Quatam

Cefepime hydrochloride, sulbactam sodium.

Each vial contains: Cefepime (as hydrochloride) USP 1 g (Sterile mixture of Cefepime hydrochloride and L-arginine), Sulbactam (as sodium) USP 500 mg.

Pharmacology: Pharmacodynamics: Cefepime: Mechanism of action: The mechanism of action of cefepime is based on inhibition of bacterial cell wall synthesis (in the growth phase), due to inhibition of penicillin-binding proteins (PBPs) e.g. transpeptidases. This results in a bactericidal action.
Pharmacokinetic/Pharmacodynamic relationship: Efficacy is largely dependent on the length of time during which drug levels exceed the minimal inhibitory concentration (MIC) of the pathogen concerned.
Mechanisms of resistance: Cefepime has a low affinity for chromosomally-encoded beta-lactamases and is highly resistant to hydrolysis by most beta-lactamases.
Bacterial resistance to cefepime may be due to one or more of the following mechanisms: reduced affinity of penicillin-binding proteins for cefepime; production of β-lactamases which are able to hydrolyse cefepime efficiently (e.g. several of the extended-spectrum and chromosomally mediated-β-lactamases); outer membrane impermeability, which restricts access of cefepime to penicllin binding proteins in gram-negative organisms, efflux pumps for active substances.
There is partial or complete cross resistance between cefepime and other cephalosporins and penicillins.
Sulbactam: Sulbactam Sodium is the sodium salt form of sulbactam, a beta-lactam with weak antibacterial property. Sulbactam sodium contains a beta-lactam ring and irreversibly binds to beta-lactamase at or near its active site, thereby blocking enzyme activity and preventing metabolism of other beta-lactam antibiotics. Combining this agent with a beta-lactamase sensitive antibiotic such as penicillins and cephalosporins against penicillinase-producing and beta-lactamase-producing organisms, results in a decreased turnover rate of the sensitive antibiotic and enhances its antibacterial property.
Pharmacokinetics: Cefepime: The pharmacokinetic properties of cefepime are linear within the range of 250 mg to 2 g i.v. and 500 mg to 2 g IM; they do not differ with regard to duration of treatment.
Absorption: After IV administration of 2 g over 30 minutes to healthy volunteers, peak plasma concentrations (Cmax) were 126-193 μg/ml and following IM administration of this same dose - 57.5 μg/ml.
Distribution: Cefepime is well distributed in bodily fluids and tissues.
Within the range of 250 mg to 2 g, the relative tissue distribution of cefepime does not vary in relation to the administered dose. The mean steady-state volume of distribution is 181. There is no evidence of any accumulation in healthy subjects given doses of up to 2 g IV at 8-hourly intervals over a 9 day period.
Serum protein binding of cefepime is <19% and is not dependent on serum concentrations.
The mean elimination half-life is approximately 2 hours.
Biotransformation: Cefepime is metabolised to a minor extent. The primary urinary metabolite is N-methylpyrrolidine oxide, a tertiary amine, accounting for only around 7% of the dose.
Elimination: Mean total body clearance is 120 ml/min. The mean renal clearance of cefepime is 110 ml/min; this shows that cefepime is almost exclusively eliminated via renal mechanisms, mainly by glomerular filtration. Urine recovery of unchanged cefepime is approximately 85% of the dose, leading to high urinary concentrations of cefepime. Following IV administration of 500 mg cefepime, cefepime was no longer detectable after 12 hours in plasma and after 16 hours in urine.
Elderly: Distribution of cefepime has been tested in elderly male and female patients (>65 years).
Safety and efficacy in elderly patients is comparable with adults, whilst a slight prolongation of the elimination half-life and lower renal clearance values were observed in elderly patients. Dose adjustment is required when there is concomitant impairment of renal function.
With single-dose administration of 1 g, the kinetics of cefepime is unchanged in patients with cystic fibrosis and hepatic dysfunction. Thus, no dose adjustment is required.
Paediatric population: The pharmacokinetics with respect to single and multiple doses of cefepime has been evaluated in patients aged between 2 months and 16 years who received doses of 50 mg/kg, administered via I.V. infusion; multiple doses were administered every 8 or 12 hours for a period of at least 48 hours.
The mean plasma concentrations of cefepime after the first dose were similar to those in steady-state, and a slight accumulation was observed with the administration of additional doses.
The values of the other pharmacokinetic parameters in infants and children, determined both after the first dose and in steady-state, did not differ, regardless of the dosage schedule (every 12 hours or every 8 hours). There were no differences in the pharmacokinetic values, neither between the patients of different ages, nor between males and females.
After the administration of a single I.V. dose, the average total body clearance was 3.3 ml/min/kg and the distribution volume was 0.3 l/kg. The total average elimination half-life was 1.7 hours. The proportion of cefepime recovered unchanged in the urine was 60.4% of the administered dose and renal clearance was the main route of elimination with an average value of 2.0 ml/min/kg.
Renal impairment: Studies in patients with various degrees of renal insufficiency have indicated a significant prolongation of the elimination half-life. There is a linear relationship between the individual body clearance and the creatinine clearance in subjects with renal impairment.
The average elimination half-life in dialysis patients is 13 hours (haemodialysis) and 19 hours for continuous ambulatory peritoneal dialysis.
Hepatic impairment: With single-dose administration of 1 g, the kinetics of cefepime is unchanged in patients with cystic fibrosis and hepatic dysfunction. Thus, no dose adjustment is required.

Indicated for the treatment of the severe infections listed as follows caused by cefepime-susceptible pathogens.
In adults and children over 12 years of age and with a bodyweight of = 40 kg: Pneumonia, Complicated urinary tract infections (including pyelonephritis), Complicated intra-abdominal infections, Peritonitis associated with dialysis in patients on CAP.
In adults: Acute biliary tract infections.
In children aged 2 months up to 12 year and with a bodyweight of = 40 kg: Pneumonia, Complicated urinary tract infections (including pyelonephritis), Bacterial meningitis.
Treatment of patients with bacteraemia that occurs in association with, or is suspected to be associated with, any of the infections listed as previously mentioned.
Cefepime may be used in the empirical treatment of adults, adolescents and children aged 2 months to 12 years with febrile neutropenia that is suspected to be due to a bacterial infection. In patients at high risk of severe infections (e.g. patients with recent bone marrow transplantation, hypotension at presentation, underlying haematological malignancy, or severe or prolonged neutropenia), antimicrobial monotherapy may be inappropriate. No sufficient data exists to support the efficacy of cefepime monotherapy in such patients. A combination therapy with an aminoglycoside or glycopeptide antibiotic may be advisable, taking into consideration the patient's individual risk profile.
Cefepime should be co-administered with other antibacterial agents whenever the possible range of causative bacteria would not fall within its spectrum of activity. Consideration should be given to official guidance on the appropriate use of antibacterial agents.
Cefepime can either be administered intravenously as an injection or as a short infusion (over 30 min) or via deep intramuscular injection into a large muscle mass.

It is administered as twice or thrice a day in equally divided doses depending on the type and severity of infection. Maximum daily dose up to 9 g. Dosage regimen of cefepime and sulbactam combination should be adjusted in patients with marked decrease in renal function (creatinine clearance of less than 30 ml/min) to compensate for the reduced clearance of cefepime and sulbactam. The status of renal function should be estimated by measurement of serum creatinine concentration or calculation of the creatinine clearance rate. It is desirable to measure both peak and trough serum concentrations intermittently during therapy.
When only serum creatinine is available, the following formula (based on sex, weight, and age of the patient) may be used to convert this value in to creatinine clearance.
Males: Weight in (kg) x (140-age) /72 x Serum creatinine.
Females: (0.85) x (above value).
Intravenous administration: For intravenous infusion, constitute vial and then with an appropriate quantity of one of the compatible IV fluids (See Compatibility as follows). The resulting solution should be administered over 30-60 minutes.
Intramuscular administration: For IM administration, Product should be constituted with one of the following diluents: solvent, sterile water for injection, 0.9% Sodium Chloride, 5% Dextrose, 0.5% or 1% Lidocaine Hydrochloride, or sterile bacteriostatic water for injection with Parabens or Benzyl Alcohol if needed. IM route of administration is indicated only for mild to moderate, uncomplicated UTI due to susceptible pathogens.
Compatibility: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever the solution and container permits.
Intravenous Cefepime and sulbactam is compatible with sterile water for injection and the following IV infusion fluids: 0.9% sodium chloride, 5% and 10% dextrose, M/6 sodium lactate, 5% dextrose and 0.9% sodium chloride, lactated ringers and 5% dextrose. Solutions of cefepime and sulbactam, like those of most beta-lactam antibiotics, should not be added to solutions of ampicillin at a concentration greater than 40 mg/ml, and should not be added to metronidazole, vancomycin, gentamicin, tobramycin, netilmicin sulfate or aminophylline because of potential interaction. However, if concurrent therapy with cefepime and sulbactam is indicated, each of these antibiotics can be administered separately.

In case of severe overdose, especially in patients with compromised renal function, haemodialysis will aid in the removal of cefepime from the body; peritoneal dialysis is of no value. Accidental overdosing has occurred when large doses were given to patients with impaired renal function. Symptoms of overdose include encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, and coma), myoclonus, and seizures.

Cefepime is contraindicated in patients who have had previous hypersensitivity reactions to cefepime, to any of the excipients, to any other cephalosporin or to any other beta-lactam antibiotics agent (e.g. penicillins, monobactams and carbapenems). Due to its L-arginine content, this product is further contraindicated in patients with L-arginine hypersensitivity and acidosis. Caution is therefore advised in cases of hyperkalemia.

Hypersensitivity reactions: As with all beta-lactam antibacterial agents, serious and occasionally fatal hypersensitivity reactions have been reported. In case of severe hypersensitivity reactions, treatment with cefepime must be discontinued immediately and adequate emergency measures must be initiated. Before beginning treatment, careful inquiry should be made to determine whether the patient has had previous hypersensitivity reactions to cefepime, beta-lactams or other medicinal products. In 10% of the cases there is cross-reactivity between hypersensitivity to penicillin and cephalosporins.
Cefepime should be administered with caution to patients with a history of asthma or allergic diathesis. The patient must be carefully monitored during the first administration. If an allergic reaction occurs, treatment must be discontinued immediately. Adequate emergency measures must be initiated.
Renal impairment: In patients with impaired renal function, (creatinine clearance = 50 ml/min) or other conditions that may compromise renal function, the dosage of cefepime should be adjusted to compensate for the slower rate of renal elimination. Because high and prolonged serum antibiotic concentrations can occur from usual dosages in patients with renal insufficiency or other conditions that may compromise renal function, the maintenance dosage should be reduced when cefepime is administered to such patients. Continued dosage should be determined by degree of renal impairment, severity of infection, and susceptibility of the causative organisms.
During postmarketing surveillance, the following serious adverse events have been reported: reversible encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, and coma), myoclonus, seizures (including nonconvulsive status epilepticus), and/or renal failure. Most cases occurred in patients with renal impairment who received doses of cefepime that exceeded recommendations.
In general, symptoms of neurotoxicity resolved after discontinuation of cefepime and/or after hemodialysis, however, some cases included a fatal outcome. Renal function should be monitored carefully if drugs with nephrotoxic potential, such as aminoglycosides and potent diuretics are administered with cefepime.

Clostridium difficile associated diarrhoea (CDAD) has been reported with use of nearly all antibacterial agents, including cefepime, and may range in severity from mild diarrhoea to fatal colitis. CDAD must be considered in all patients who present with diarrhoea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. As with other antibiotics, use of cefepime may result in overgrowth of nonsusceptible organisms. Should superinfection occur during therapy, appropriate measures should be taken.
Antibacterial activity of cefepime: Due to the relatively limited spectrum of antibacterial activity of cefepime it is not suitable for treatment of some types of infections unless the pathogen is already documented and known to be susceptible or there is a very high suspicion that the most likely pathogen(s) would be suitable for treatment with cefepime.
Interference with serological testing: A positive Coombs test, without evidence of haemolysis, has been described in patients treated with cefepime twice daily.
Cephalosporin antibiotics may produce a false-positive reaction for glucose in the urine with copper reduction tests (Benedict's or Fehling's solution or with Clinitest tablets), but not with enzyme-based tests (glucose oxidase) for glycosuria. Therefore, it is recommended that glucose tests based on enzymatic glucose oxidase reactions be used.
Effects on ability to drive and use machines: The effects of medicinal product on ability to drive and use machines have not been studied.
However, possible adverse reactions like altered state of consciousness, dizziness, confusional state or hallucinations may alter the ability to drive and use machines.
Use in the Elderly: Of the more than 6400 adults treated with cefepime in clinical studies, 35 % were 65 years or older while 16% were 75 years or older. For geriatric patients in clinical studies, who received the usual recommended adult dose, clinical efficacy and safety were comparable to clinical efficacy and safety in non-geriatric adult patients, unless the patients had renal insufficiency. There was a modest prolongation in elimination half-life and lower renal clearance values compared to those seen in younger persons. Dosage adjustments are recommended if renal function is compromised.
Cefepime is known to be substantially excreted by the kidney and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection and renal function should be monitored. Serious adverse events, including reversible encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, and coma), myoclonus, seizures (including nonconvulsive status epilepticus), and/or renal failure have occurred in geriatric patients with renal insufficiency given the usual dose of cefepime.

Pregnancy: Reproductive studies in mice, rats, and rabbits showed no evidence of fetal damage, however there are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Lactation: Cefepime is excreted in human breast milk in very low concentrations. Caution should be used when cefepime is administered to a nursing woman, then the infant should be monitored closely.

Undesirable effects are classified into the following categories, according to system organ class, MedDRA terminology and MedDRA frequencies: Very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000) and not known (frequency cannot be estimated from the available data).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. (See table.)

Click on icon to see table/diagram/image

Paediatric population: The safety profile of cefepime in infants and children is similar to that seen in adults. The most frequently reported adverse event considered related to cefepime in clinical trials was rash.

No interaction studies have been performed.
Concomitant treatment with bacteriostatic antibiotics may interfere with beta action of beta lactam antibiotics

Instruction and Special Precautions for Handling and Disposal: Any unused product or waste material should be disposed of in accordance with local requirements.

Store at temperatures not exceeding 30°C.

Cephalosporins

J01DE51 - cefepime and beta-lactamase inhibitor ; Belongs to the class of fourth generation cephalosporins. Used in the systemic treatment of infections.

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