Altamax

Each vial contains: Sterile mixture of Cefepime HCl and Arginine 1 g.
Cefepime injection is a sterile, dry mixture of Cefepime Hydrochloride and L-Arginine.
The L-Arginine, at an approximate concentration of 725 mg/g of Cefepime, is added to control the pH of the constituted solution at 4.0-6.0.

Pharmacology: Pharmacokinetics: The average plasma concentrations of cefepime observed in healthy adult male volunteers (n=9) at various times following single 30 minute infusions (IV) of cefepime 500 mg, 1 g, and 2 g are summarized in Table 1. Elimination of cefepime is principally via renal excretion with an average (±SD) half-life of 2.0 (±0.3) hours and total body clearance of 120.0 (±8.0) mL/min in healthy volunteers. Cefepime pharmacokinetics are linear over the range 250 mg to 2 g. There is no evidence of accumulation in healthy adult male volunteers (n=7) receiving clinically relevant doses for a period of 9 days.
Absorption: The average plasma concentrations of cefepime and its derived pharmacokinetic parameters after intravenous (IV) administration are portrayed in Table 1. (See Table 1.)

Click on icon to see table/diagram/image
Following intramuscular (IM) administration, cefepime is completely absorbed. The average plasma concentrations of cefepime at various times following a single intramuscular injection are summarized in Table 2. The pharmacokinetics of cefepime are linear over the range of 500 mg to 2 g intramuscularly and do not vary with respect to treatment duration. (See Table 2.)

Click on icon to see table/diagram/image

Distribution: The average steady-state volume of distribution of cefepime is 18.0 (±2.0) L. The serum protein binding of cefepime is approximately 20% and is independent of its concentration in serum.
Cefepime is excreted in human milk. A nursing infant consuming approximately 1000 mL of human milk per day would receive approximately 0.5 mg of cefepime per day.
Concentrations of cefepime achieved in specific tissues and body fluids are listed in Table 3. (See Table 3.)

Click on icon to see table/diagram/image

Data suggest that cefepime does cross the inflamed blood-brain barrier. The clinical relevance of these data are uncertain at this time.
Metabolism and Excretion: Cefepime is metabolized to N-methylpyrrolidine (NMP) which is rapidly converted to the N-oxide (NMP-N-oxide). Urinary recovery of unchanged cefepime accounts for approximately 85% of the administered dose. Less than 1% of the administered dose is recovered from urine as NMP, 6.8% as NMP-N-oxide, and 2.5% as an epimer of cefepime. Because renal excretion is a significant pathway of elimination, patients with renal dysfunction and patients undergoing hemodialysis require dosage adjustment.
Microbiology: Cefepime is a bactericidal agent that acts by inhibition of bacterial cell wall synthesis. Cefepime has a broad spectrum of in vitro activity that encompasses a wide range of Gram-positive and Gram-negative bacteria. Cefepime has a low affinity for chromosomally-encoded beta-lactamases. Cefepime is highly resistant to hydrolysis by most beta-lactamases and exhibits rapid penetration into Gram-negative bacterial cells. Within bacterial cells, the molecular targets of cefepime are the penicillin binding proteins (PBP).
Cefepime has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections as described in Indications/Uses.
Aerobic Gram-Negative Microorganisms: Enterobacter; Escherichia coli; Klebsiella pneumoniae; Proteus mirabilis; Pseudomonas aeruginosa.
Aerobic Gram-Positive Microorganisms: Staphylococcus aureus (methicillin-susceptible isolates only); Streptococcus pneumoniae; Streptococcus pyogenes (Lancefield's Group A streptococci); Viridans group streptococci.
The following in vitro data are available, but their clinical significance is unknown. Cefepime has been shown to have in vitro activity against most isolates of the following microorganisms; however, the safety and effectiveness of cefepime in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled trials.
Aerobic Gram-Positive Microorganisms: Staphylococcus epidermidis (methicillin-susceptible isolates only); Staphylococcus saprophyticus; Streptococcus agalactiae (Lancefield's Group B streptococci).
NOTE: Most isolates of enterococci, eg, Enterococcus faecalis, and methicillin-resistant staphylococci are resistant to cefepime.
Aerobic Gram-Negative Microorganisms: Acinetobacter calcoaceticus subsp. Iwoffii; Citrobacter diversus; Citrobacter freundii; Enterobacter agglomerans; Haemophilus influenzae (including beta-lactamase producing isolates); Hafnia alvei; Klebsiella oxytoca; Moraxella catarrhalis (including beta-lactamase producing isolates); Morganella morganii; Proteus vulgaris; Providencia rettgeri; Providencia stuartii; Serratia marcescens.
NOTE: Cefepime is inactive against many isolates of Stenotrophomonas (formerly Xanthomonas maltophilia and Pseudomonas maltophilia).
Anaerobic Microorganisms: NOTE: Cefepime is inactive against most isolates of Clostridium difficile.

Cefepime is indicated in the treatment of the following infections caused by susceptible strains of the designated microorganisms.
For the treatment of infections due to susceptible organisms including infections of the urinary tract, respiratory tract, and the skin.

The recommended adult and pediatric dosages and routes of administration are outlined in Table 4. Cefepime should be administered intravenously over approximately 30 minutes. (See Table 4.)

Click on icon to see table/diagram/image

Pediatric Patients (2 months up to 16 years): The maximum dose for pediatric patients should not exceed the recommended adult dose. The usual recommended dosage in pediatric patients up to 40 kg in weight for uncomplicated and complicated urinary tract infections (including pyelonephritis), uncomplicated skin and skin structure infections, and pneumonia is 50 mg per kg per dose, administered every 12 hours (50 mg per kg per dose, every 8 hours for febrile neutropenic patients), for durations as given previously.
Patients with Hepatic Impairment: No adjustment is necessary for patients with hepatic impairment.
Patients with Renal Impairment: In patients with creatinine clearance less than or equal to 60 mL/min, the dose of Cefepime should be adjusted to compensate for the slower rate of renal elimination. The recommended initial dose of Cefepime should be the same as in patients with normal renal function except in patients undergoing hemodialysis. The recommended doses of Cefepime in patients with renal impairment are presented in Table 5.
When only serum creatinine is available, the following formula (Cockroft and Gault equation) may be used to estimate creatinine clearance. The serum creatinine should represent a steady state of renal function: (See Formula.)

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

In patients undergoing continuous ambulatory peritoneal dialysis, Cefepime may be administered at normally recommended doses at a dosage interval of every 48 hours (see Table 5).
In patients undergoing hemodialysis, approximately 68% of the total amount of cefepime present in the body at the start of dialysis will be removed during a 3-hour dialysis period. The dosage of Cefepime for hemodialysis patients is 1 g on Day 1 followed by 500 mg every 24 hours for the treatment of all infections except febrile neutropenia, which is 1 g every 24 hours. Cefepime should be administered at the same time each day and following the completion of hemodialysis on hemodialysis days (see Table 5).
Data in pediatric patients with impaired renal function are not available; however, since cefepime pharmacokinetics are similar in adults and pediatric patients, changes in the dosing regimen proportional to those in adults (see Tables 4 and 5) are recommended for pediatric patients.
Administration: Intravenous Administration: For intravenous infusion, constitute the 500 mg, 1 g, or 2 g vial, and add an appropriate quantity of the resulting solution to an intravenous container with one of the compatible intravenous fluids listed in Cautions for Usage. The resulting solution should be administered over approximately 30 minutes.
Intramuscular Administration: For intramuscular administration, Cefepime (cefepime hydrochloride) should be constituted with one of the following diluents: Sterile Water for Injection, 0.9% Sodium Chloride, 5% Dextrose Injection, 0.5% or 1.0% Lidocaine Hydrochloride, or Sterile Bacteriostatic Water for Injection with Parabens or Benzyl Alcohol (see Table 6).
Preparation of Cefepime solutions is summarized in Table 6.

Click on icon to see table/diagram/image

Patients who receive an overdose should be carefully observed and given supportive treatment. In the presence of renal insufficiency, hemodialysis, not peritoneal dialysis, is recommended to aid in the removal of cefepime from the body. 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, seizures, neuromuscular excitability, and non-convulsive status epilepticus.

Cefepime is contraindicated in patients who have shown immediate hypersensitivity reactions to cefepime or the cephalosporin class of antibiotics, penicillins or other beta-lactam antibiotics.

Before therapy with cefepime for injection is instituted, careful inquiry should be made to determine whether the patient has had previous immediate hypersensitivity reactions to cefepime, cephalosporins, penicillins, or other drugs. If this product is to be given to penicillin-sensitive patients, caution should be exercised because cross-hypersensitivity among beta-lactam antibiotics has been clearly documented and may occur in up to 10% of patients with history of penicillin allergy. If an allergic reaction to cefepime occurs, discontinue the drug. Serious acute hypersensitivity reactions may require treatment with epinephrine and other emergency measures including oxygen, corticosteroids, intravenous fluids, intravenous antihistamines, pressor amines, and airway management, as clinically indicated.
In patients with creatinine clearance less than or equal to 60 mL/min, the dose 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 impairment 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, serious adverse events have been reported including life-threatening or fatal occurrences of the following: encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, and coma), myoclonus, seizures, and non-convulsive status epilepticus. Most cases occurred in patients with renal impairment who received doses of cefepime that exceeded the recommended dosage schedules. However, some cases of encephalopathy occurred in patients receiving a dosage adjustment for their renal function. In the majority of cases, symptoms of neurotoxicity were reversible and resolved after discontinuation of cefepime and/or after hemodialysis.
Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Cefepime, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.
C. difficile produces toxins A and B, which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea 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. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

General: Prescribing Cefepime in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
As with other antimicrobials, prolonged use of Cefepime may result in overgrowth of nonsusceptible microorganisms. Repeated evaluation of the patient's condition is essential. Should superinfection occur during therapy, appropriate measures should be taken.
Many cephalosporins, including cefepime, have been associated with a fall in prothrombin activity. Those at risk include patients with renal or hepatic impairment, or poor nutritional state, as well as patients receiving a protracted course of antimicrobial therapy.
Prothrombin time should be monitored in patients at risk, and exogenous vitamin K administered as indicated.
Positive direct Coombs' tests have been reported during treatment with Cefepime. In hematologic studies or in transfusion cross-matching procedures when antiglobulin tests are performed on the minor side or in Coombs' testing of newborns whose mothers have received cephalosporin antibiotics before parturition, it should be recognized that a positive Coombs' test may be due to the drug.
Cefepime (cefepime hydrochloride) should be prescribed with caution in individuals with a history of gastrointestinal disease, particularly colitis.
Arginine has been shown to alter glucose metabolism and elevate serum potassium transiently when administered at 33 times the amount provided by the maximum recommended human dose of Cefepime. The effect of lower doses is not presently known.
Information for Patients: Before therapy with Cefepime is instituted, careful inquiry should be made to determine whether the patient has had previous immediate hypersensitivity reactions to cefepime, cephalosporins, penicillins, or other drugs. Exercise caution if this product is to be given to penicillin-sensitive patients because cross-hypersensitivity among beta-lactam antibiotics has been clearly documented and may occur in up to 10% of patients with a history of penicillin allergy. If an allergic reaction to Cefepime occurs, discontinue the drug. Serious acute hypersensitivity reactions may require treatment with epinephrine and other emergency measures including oxygen, corticosteroids, intravenous fluids, intravenous antihistamines, pressor amines, and airway management, as clinically indicated.
Patients should be counseled that antibacterial drugs including Cefepime should only be used to treat bacterial infections. They do not treat viral infections (eg, the common cold). When Cefepime is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Cefepime or other antibacterial drugs in the future.
Diarrhea is a common problem caused by antibiotics, which usually ends when the antibiotic is discontinued.
Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.
Patients should be advised of neurological adverse events that could occur with Cefepime use. Patients should be instructed to inform their healthcare provider at once of any neurological signs and symptoms, including encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, and coma), myoclonus, seizures, and non-convulsive status epilepticus, for immediate treatment, dosage adjustment or discontinuation of Cefepime.
Drug/Laboratory Test Interactions: The administration of cefepime may result in a false-positive reaction for glucose in the urine when using Clinitest tablets. It is recommended that glucose tests based on enzymatic glucose oxidase reactions (such as Clinistix) be used.
Carcinogenesis, Mutagenesis, Impairment of Fertility: No animal carcinogenicity studies have been conducted with cefepime. ln chromosomal aberration studies, cefepime was positive for clastogenicity in primary human lymphocytes, but negative in Chinese hamster ovary cells. In other in vitro assays (bacterial and mammalian cell mutation, DNA repair in primary rat hepatocytes, and sister chromatid exchange in human lymphocytes), cefepime was negative for genotoxic effects. Moreover, in vivo assessments of cefepime in mice (2 chromosomal aberration and 2 micronucleus studies) were negative for clastogenicity.
No untoward effects on fertility were observed in rats when cefepime was administered subcutaneously at doses up to 1000 mg/kg/day (1.6 times the recommended maximum human dose calculated on a mg/m² basis).
Labor and Delivery: Cefepime has not been studied for use during labor and delivery. Treatment should only be given if clearly indicated.
Use in Pregnancy & Lactation: Teratogenic Effects: Pregnancy Category B. Cefepime was not teratogenic or embryocidal when administered during the period of organogenesis to rats at doses up to 1000 mg/kg/day (1.6 times the recommended maximum human dose calculated on a mg/m² basis) or to mice at doses up to 1200 mg/kg (approximately equal to the recommended maximum human dose calculated on a mg/m² basis) or to rabbits at a dose level of 100 mg/kg (0.3 times the recommended maximum human dose calculated on a mg/m² basis). There are, however, no adequate and well-controlled studies of cefepime use 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.
Cefepime is excreted in human breast milk in very low concentrations (0.5 mcg/mL). Caution should be exercised when cefepime is administered to a nursing woman.
Pediatric Use: The safety and effectiveness of cefepime in the treatment of uncomplicated and complicated urinary tract infections (including pyelonephritis), uncomplicated skin and skin structure infections, pneumonia, and as empiric therapy for febrile neutropenic patients have been established in the age groups 2 months up to 16 years. Use of Cefepime in these age groups is supported by evidence from adequate and well-controlled studies of cefepime in adults with additional pharmacokinetic and safety data from pediatric trials.
Safety and effectiveness in pediatric patients below the age of 2 months have not been established. There are insufficient clinical data to support the use of Cefepime in pediatric patients under 2 months of age or for the treatment of serious infections in the pediatric population where the suspected or proven pathogen is Haemophilus influenzae type b.
In those patients in whom meningeal seeding from a distant infection site or in whom meningitis is suspected or documented, an alternate agent with demonstrated clinical efficacy in this setting should be used.
Geriatric Use: 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. When geriatric patients received the usual recommended adult dose, clinical efficacy and safety were comparable to clinical efficacy and safety in nongeriatric adult patients.
Serious adverse events have occurred in geriatric patients with renal insufficiency given unadjusted doses of cefepime, including life-threatening or fatal occurrences of the following: encephalopathy, myoclonus, and seizures.
This drug 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.

Pregnancy: Teratogenic Effects: Pregnancy Category B.
Cefepime was not teratogenic or embryocidal when administered during the period of organogenesis to rats at doses up to 1000 mg/kg/day (1.6 times the recommended maximum human dose calculated on a mg/m² basis) or to mice at doses up to 1200 mg/kg (approximately equal to the recommended maximum human dose calculated on a mg/m² basis) or to rabbits at a dose level of 100 mg/kg (0.3 times the recommended maximum human dose calculated on a mg/m² basis).
There are, however, no adequate and well-controlled studies of cefepime use 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.
Nursing Mothers: Cefepime is excreted in human breast milk in very low concentrations (0.5 mcg/mL). Caution should be exercised when cefepime is administered to a nursing woman.

Clinical Trials: The following adverse events were thought to be probably related to cefepime during evaluation of the drug in clinical trials conducted in North America (n=3125 cefepime-treated patients). (See Table 7.)

Click on icon to see table/diagram/image

At the higher dose of 2 g every 8 hours, the incidence of probably-related adverse events was higher among the 795 patients who received this dose of cefepime. They consisted of rash (4%), diarrhea (3%), nausea (2%), vomiting (1%), pruritus (1%), fever (1%), and headache (1%). The following adverse laboratory changes, irrespective of relationship to therapy with cefepime, were seen during clinical trials conducted in North America. (See Table 8.)

Click on icon to see table/diagram/image
A similar safety profile was seen in clinical trials of pediatric patients.
Postmarketing Experience: In addition to the events reported during North American clinical trials with cefepime, the following adverse experiences have been reported during worldwide postmarketing experience.
As with some other drugs in this class, encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, and coma), myoclonus, seizures, and non-convulsive status epilepticus have been reported. Although most cases occurred in patients with renal impairment who received doses of cefepime that exceeded the recommended dosage schedules, some cases of encephalopathy occurred in patients receiving a dosage adjustment for their renal function.
If seizures associated with drug therapy occur, the drug should be discontinued. Anticonvulsant therapy can be given if clinically indicated. Precautions should be taken to adjust daily dosage in patients with renal insufficiency or other conditions that may compromise renal function to reduce antibiotic concentrations that can lead or contribute to these and other serious adverse events, including renal failure.
As with other cephalosporins, anaphylaxis including anaphylactic shock, transient leukopenia, neutropenia, agranulocytosis and thrombocytopenia have been reported.
Cephalosporin-Class Adverse Reactions: In addition to the adverse reactions listed previously, that have been observed in patients treated with cefepime, the following adverse reactions and altered laboratory tests have been reported for cephalosporin-class antibiotics: Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, renal dysfunction, toxic nephropathy, aplastic anemia, hemolytic anemia, hemorrhage, hepatic dysfunction including cholestasis, and pancytopenia.

Renal function should be monitored carefully if high doses of aminoglycosides are to be administered with Cefepime because of the increased potential of nephrotoxicity and ototoxicity of aminoglycoside antibiotics. Nephrotoxicity has been reported following concomitant administration of other cephalosporins with potent diuretics such as furosemide.

Compatibility and Stability: Intravenous: Cefepime is compatible at concentrations between 1 mg per mL and 40 mg per mL with the following intravenous fluids: 0.9% Sodium Chloride Injection, 5% and 10% Dextrose Injection, M/6 Sodium Lactate Injection, 5% Dextrose and 0.9% Sodium Chloride Injection, and Lactated Ringers and 5% Dextrose Injection. These solutions may be stored up to 24 hours at controlled room temperature 20°-25°C (68°-77°F) or 7 days in refrigerator 2°-8°C (36°-46°F).
Solutions of Cefepime, like those of beta-lactam antibiotics, should not be added to solutions of ampicillin at a concentration greater than 40 mg per 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 is indicated, each of these antibiotics can be administered separately.
Intramuscular: Cefepime (cefepime hydrochloride) constituted as directed is stable for 24 hours at controlled room temperature 20°-25°C (68°-77°F) or 7 days in refrigerator 2°-8°C (36°-46°F) with the following diluents: Sterile Water for Injection, 0.9% Sodium Chloride Injection, 5% Dextrose Injection, Sterile Bacteriostatic Water for Injection with Parabens or Benzyl Alcohol, or 0.5% or 1% Lidocaine Hydrochloride.
NOTE: Parenteral drugs should be inspected visually for particulate matter before administration.
As with other cephalosporins, the color of Cefepime powder, as well as its solutions, tend to darken depending on storage conditions; however, when stored as recommended, the product potency is not adversely affected.

Store at temperatures not exceeding 30°C. Protect from light.

Cephalosporins

J01DE01 - cefepime ; Belongs to the class of fourth generation cephalosporins. Used in the systemic treatment of infections.

Rx