. When the dose is. However, most of these adverse reactions occur in patients with existing central nervous system disorders (such as brain damage or history of epilepsy) and / or renal dysfunction, because these patients will develop drug accumulation. Therefore, it is necessary to strictly follow the recommended dosage schedule, especially for the above patients (see "Usage and Dosage"). Patients with seizures should continue to be treated with anticonvulsants.

In the case of focal tremor, myoclonus or epilepsy, neurological examination should be performed; if anticonvulsant treatment has not been performed, treatment should be given. If the symptoms of the central nervous system persist, the dose of this product should be reduced or discontinued.

Patients with creatinine clearance ≤5ml/min/1.73m2 should not use this product unless hemodialysis is performed within 48 hours. Hemodialysis patients are also considered only when the benefits of using this product are greater than the risk of seizures.

When the recommended dose is exceeded, the risk of seizures in adult patients with creatinine clearance ≤20 ml/min/1.73 m2 is higher than in patients without renal impairment, regardless of whether or not hemodialysis is performed. Therefore, it is recommended that such patients strictly adhere to the recommended guidance dose. (see usage and dosage)

Patients are urged to adhere strictly to the recommended dose and dose schedules, particularly those with known factors that can trigger convulsions. Anticonvulsant therapy should continue for patients with known epilepsy. In the event of focal tremor, myoclonus or epilepsy, the patient should be assessed for neurological function and anticonvulsant therapy (if not performed) and the dose of the product should be reassessed to determine if the dose should be reduced or discontinued.

Patient notice

Patients should be advised to tell their doctor if they are taking valproic acid or sodium valproate. When administered with this product, the concentration of valproic acid in the blood may drop below the therapeutic concentration. If treatment with this product is necessary and sustained, anti-convulsant drugs need to be replaced or supplemented to prevent and/or treat seizures.

Patients should be informed that antibiotics, including this product, are only used to treat bacterial infections and not to treat viral infections (such as colds). When this product is used to treat bacterial infections, although it usually feels better in the early stages of treatment, it should be strictly prescribed according to the doctor's advice. Missing doses to complete a course of treatment may result in: (1) reducing the effectiveness of the treatment, and (2) increasing the likelihood of bacterial resistance, and will not be cured by this or other antimicrobial agents in the future.

Diarrhea is a common problem caused by antibiotics, usually when antibiotics are discontinued. Sometimes after starting treatment with antibiotics, patients may still have watery stools and bloody stools (with or without stomach cramps and fever) after two or more months after the last antibiotic use. If this happens, patients should contact their physician as soon as possible.

Laboratory inspection

Although this product has the typical characteristics of low toxicity of β-lactam antibiotics, it is recommended to perform regular assessment of organ system function in long-term treatment, including kidney, liver and hematopoietic organs.

【Pregnant women and lactating women】

In the use of this product in pregnant women, there is not enough and well-controlled research data, only in the case of greater than the potential risk of the fetus, can be administered during pregnancy.

Lactating women:

Imipenem can be measured in human milk. If it is necessary to use this product for lactating women, the patient needs to stop breastfeeding.

【Children's medication】

This product is sufficient and rigorous in controlled trials in adult patients, and subsequent clinical trials and published literature in children, supporting the use of this product in pediatric patients under 16 years of age: based on published 178 cases of age ≥ 3 The monthly test results for pediatric patients (no central nervous system infection), the recommended dose of this product is 15 ~ 25mg / kg, once every six hours. The dose of patients from 3 months to <3 years old was 25 mg/kg, and that of 3 to 12 years old was 15 mg/kg. After multiple 60-minute infusions, the corresponding imipenem average trough concentrations were 1.1±0.4 g/mL and 0.6, respectively. ±0.2 g/mL; both doses of imipenem urinary concentration exceeded 10 g/mL. These doses provide sufficient blood and urinary concentrations to treat non-central nervous system infections. Based on adult trials, the maximum dose for treatment of highly sensitive biological infections was 2.0 g/day, and moderately sensitive organisms (mainly some Pseudomonas aeruginosa strains) were infected at 0.4 g/day. High doses (up to 90 mg/kg/day for older children) have been used in patients with cystic fibrosis.

Based on 135 trials of pediatric patients aged ≤ 3 months (weight ≥ 1500 g), the following dose schedules are recommended for non-central nervous system infections:

<1 week old: 25 mg/kg, once every 12 hours;

1-4 weeks old: 25mg/kg, once every 8 hours;

4 weeks old - 3 months old: 25 mg/kg, administered once every 6 hours.

In the published dose probe of the first premature infant (670~1890g) in the first week of age, 20mg/kg, the dose was administered every 12 hours for 15-30 minutes, and the average dose of imipenem after multiple doses. The peak concentration and the trough concentration were 43 g/mL and 1.7 g/mL, respectively. However, neonates may develop moderate accumulation of cilastatin after multiple doses. This cumulative security is unknown.

This product is not recommended for use in pediatric patients with central nervous system infections because of the risk of seizures.

This product is not recommended for <30kg pediatric patients with impaired renal function, as there is no corresponding data available.

【Geriatric Use】

In approximately 3,600 patients aged ≥ 18 years, including clinical trials, approximately 2,800 patients received this product. Among the patients who received this product, there were about 800 patients aged 65 years and older, including about 300 patients aged 75 years and older. No overall differences in safety and efficacy were observed between these subjects and young subjects. Other reported clinical experiences have not yet determined the difference in response between elderly and young patients, but some older people cannot be excluded from being more sensitive.

This drug is known to be excreted primarily through the kidneys, and patients with impaired renal function are at greater risk of toxic side effects. Because elderly patients may have renal dysfunction, attention should be paid to the choice of dose and renal function if necessary.

There is no need to adjust the dose according to age. Dose adjustment is necessary in patients with impaired renal function.

【medicine interactions】

There have been reports of intravenous infusion of ganciclovir and this product in patients with seizures. This situation should not be accompanied by use unless its benefits outweigh the risks.

Due to the combination of this product and probenecid, the plasma level and plasma half-life of imipenem are slightly increased. It is not recommended to use probenecid together with this product.

This product should not be mixed with other antibiotics or added to other antibiotics. However, this product can be combined with certain antibiotics such as aminoglycosides.

Case reports in the literature indicate that patients receiving valproic acid or sodium valproate have the following results after treatment with carbapenems, including imipenem: a decrease in valproic acid concentration. As a result of this mutual use, the valproic acid concentration may be lower than the therapeutic range, thus increasing the risk of seizures. Although this mechanism of mutual use is unknown, data from in vitro and animal studies indicate that carbapenem antibiotics may inhibit the hydrolysis of valproic acid glucuronide metabolite (VPA-g) to valproic acid, thereby reducing valproate Plasma concentration of acid.

【Drug overdose】

The acute toxicity of imipenem-cilastatin sodium 1:1 was measured by intravenous injection of 751 to 1359 mg/kg in mice. After the administration, the movement disorder rapidly appeared, and clonic convulsions occurred at about 45 minutes. All doses died within 4 to 56 minutes.

At a dose of 771 to 1583 mg/kg, intravenous injection of imipenem-cilastatin sodium in rats produced acute toxicity within 5 to 10 minutes. In all dose groups, females showed reduced activity, slow breathing, and ptosis with pre-clinical convulsions. All male doses showed ptosis and tremor and clonic convulsions except for the lowest dose (771 mg/kg). In another rat study, female rats showed movement disorders, slow breathing, and decreased activity except for the lowest dose (550 mg/kg); clonic convulsions occurred before death. Male rats trembled at all doses, with clonic convulsions and ptosis at only the two highest doses (1130 and 1734 mg/kg). At a dose of 771 to 1734 mg/kg, death occurred between 6 and 88 minutes.

When the product is overdose, the drug should be stopped, symptomatic treatment should be given, and rescue measures should be taken as needed. Imipenem-cilastatin sodium can be hemodialysis. However, it is debatable whether over-treatment is useful in adopting this measure.

【Pharmacology and Toxicology】

This product (imipenem cilastatin sodium for injection) is a broad-spectrum β-lactam antibiotic supplied in an intravenous drip form. This product contains two components: (1) imipenem, a new type of β-lactam antibiotic-imipenem, which is characterized by a broader spectrum of bactericidal spectrum than any other antibiotics studied. (2) cilastatin sodium, a specific enzyme inhibitor that blocks the metabolism of imipenem in the kidney, thereby increasing the concentration of the imipenem prodrug in the urinary tract. In this product, the weight ratio of imipenem to cilastatin is 1:1.

microbiology

The broad-spectrum bactericidal effect of this product is due to its strong ability to inhibit bacterial cell wall synthesis. It can kill most of the gram-positive and gram-negative aerobic and anaerobic pathogens.

This product has a broad spectrum of antibacterial activity against Gram-negative bacteria, as well as a new generation of cephalosporins and penicillins. It also has a strong killing ability against Gram-positive bacteria, and this characteristic is only in the earlier narrow-spectrum. Only β-lactam antibiotics have. The antibacterial spectrum of this product includes different kinds of pathogens such as Pseudomonas aeruginosa, Staphylococcus aureus, Enterococcus faecalis and Bacteroides fragilis, and these pathogens are usually resistant to other antibiotics.

This product has the ability to resist the degradation of β-lactamase produced by bacteria, so that it can have obvious antibacterial effects on most pathogens such as Pseudomonas aeruginosa, Serratia and Enterobacter; these pathogens are large Most β-lactam antibiotics are naturally resistant.

The antibacterial spectrum of this product is broader than any other antibiotics that have been studied, and actually includes all clinically significant pathogens. The antibacterial range of this product in vitro includes:

Gram-negative aerobic bacteria: Acinetobacter spp., Acinetobacter sp. (formerly known as H. albicans), Aeromonas hydrophila, Alcaligenes, B. bronchiseptica, Borealis Bacillus, Bordetella pertussis, Brucella maltese, Burkholderia typhimurium (formerly known as Pseudomonas sinensis), Burkholderia berghei (formerly known as Pseudomonas aeruginosa), curved Bacillus, Carbonophilic phage, Citrobacter bacterium, Citrobacter citrate, Citrobacter citrate (formerly known as citric acid bacterium), Escherichia coli, Enterobacter, Aerogenes , Enterobacter agglomerans, Enterobacter cloacae, Escherichia coli, V. vaginalis, Haemophilus ducrei, Haemophilus influenzae (including β-lactamase producing strains), Haemophilus parainfluenzae, Hive Haf Nitrobacter, Klebsiella, Oxcino Klebsiella, Klebsiella pneumoniae, Klebsiella pneumoniae, Moraxella, Mohs's bacteria (formerly known as M. variabilis), gonorrhea Streptococcus (including strains producing penicillinase), meninges Neisseria, Pasteurella, Pasteurella multocida, Pseudomonas, Proteus, Proteus mirabilis, Proteus vulgaris, Providencia, Ald Provence Actinomycetes, Provedus serrata (formerly known as Proteus reed), Providencia stellaria, Pseudomonas **, Pseudomonas aeruginosa, Pseudomonas fluorescens, stinking Monocytogenes, Salmonella, Salmonella typhi, Serratia, Serratia marcescens (formerly known as Serratia liquefaciens), Serratia marcescens, Shigella, Nystonia Genus (formerly known as Pasteurella), N. enterocolitica, and pseudotuberculosis Nerve bacteria.

**S. maltophilia (formerly known as Stenotrophomonas maltophilia, Pseudomonas maltophilia) and some Burkholderia onions (formerly known as Pseudomonas cepacia) are generally not sensitive.

Gram-positive aerobic bacteria: Bacillus, Enterococcus faecalis, Mycobacterium typhimurium, Listeria monocytogenes, Nocardia, Staphylococcus, Staphylococcus aureus (including strains producing penicillinase) ), Staphylococcus epidermidis (including strains producing penicillinase), Staphylococcus aureus, Streptococcus agalactiae, Streptococcus C, Streptococcus G, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus hemolyticus (including Group A hemolytic streptococcus and group B hemolytic streptococcus).

Enterococcus faecium and methicillin-resistant Staphylococcus are not sensitive to this product.

Gram-negative anaerobic bacteria: Bacteroides, Bacteroides fragilis, Bacteroides fragilis, Bacteroides ovum, Bacteroides variabilis, Bacteroides blacei, Bacteroides, Bilophila wadsworthia, Fusobacterium, gangrene Bacillus, Rhizoctonia nucleatum, non-sugar brown erythromycin (formerly known as Bacteroides saccharolyticus), two-way Prevobacterium (formerly known as Bacteroides), and lyophilized prion Previously referred to as Bacteroides sinensis, P. intermedia (previously known as Bacteroides intermedia), Prevotella melanin (formerly known as Bacteroides melanogis), and Vesococcus.

Gram-positive anaerobic bacteria: actinomycetes, Bifidobacterium, Clostridium, Clostridium perfringens, Eubacteria, Lactobacillus, Campylobacter, Microaerobacteria , Digestive genus, Streptococcus mutans, Propionibacterium (including Propionibacterium acnes).

Other: Mycobacteria, Mycobacterium smegmatis.

In vitro tests have shown that imipenem and aminoglycoside antibiotics have synergistic effects on certain isolated Pseudomonas aeruginosa.

Toxicological research

Long-term animal studies have not been conducted to assess the potential carcinogenicity of imipenem-cilastatin. Various bacterial and mammalian in vivo and in vitro tests were conducted to study genotoxicity. The trials used included: V79 mammalian cell mutation test (imitramine-cilastatin sodium alone, imipenem alone), Ames test (cilastatin sodium alone, imide culture) Southern alone), unconventional DNA synthesis assay (imipenem-cilastatin sodium) and mouse cytogenetic assay (imipenem-cilastatin sodium). These trials did not find any evidence of genetic variation.

Male and female rats were tested for reproduction, imipenem-cilastatin sodium 80 mg/kg/day, subcutaneous dose 320 mg/kg/day, which is equivalent to the highest recommended human dose for intravenous preparations (based on Mg/m2 body surface area basis). The weight of the live fetus in the highest dose group was only slightly reduced. No other adverse effects on fertility, fertility and the ability to survive, grow or develop the fetus were observed.

Teratogenic use

Intravenous injection of cilastatin sodium to rabbits at 30, 100 and 300 mg/kg/day has been completed (maximum dose is equivalent to the maximum recommended dose for adults based on body surface area (imipenem-cilastatin sodium 50 mg/kg) / day) 1.9 times) three doses of long-term toxicity test, subcutaneous injection of cilastatin sodium 40, 200 and 1000 mg / kg / day in rats (maximum dose is equivalent to the maximum recommended dose in adults according to body surface area ( There was no evidence of teratogenicity of cilastatin sodium in the three-dose long-toxicity test of 3.2 times of imipenem-cilastatin sodium 50 mg/kg/day. Intravenous injection of imipenem to rabbits at 15, 30 and 60 mg/kg/day has been completed (maximum dose is equivalent to the maximum recommended dose for adults based on body surface area (imipenem-cilastatin sodium 50 mg/kg/ 0.4 times in days) three doses of long-toxicity test, subcutaneous injection of imipenem 225, 450 and 900 mg/kg/day in rats (maximum dose is equivalent to the maximum recommended dose for adults (imine culture) No evidence of imipenem teratogenicity was observed in three doses of the long-toxicity test at 2.9 times the South-cilastatin sodium 50 mg/kg/day.

In the malformation study of pregnant rodents during the main organ formation period, imipenem-cilastatin sodium was administered at an intravenous dose of 20 and 80, and the subcutaneous dose was 320 mg/kg/day, approximately 0.5-fold (mouse).至 double (rat) (maximum dose is equivalent to the maximum recommended dose for adults (imitramine-cilastatin sodium 50mg/kg/day) based on body surface area), no evidence of teratogenicity .

The imipenem-cilastatin sodium is administered subcutaneously to the pregnant rabbit at a dose equivalent to the usual human dose of the intravenous preparation and above the dose (1000 to 4000 mg/day), causing weight loss, diarrhea and maternal death. Weight loss, diarrhea and death were also observed when a comparable dose of imipenem-cilastatin sodium was administered to non-pregnant rabbits. This intolerance differs from other beta-lactam antibiotics in the performance of this species, probably due to changes in the intestinal flora.

Administration of imipenem-cilastatin sodium to pregnant macaques at a dose of 40 mg/kg/day (intravenous bolus injection) or 160 mg/kg/day (subcutaneous injection), resulting in maternal toxicity including vomiting, loss of appetite, body weight Reduce, diarrhea, miscarriage and, in some cases, death. In contrast, no significant toxicity was observed in non-pregnant macaques given imipenem-cilastatin sodium doses up to 180 mg/kg/day (subcutaneous injection). When imipenem-cilastatin sodium (dose about 100mg/kg/day, or about the maximum recommended daily human dose of intravenous preparations is 0.6 times), pregnant mothers are given according to the intravenous infusion rate of human clinical use. The mother does not. The least tolerant (occasionally vomiting), no death of pregnant macaques, no evidence of teratogenicity, but increased abortion relative to the control group.

Rats were given imipenem-cilastatin sodium subcutaneously at the end of pregnancy at a dose of up to 320 mg/kg/day, which is equivalent to the maximum recommended dose in adults, which has no adverse effects on the fetus or lactation.

【Pharmacokinetics】

After intravenous injection of 250 mg, 500 mg or 1000 mg of this product (measured according to imipenem), the peak plasma concentration was 20 mg/ml, 35 mg/ml or 66 mg/ml, respectively, and the protein binding rate was about 20%. The product is widely distributed in the body, with the highest concentration of intercellular fluid, kidney, maxillary sinus, cervix, ovary, pelvis, lung, etc., and the concentration in the gallbladder, prostate, tonsil, and sputum is also high, and it is difficult to pass through the placenta. Blood-cerebrospinal fluid barrier. The half-life is about 1 hour and is mainly excreted by the kidneys. When renal function declines, the amount of excretion decreases, the blood concentration increases, and the half-life is prolonged.

Imipenem alone, decomposed by the influence of renal peptidase, can only recover a small amount of the original drug in the urine. Cistatin is a renal peptidase inhibitor that protects imipenem from damage in the kidneys, so the original drug recovered in urine can reach 70%. And cilastatin can inhibit imipenem into the renal tubular epithelial tissue, thereby reducing the excretion of imipenem and reducing the nephrotoxicity of the drug.

【Storage】

Store at 25 ° C or below.

【Packaging】 vial, 1 bottle / box

【Validity Period】 24 months

【Executive Standards】

(1) 1.0g per bottle: National Food and Drug Administration Standard YBH04172009.

(2) 0.5g per bottle: National Food and Drug Administration Standard YBH03102013.

【Approval Number】

(1) 1.0g per bottle: National Medicine Standard H20093435.

(2) 0.5g per bottle: National Medicine Standard H20133239.

【manufacturer】

Company Name: Shandong New Times Pharmaceutical Co., Ltd.

Production address: No. 1 North Outer Ring Road, Feixian County, Shandong Province

Postal code: 273400

Phone number: 0539-8336336 (Sales) 5030608 (Quality Management Department)

Fax number: 0539-5030900

Website: www.LUNAN.com.cn

24-hour customer service hotline: 400-0539-310