Cefpirome sodium for injection instructions
Please read the instructions carefully and use under the guidance of a physician.
Drug name】
Generic name: Cefpirome sodium for injection
Trade name: Ceftobiprole®/Zevtera®
English name: Ceftobiprole Medocaril Sodium for Injection
Hanyu Pinyin: Zhusheyong Toubaobiluozhina
Ingredients
The active ingredient of this product is cefpirome sodium.
Chemical name: (6R, 7R)-7-((Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetylamino)-3-((E)-((R)-1′-(((5-methyl-2-oxo-1,3-dioxolan-4-yl)methoxy)carbonyl)-2-oxo-[1,3′-bipyrrolidin]-3-ylidene (methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid monosodium salt
Chemical structure formula.
Molecular formula: C26H25N8NaO11S2
Molecular weight: 712.64
Excipients: citric acid, sodium hydroxide.
【Properties】.
This product is white, off-white to light brown loose mass or powder.
Indications】
This product is indicated for the treatment of the following infections in adults.
Hospital-acquired pneumonia (HAP), except ventilator-associated pneumonia (VAP)
Community-acquired pneumonia (CAP)
Specification
500mg (based on C20H22N8O6S2)
Dosage]
The recommended dose of this product is 500 mg every 8 hours for 2 hours per intravenous infusion. In the treatment of CAP, if intravenous treatment with cefpirome sodium has been administered for at least 3 days, a switch to an appropriate oral antibiotic treatment may be considered depending on the patient’s clinical response.
Renal injury
In patients with mild renal impairment (i.e., creatinine clearance [CLCR] of 50-80 mL/min), no dose adjustment of this product is required. In patients with moderate renal impairment (CLCR of 30-<50 mL/min), the recommended dose is 500 mg every 12 hours as a 2-hour intravenous infusion. In patients with severe renal impairment (CLCR <30 mL/min), the recommended dose is 250 mg administered intravenously over 2 hours every 12 hours. Caution should be exercised in the use of this product in patients with severe renal impairment due to the limited clinical data available and the anticipated increased exposure to this product and its metabolites in these patients.
End-stage renal disease requiring dialysis
Cefpirome is a substance that can be hemodialyzed. For patients with end-stage renal disease with or without intermittent hemodialysis, the recommended dose is 250 mg every 24 hours.
Patients with creatinine clearance >150 mL/min
Prior to initiating therapy, the prescriber should assess the patient’s renal function based on creatinine clearance (mL/min).
If the patient has a high creatinine clearance (>150 mL/min), it is recommended that the infusion duration be extended to 4 hours based on pharmacokinetic/pharmacodynamic considerations.
Liver injury
There is no experience with dosing in patients with hepatic injury. However, since cefpirome is rarely metabolized hepatically and its elimination is mainly via the kidney, no dose adjustment is considered necessary in patients with hepatic injury.
Dosing method
Each vial is for a single dose only.
The product must be reconstituted and then further diluted before a 2-hour infusion.
Precipitation may occur when this product is mixed with calcium-containing solutions in the same intravenous line. Therefore, with the exception of Ringer’s Lactate, this product and calcium-containing solutions should not be mixed or administered together in the same intravenous line.
Step 1: Re-dissolve
Add 10 ml of sterile water for injection or 50 mg/ml (5%) glucose injection to the vial and shake the vial vigorously until completely dissolved, which in some cases may take up to 10 minutes. The volume of the resulting concentrate was approximately 10.6 ml. The foam was eliminated and the solution was visually inspected to ensure that the drug was a solution and that no particulate matter was present. The reconstituted concentrate contains 50 mg/ml of cefpirome, which must then be further diluted before administration. It is recommended that further dilution of the reconstituted solution be performed immediately. However, if immediate dilution is not possible, the reconstituted solution can be stored at room temperature for up to 1 hour or in a refrigerator (2°C to 8°C) for up to 24 hours.
Step 2: Dilution
Preparation of 500mg dose of this product infusion
10ml of the solution after re-dissolution should be drawn from the vial and then injected into a suitable container (e.g. PVC or PE infusion bag, glass bottle) containing 9mg/ml (0.9%) sodium chloride injection, 50mg/ml (5%) glucose injection or 250ml of lactate Ringer’s injection. Mix the infusion solution by gently turning it over for 5 to 10 minutes to form a homogeneous solution. Vigorous stirring should be avoided to prevent foaming. The entire contents of the infusion bag should be infused, equivalent to the administration of a 500 mg dose of this product.
Preparation of a 250 mg dose of this product infusion for patients with moderate to severe kidney injury
5 ml of the reconstituted solution should be drawn from the vial and injected into a suitable container (e.g., PVC or PE infusion bag, glass vial) containing 9 mg/ml (0.9%) sodium chloride injection, 50 mg/ml (5%) glucose injection, or 125 ml of lactated Ringer’s injection. Mix the infusion solution by gently turning it over for 5 to 10 minutes to form a homogeneous solution. Vigorous stirring should be avoided to prevent foaming. The entire contents of the infusion bag should be infused, equivalent to the administration of a 250 mg dose of this product.
The infusion solution should be a clarified to slightly milky or yellowish solution. The infusion solution should be visually inspected for the presence of particulate matter prior to administration. If particulate matter is visible, the vial of drug should be discarded.
Chemical and physical data obtained from stability tests during drug use support the length of stability of the reconstituted and infused solution (2.67 mg/ml) as described in the following table.
Total length of time that reconstitution, dilution and infusion must be completed (including 2 hours infusion time)
Infusion solution diluent stored at 25 ℃ infusion solution stored at 2 ℃ ~ 8 ℃ (refrigerator) infusion solution
Protected from light Protected from light Not protected from light 9 mg/ml (0.9%) sodium chloride injection 24 hours 8 hours 96 hours 50 mg/ml (5%) dextrose injection 12 hours 8 hours 96 hours Ringer’s lactate injection 24 hours 8 hours Not refrigerated To minimize the possibility of microbial contamination, this product should be used immediately unless under controlled and verified sterile conditions Resolvable/diluted. If not used immediately, the user is responsible for the duration and conditions of storage of the product prior to use.
Neither the reconstituted solution nor the infusion solution should be frozen or exposed to direct sunlight.
If the infusion solution is stored in a refrigerator, it should be allowed to equilibrate to room temperature prior to administration. The infusion solution does not need to be protected from light during administration.
[Adverse Reactions].
In therapeutic clinical studies, a total of 1668 subjects received this product. In these trials, a total of 1239 subjects (696 subjects with community-acquired pneumonia and hospital-acquired pneumonia and 534 subjects with complicated skin soft tissue infections, cSSTI) received the 500 mg, 3 times daily regimen, 389 subjects (cSSTI) received the 500 mg, 2 times daily regimen, and an additional 40 subjects (cSSTI) received the 750 mg, twice daily regimen.
The most common adverse reactions seen in ≥3% of patients treated with this product were nausea, vomiting, diarrhea, local reactions, hypersensitivity reactions (including urticaria, itchy rash, and drug allergic reactions), and taste disturbances.
Less commonly reported but more serious adverse reactions include thrombocytopenia, granulocyte deficiency, allergic reactions, Clostridium difficile colitis, convulsions, agitation (including anxiety, panic, and nightmares), and renal failure.
List of Adverse Reactions
The following adverse reactions were reported during treatment and follow-up and their frequency was categorized as: very common (1/10); common (1/100-<1/10); uncommon (1/1000-<1/100); rare (1/10,000-<1/1,000); very rare (<1/10,000); and unknown (cannot be estimated based on available data).
Adverse reactions from clinical studies and post-marketing reports
Systemic organ classification frequency: adverse events infections and infections common: fungal infections (including vulvovaginal, oral and cutaneous fungal infections)
Uncommon: Clostridium difficile colitis** Blood and lymphatic system disorders Uncommon: eosinophilia***, leukopenia, anemia, thrombocythemia, thrombocytopenia
Unknown: granulocyte deficiency* Immune system disorders common: hypersensitivity reactions (including urticaria, itchy rash, and drug allergic reactions)
Unknown: allergic reactions** Metabolic and nutritional disorders common: hyponatremia
Uncommon: hypokalemia Psychiatric disorders uncommon: insomnia, mental agitation (including anxiety, panic and nightmares) Neurological disorders common: taste disturbances, headache, dizziness, drowsiness***
Unknown: convulsions*,** Respiratory, thoracic, and mediastinal disorders Uncommon: dyspnea, sore throat***, asthma Gastrointestinal disorders Common: nausea, vomiting, diarrhea, abdominal pain, dyspepsia Hepatobiliary disorders Common: elevated liver enzymes (including AST, ALT, LDH, and alkaline phosphatase) Skin and subcutaneous tissue disorders Common: rash (including maculopapular, papular, maculopapular, and panniculopapular rashes), pruritus Musculoskeletal and connective tissue disorders uncommon: muscle cramps*** Renal and urinary disorders uncommon: renal failure systemic disorders and administration site conditions common: infusion site reactions
Uncommon: peripheral edema Abnormal test results Uncommon: elevated blood triglycerides, elevated blood creatinine, elevated blood glucose
Unknown: Positive Coombs direct test* based on post-marketing reports. Because these reactions are spontaneously reported post-marketing, it is not possible to reliably estimate their frequency and therefore to obtain their classification.
** See [Caution].
*** Only seen in cSSTI studies. [Contraindications].
This product is contraindicated in persons with hypersensitivity to the active ingredient or any of the excipients.
This product is contraindicated in persons with hypersensitivity to cephalosporin-based antibacterial drugs.
This product is contraindicated in persons with tachyphylaxis and severe allergic reactions (e.g., anaphylactic reactions) to β-lactam antibacterial agents (e.g., penicillins or carbapenems).
Precautions]
Allergic reactions
As with all β-lactam antibacterials, severe hypersensitivity (allergic) reactions have been reported, and occasionally fatal hypersensitivity (allergic) reactions have been reported. In the event of a severe hypersensitivity reaction, the product must be discontinued immediately and appropriate emergency measures initiated.
Prior to initiating therapy, patients should be confirmed to have a history of severe allergic reactions to this product, other cephalosporins, or any other type of beta-lactams. This product should be used with caution if the patient has a history of non-serious allergic reactions to other beta-lactams.
When doses are administered above the recommended dose range
No clinical experience has been gained with doses higher than the recommended dose of 500 mg every 8 hours.
Patients with a history of seizure disorders
Seizures may be triggered during the use of this product. Seizures are most commonly seen in patients with a history of CNS disease/seizure disorder during treatment with this product; therefore, caution is advised when treating these patients.
Clostridium difficile-associated diarrhea
Antimicrobial-associated colitis and pseudomembranous colitis have been reported during the use of this product and vary in severity from mild to life-threatening. This diagnosis should be considered in patients with diarrhea during and after administration of this drug. Treatment with this product must be discontinued and consideration should be given to the administration of specific drugs for C. difficile. Drugs that inhibit intestinal motility should not be given.
Overlapping infections of non-susceptible organisms
Overgrowth of non-susceptible bacteria, including fungi, may occur with the use of this product. If there is evidence of overlapping infections during treatment, appropriate measures should be taken.
Nephrotoxicity in animals
In animal studies, reversible nephrotoxicity was observed at high doses and was accompanied by the precipitation of drug-like material in the distal tubules. Although the clinical significance of this observation is not known, correction of hypovolemia is recommended in patients receiving this product to maintain normal urinary excretion.
Precipitation with calcium-containing solutions
Precipitation may occur when this product is mixed with calcium-containing solutions in the same intravenous infusion line. Therefore, with the exception of Ringer’s Lactate Injection, this product and calcium-containing solutions should not be mixed or administered simultaneously in the same intravenous line.
Limitations of Clinical Data
There is no experience with the use of cefpirome in the treatment of HAP (except VAP) and CAP in patients with AIDS, neutropenia, immune insufficiency, and myelosuppression. Caution should be exercised when treating these patients.
Patients with ventilator-associated pneumonia (VAP): This product has not been shown to be effective in treating patients with VAP. Therefore, this product should not be initiated for the treatment of patients with VAP. In addition, the results of the regression analysis showed a tendency to support the use of cefpirome, so it is recommended that this product should be used with caution in patients with hospital-acquired pneumonia (HAP) who require subsequent ventilator use.
Clinical efficacy against specific pathogens
Susceptibility to Enterobacteriaceae: As with other cephalosporins, Enterobacteriaceae, including many ultra broad-spectrum β-lactamases (ESBL), serine carbapenemases, and class B metallo-β-lactamases (among others), readily hydrolyze cefpirome. Therefore, epidemiological information on ultra broad-spectrum beta-lactamase (ESBL) producing Enterobacteriaceae should be considered when selecting this product for treatment.
Interference with serological tests
Direct antiglobulin test (Coombs test) seroconversion and potential risk of hemolytic anemia: Positive direct antiglobulin tests may occur during cephalosporin therapy. In clinical studies, no evidence of hemolytic anemia was found. However, the possibility that hemolytic anemia may occur during treatment with this product cannot be ruled out. This possibility should be examined in patients who develop hemolytic anemia during or after treatment with this product.
Possible interference with serum creatinine testing
It is not known whether cefpirome, like some cephalosporins, interferes with the alkaline picric acid method of measuring serum creatinine (Jaffé reaction), which may result in obtaining inaccurately high creatinine measurements. During treatment with this product, enzymatic determination of serum creatinine is recommended.
Possible interference with urine glucose testing
During treatment with this product, enzymatic measurement of urine glucose is recommended, as measurement by the copper sulfate method may be interfered with.
Control of sodium intake
This product contains approximately 1.3 mmol (29 mg) of sodium per dose. Therefore, patients should consider controlling sodium intake in their diet.
Contraindications
This product should not be administered via the Y-connection with acyclovir sodium, amikacin sulfate, amiodarone hydrochloride, amphotericin B (colloid), calcium gluconate, caspofungin acetate, ciprofloxacin, cisbenzenesulfatracurium, diazepam, diltiazem hydrochloride, diphenhydramine hydrochloride, dobutamine hydrochloride, dopamine hydrochloride, esomeprazole sodium, famotidine, filgrastim, gentamicin sulfate Haloperidol lactate, hydromorphone hydrochloride, hydroxyzine hydrochloride, regular human insulin, lysergic acid insulin, labetalol hydrochloride, levofloxacin, lidocaine hydrochloride, magnesium sulfate, pethidine hydrochloride, metoclopramide hydrochloride, midazolam hydrochloride, milrinone lactate, morphine sulfate, moxifloxacin hydrochloride, ondansetron hydrochloride, pantoprazole sodium, dipotassium phosphate, isoproterenol hydrochloride, remifentanil hydrochloride, Sodium phosphate, Tobramycin sulfate.
Effects on the ability to drive and use machines
No studies have been conducted to examine the effect of this product on the ability to drive or use machinery. However, because dizziness is a common adverse effect, it is recommended that driving or use of machinery be avoided when this product is used for treatment.
Pregnant women and nursing mothers
No adequate, well-controlled studies have been conducted on this product in pregnant women. Animal studies have shown no direct or indirect adverse effects on pregnancy, embryo/fetus development, delivery or postnatal development.
Because exposure data are not available in pregnant women, this product should not be used during pregnancy unless extremely necessary.
Animal studies have shown that cefpirome/metabolites can be secreted into the breast milk of animals. It is not known whether cefpirome is secreted into human breast milk and therefore the risk of diarrhea and mucosal fungal infections in breastfed infants cannot be excluded. The possibility of sensitization should be considered. The decision to discontinue breastfeeding or to discontinue/avoid the use of this product must be made taking into account both the breastfeeding benefit to the infant and the therapeutic benefit to the mother.
[Pediatric Use].
The safety and efficacy of this product have not been established in children under the age of 18 years. This product is not recommended for use in children or adolescents younger than 18 years of age.
Geriatric Use]
No dose adjustment is necessary for geriatric patients except in the presence of moderate to severe renal impairment.
Drug Interactions]
In vitro studies have been conducted to examine potential interactions at the CYP enzyme level. However, because the concentration of cefpirome used in these studies was limited by solubility, the possibility of interaction with CYP drugs cannot be ruled out.
In vitro studies have shown that cefpirome inhibits OATP1B1 and OATP1B3 with IC50 values of 67.6 μM and 44.1 μM, respectively. cefpirome may cause elevated concentrations of drugs that are eliminated by OATP1B1 and OATP1B3, for example, statins (pitavastatin, pravastatin, rasuvastatin), glibenclamide, and bosentan.
No clinical interaction studies have been conducted. Caution is advised when combining this product with drugs that have a narrow therapeutic window.
Precipitation with calcium-containing solutions
Precipitation may occur when this product is mixed with calcium-containing solutions in the same intravenous infusion line. Therefore, except for Lactated Ringer’s Injection, this product and calcium-containing solution should not be mixed or administered together in the same intravenous line.
Drug overdose]
The maximum total daily dose in Phase I trials was 3 g (1 g every 8 hours). In case of overdose, symptomatic treatment should be administered. The plasma concentration of cefpirome can be reduced by means of hemodialysis.
[Clinical trial].
Community-acquired pneumonia
A multicenter, randomized, double-blind, positive-controlled phase III trial conducted in 781 patients with CAP. Ceftopiro (500 mg every 8 hours, intravenously) was compared to ceftriaxone with or without linezolid (ceftriaxone: 2 g every 24 hours, intravenously; linezolid: 600 mg every 12 hours, intravenously). Both groups allowed subjects who had received a minimum of 3 days of intravenous therapy to switch from intravenous infusion of study drug to oral cefuroxime (500 mg, twice daily, orally) for the study’s planned treatment duration of 7-14 days. Three hundred fourteen patients in the intention-to-treat analysis set were randomized to the cefpirome group and 324 patients were randomized to the ceftriaxone with or without linezolid. The clinically evaluable analysis set contained 231 (74%) patients in the ceftopiro treatment arm and 238 (73%) patients in the ceftriaxone plus or without galactazolamide treatment arm. The primary endpoint of the study was the clinical cure rate at the TOC visit, and details of the data are shown in the table.
Clinical cure rates at the TOC visit in the different analysis sets
Analysis set Cefpirome group n/N (%) Ceftriaxone plus or without galactazolamide n/N (%) Clinically evaluable Analysis set 200/231 (86.6%) 208/238 (87.4%) Intention-to-treat Analysis set 240/314 (76.4%) 257/324 (79.3%) Hospital-acquired pneumonia
A multicenter, randomized, double-blind, positive-controlled phase III trial in patients with HAP (including VAP). Cefpirome (500 mg every 8 hours intravenously) was compared with ceftazidime plus linezolid (ceftazidime: 2 g every 8 hours intravenously; linezolid: 600 mg every 12 hours intravenously). Total study treatment duration was 7-14 days. The intention-to-treat analysis set contained 391 patients randomized to the cefpirome group and 390 patients randomized to the ceftazidime plus linezolid group. The clinically evaluable analysis included 251 (64%) patients in the cefpirome treatment arm and 244 (63%) patients in the ceftazidime galinazomib treatment arm. The primary endpoint of the study was the clinical cure rate at the TOC visit, and details of the data are shown in the table.
Clinical cure rates at the TOC visit in the different analysis sets
Analysis set Cefpirome group n/N (%) Ceftazidime galinazolamide n/N (%) Clinically evaluable Analysis set 174/251 (69.3%) 174/244 (71.3%) Intent-to-treat Analysis set 195/391 (49.9%) 206/390 (52.8%)* In patients with VAP (i.e., pneumonia developed after 48 hours after initiation of ventilator of patients) has not been able to demonstrate non-inferiority between this product and the control drug group. In the VAP clinically evaluable analysis set, the cefpirome group had a clinical cure rate of 37.7% (20/53 patients) compared with 55.9% (33/59 patients) in the ceftazidime plus nexium group. In the VAP intention-to-treat analysis set, the clinical cure rate was 23.1% (24/104 patients) in the cefpirome group and 36.8% (39/106 patients) in the ceftazidime galinazolamide group.
Pharmacology and toxicology]
Pharmacological effects
Mechanism of action
Cefpirome exerts bactericidal activity in sensitive strains by binding to penicillin-binding proteins (PBPs), including PBPs with reduced susceptibility to a variety of β-lactams, such as PBP2a in methicillin-resistant Staphylococcus aureus (MRSA) and PBP2b and PBP2x in Streptococcus pneumoniae (penicillin-mediated and resistant).
Mechanisms of resistance
The mechanisms of cefpirome resistance are mainly hydrolytic inactivation of β-lactamases, mutations in penicillin-binding proteins (PBPs), and decreased drug penetration/increased efflux.
The following Enterobacteriaceae isolates are resistant to cefpirome: Ambler class A [especially TEM, SHV and CTX-M type ultra broad spectrum β-lactamases (ESBL) and KPC type carbapenemases], class B and D β-lactamases [especially ESBL variants and carbapenemases (OXA-48)] producing strains.
The following P. aeruginosa isolates are resistant to cefpirome: strains producing Ambler class A enzymes (e.g., PSE-1), class B (e.g., IMP-1, VIM-1, VIM-2), and class D enzyme β-lactamases (e.g., OXA-10), with acquired mutations in regulatory genes resulting in de-blocked Ambler class C β-lactamase expression levels or Mex XY strains with overexpression of the efflux pump.
The following Bacillus spp. isolates are resistant to cefpirome: Ambler class A (e.g., VEB-1), class B (e.g., IMP-1, IMP-4) and class D β-lactamase (e.g., OXA-25, OXA-26) producing strains, and Ambler class C β-lactamase expression level derepressed strains.
Antibacterial activity
Cefpirome has been shown to have antibacterial activity in vitro and in the clinical infections described in the [Indications] section against most of the following isolated pathogens.
Gram-positive bacteria.
Staphylococcus aureus (including MRSA)
Streptococcus pneumoniae (including MDRSP)
Gram-negative bacteria.
Escherichia coli
Klebsiella pneumoniae
The clinical effectiveness of cefpirome has not been established for the following pathogens, although in vitro studies have shown that these pathogens are usually susceptible to cefpirome in the absence of acquired resistance.
Bacteroides immobilis spp.
Citrobacter spp.
Enterobacter spp.
Haemophilus influenzae
Acid-producing Klebsiella
Katamora
Morganella morganii
Aspergillus singularis
Propionibacterium spp.
Pseudomonas spp.
Serratia spp.
In vitro data show that the following species are not susceptible to cefpirome.
Chlamydia pneumoniae
Burkholderia cepacia complex
Mycoplasma pneumoniae
Bifidobacterium spp.
Nocardia spp.
Stenotrophomonas maltophilia
Susceptibility Testing Fold Points
The minimum inhibitory concentration (MIC) fold points established by the European Committee for Antimicrobial Susceptibility Testing (EUCAST) are as follows.
Minimum inhibitory concentration fold (mg/L) Pathogen susceptible (≤ S) resistant (R >) Staphylococcus aureus (including MRSA) 22 Streptococcus pneumoniae 0.50.5 Enterobacteriaceae 0.250.25 Pseudomonas aeruginosa IEa IEa non-species specific fold b44a
Insufficient evidence
b
PK/PD targets based on Gram-negative bacteria
PK/PD relationship
As with other β-lactam antimicrobials, the percentage of time (%T > MIC) that the concentration exceeds the minimum inhibitory concentration (MIC) of the infecting microorganism during the dosing interval is the parameter most relevant to the efficacy of cefpirome.
Toxicological studies
Genotoxicity
Cefpirome sodium Ames test, CHO/HPRT forward mutation test, in vivo programmed in vitro DNA synthesis test in rat hepatocytes and in vivo bone marrow micronucleus test in mice were negative; mouse lymphoma cell test and in vitro chromosomal aberration test in human peripheral blood lymphocytes were positive.
In the cefpirome mouse lymphoma cell in vitro assay, it was positive at cytotoxic concentrations.
Reproductive toxicity
In the toxicity test of fertility and early embryonic development in rats, cefpirome sodium 360mg/kg was administered intravenously to male and female rats, and no significant effects on fertility and early embryonic development were observed in male and female rats.
No significant effects on embryo-fetal development were observed in pregnant rats and pregnant crab-monkeys when cefpirome sodium 360 and 120 mg/kg were administered intravenously, respectively.
In rats, cefpirome sodium was given intravenously from day 6 of gestation to day 21 of lactation at 175, 250 and 360 mg/kg, and a slight decrease in litter size and live births was observed at 360 mg/kg. Cefpirome can be secreted through rat milk, and the level of cefpirome in milk is about 20% of the maternal plasma drug level.
Other Toxicity
Reversible nephrotoxicity due to deposition of drug-like material was seen in the distal renal tubules of small animals (rats and marmosets) following administration of cefpirome sodium by intravenous infusion at high doses. No nephrotoxicity was seen in animals with urine drug concentrations up to 12 times the urine drug concentration at therapeutic doses in humans. Convulsions were seen at greater than or equal to 6 times the human exposure (based on Cmax) after both single and multiple dosing.
Infusion site irritation (leading to thrombosis) was seen in small animals (rats and marmosets), but not in dogs.
Pharmacokinetics]
Plasma concentrations
The mean pharmacokinetic parameters of this product for adults receiving a single dose of 500 mg (2-hour infusion) and for adults receiving multiple doses of 500 mg every 8 hours (2-hour infusion) are summarized in Table 1. The pharmacokinetic profiles were similar for single and multiple doses.
Mean pharmacokinetic parameters [mean (standard deviation)] of this product in adults
Parameters 500 mg single dose administration, infusion 120 minutes every 8 hours 500 mg multiple dose administration, each infusion 120 minutes Cmax (µg/mL) 29.2 (5.52) 33.0 (4.83) AUC (µg-h/mL) 90.0 (12.4) 102 (11.9) t 1/2 (h) 3.1 (0.3) 3.3 (0.3) CL (L/h) 4.89 (0.69)4.98 (0.58)Distribution
Cefpirome is rarely bound to plasma proteins (16%) and this binding is independent of concentration. In humans, the steady-state volume of distribution of cefpirome (18 L) is roughly equivalent to the amount of extracellular fluid.
Metabolism
The active substance of this product is cefpirome sodium, a prodrug of the active ingredient cefpirome. The prodrug cefpirome sodium can be rapidly converted to the active ingredient cefpirome, and this conversion is mediated by non-specific plasma esterases. The concentration of the prodrug is almost negligible, and the concentration of the prodrug in plasma and urine can only be detected during the infusion. The metabolite diacetyl, obtained by cleavage of the prodrug, is an endogenous compound in humans.
A very small fraction of cefpirome is metabolized to an open-loop metabolite that is not microbiologically active. In subjects with normal renal function, systemic exposure to open-loop metabolites is much lower than that of cefpirome, accounting for approximately 4% of parent drug exposure.
In vitro studies have shown that cefpirome is an inhibitor of the hepatocyte uptake transporter proteins OATP1B1 and OATP1B3, but not of PgP, BCRP, MDR1, MRP2, OAT1, OAT3, OCT1, or OCT2. Cefpirome may be a weak substrate for the renal tubular cellular uptake transporter proteins OAT1 and OCT2.
Cefpirome has a low protein binding rate (16%) and is not an inhibitor or substrate of PgP. The potential for interaction between other drugs and cefpirome is extremely low, as only a small fraction of cefpirome is metabolized. Therefore, no relevant drug-drug interactions are expected to occur.
No renal drug-drug interactions are anticipated because cefpirome is not secreted by the renal tubules and only a portion of the drug is reabsorbed.
Elimination
Cefpirome is eliminated primarily by renal excretion in its original form with a half-life of approximately 3 hours. The primary mechanism of elimination is glomerular filtration and some active reabsorption. Following a single dose, approximately 89% of the administered dose is recovered in the urine as the active drug cefpirome (83%), open-loop metabolites (5%), and cefpirome (<1%).
Linearity/non-linearity
The pharmacokinetics of cefpirome are linear and time-dependent. The Cmax and AUC of the product can be increased in proportion to the dose in the dose range of 125 mg -1 g. Steady-state active ingredient concentrations were achieved on the first day of administration; no significant drug accumulation was observed in normal renal function subjects when administered every 8 hours.
Pharmacokinetic/pharmacodynamic relationships
Similar to other beta-lactam antimicrobials, clinical and preclinical pharmacokinetic/pharmacodynamic studies have shown that the time to exceed the minimum inhibitory concentration (%T > MIC) of the infecting microorganism is most relevant to efficacy.
Special Populations
Renal injury
Creatinine clearance should be estimated based on the Cockcroft-Gault formula, using actual body weight. During treatment with cefpirome, enzymatic determination of serum creatinine is recommended.
The pharmacokinetics of cefpirome were similar in healthy volunteers and in subjects with mild renal impairment (CLCR of 50-80 mL/min). The AUC of cefpirome in subjects with moderate (CLCR of 30-<50 mL/min) and severe (CLCR <30 mL/min) renal impairment was 2.5 and 3.3 times higher than that in healthy subjects with normal renal function, respectively. Dose adjustment is recommended for patients with moderate to severe renal impairment.
End-stage renal disease requiring dialysis
Significantly higher AUCs for both cefpirome and its microbiologically inactive open-loop metabolite were seen in patients with end-stage renal disease requiring hemodialysis compared to healthy subjects. In one study, six subjects with end-stage renal disease undergoing hemodialysis received 250 mg of this product administered as a single intravenous infusion, which confirmed that cefpirome was cleared by hemodialysis with an extraction rate of 0.7.
Patients with creatinine clearance >150 mL/min
Subjects with creatinine clearance >150 mL/min had a 40% higher systemic clearance (CLss) and 30% higher volume of distribution of cefpirome compared to subjects with normal renal function (CLCR=80-150 mL/min). In this population, a longer duration of infusion is recommended based on pharmacokinetic/pharmacodynamic considerations.
Liver injury
The pharmacokinetics of cefpirome have not been established in patients with hepatic injury. Because cefpirome is rarely hepatically metabolized and is excreted primarily in the urine in its prodrug form, hepatic injury is not expected to have an impact on the clearance of this product.
Geriatric patients
Population pharmacokinetic data indicate that age as an independent parameter does not affect the pharmacokinetics of cefpirome. No dose adjustment needs to be considered in elderly patients with normal renal function.
Gender
Systemic exposure to cefpirome is higher in women than in men (21% higher Cmax and 15% higher AUC), but the %T > MIC is similar in men and women. Therefore, no dose adjustment based on gender is necessary.
Ethnicity
Population pharmacokinetic analyses (including Caucasian white, black and other ethnic groups) and a pharmacokinetic study conducted specifically in healthy Japanese subjects showed no effect of ethnicity on the pharmacokinetics of cefpirome. Therefore, there is no need for ethnically based dose adjustment.
Body weight
In a study conducted in morbidly obese subjects, no dose adjustment based on body weight was necessary.
Storage]
Store under shade, airtight, at 2-8°C.
Package】
20ml clear type I glass bottle with bromobutyl stopper with Teflon-based fluorinated polymer coating and easy-to-open blue aluminum-plastic cap.
10 bottles per box.
Expiration date
48 months.
Execution Standard
JX20200052
Approval number】
Marketing authorization holder
Name: Basilea Pharmaceutica Deutschland GmbH
Registered office: Marie-Curie-Strasse 8,79539 Lörrach, Germany
Manufacturer
Company name: Patheon UK Limited
Production Address: Kingfisher Drive Covingham Swindon Wiltshire SN3 5BZ, United Kingdom
Contact in China
Name: Shenzhen China Resources Jiuxin Pharmaceutical Co.
Address: No. 2, Kaifeng Road, Shangmeilin Industrial Zone, Futian District, Shenzhen
Zip code: 518049
Contact：0755-83310999
Fax: 0755-83119694
Pharmacovigilance Contact：0755-83176039
Pharmacovigilance E-mail: [email protected]