Cefepime

Dosage Form: injection, powder, for solution
Cefepime FOR INJECTION, USP

SAGENT™

Rx Only

For Intravenous or Intramuscular Use

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Cefepime for injection and other antibacterial drugs, Cefepime for injection should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

DESCRIPTION

Cefepime for injection, USP is a semi-synthetic, broad spectrum, cephalosporin antibiotic for parenteral administration. The chemical name is 1-[[(6R,7R)-7-[2-(2-amino-4-thiazolyl)-glyoxylamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0] oct-2-en-3-yl]methyl]-1-methylpyrrolidinium chloride, 72-(Z)-(O-methyloxime), monohydrochloride, monohydrate, which corresponds to the following structural formula:

Cefepime hydrochloride is a white to pale yellow powder. Cefepime hydrochloride contains the equivalent of not less than 825 mcg and not more than 911 mcg of Cefepime (C19H24N6O5S2) per mg, calculated on an anhydrous basis. It is highly soluble in water.

Cefepime for injection, USP is supplied for intramuscular or intravenous administration in strengths equivalent to 1 g, and 2 g of Cefepime. (See DOSAGE AND ADMINISTRATION.) Cefepime for injection, USP is a sterile, dry mixture of Cefepime hydrochloride and L-arginine. It contains the equivalent of not less than 90 percent and not more than 115 percent of the labeled amount of Cefepime (C19H24N6O5S2). 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 to 6. Freshly constituted solutions of Cefepime for injection, USP will range in color from colorless to amber.

CLINICAL PHARMACOLOGY

Cefepime is an antibacterial agent belonging to the cephalosporin class of antibacterials with in vitro antibacterial activity against facultative Gram-positive and Gram-negative bacteria.

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 (±0.3) hours and total body clearance of 120 (±8) 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.

Table 1: Average Plasma Concentrations in mcg/mL of Cefepime and Derived Pharmacokinetic Parameters (±SD), Intravenous Administration

	Cefepime for Injection
Parameter	500 mg IV	1 g IV	2 g IV
0.5 h	38.2	78.7	163.1
1 h	21.6	44.5	85.8
2 h	11.6	24.3	44.8
4 h	5	10.5	19.2
8 h	1.4	2.4	3.9
12 h	0.2	0.6	1.1
Cmax, mcg/mL	39.1 (3.5)	81.7 (5.1)	163.9 (25.3)
AUC, h•mcg/mL	70.8 (6.7)	148.5 (15.1)	284.8 (30.6)
Number of subjects (male)	9	9	9

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.

Table 2: Average Plasma Concentrations in mcg/mL of Cefepime and Derived Pharmacokinetic Parameters (±SD), Intramuscular Administration

	Cefepime for Injection
Parameter	500 mg IM	1 g IM	2 g IM
0.5 h	8.2	14.8	36.1
1 h	12.5	25.9	49.9
2 h	12	26.3	51.3
4 h	6.9	16	31.5
8 h	1.9	4.5	8.7
12 h	0.7	1.4	2.3
Cmax, mcg/mL	13.9 (3.4)	29.6 (4.4)	57.5 (9.5)
Tmax, h	1.4 (0.9)	1.6 (0.4)	1.5 (0.4)
AUC, h•mcg/mL	60 (8)	137 (11)	262 (23)
Number of subjects (male)	6	6	12

Distribution

The average steady-state volume of distribution of Cefepime is 18 (±2) 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. (See PRECAUTIONS: Nursing Mothers.)

Concentrations of Cefepime achieved in specific tissues and body fluids are listed in Table 3.

Table 3: Average Concentrations of Cefepime in Specific Body Fluids (mcg/mL) or Tissues (mcg/g)

Tissue or Fluid	Dose/ Route	# of Patients	Average Time of Sample Post-Dose (h)	Average Concentration
Blister Fluid	2 g IV	6	1.5	81.4 mcg/mL
Bronchial Mucosa	2 g IV	20	4.8	24.1 mcg/g
Sputum	2 g IV	5	4	7.4 mcg/mL
	500 mg IV	8	0 to 4	292 mcg/mL
Urine	1 g IV	12	0 to 4	926 mcg/mL
	2 g IV	12	0 to 4	3120 mcg/mL
Bile	2 g IV	26	9.4	17.8 mcg/mL
Peritoneal Fluid	2 g IV	19	4.4	18.3 mcg/mL
Appendix	2 g IV	31	5.7	5.2 mcg/g
Gallbladder	2 g IV	38	8.9	11.9 mcg/g
Prostate	2 g IV	5	1	31.5 mcg/g

Data suggest that Cefepime does cross the inflamed blood-brain barrier. The clinical relevance of these data is 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. (See DOSAGE AND ADMINISTRATION.)

Specific Populations

Renal impairment: Cefepime pharmacokinetics have been investigated in patients with various degrees of renal impairment (n=30). The average half-life in patients requiring hemodialysis was 13.5 (±2.7) hours and in patients requiring continuous peritoneal dialysis was 19 (±2) hours. Cefepime total body clearance decreased proportionally with creatinine clearance in patients with abnormal renal function, which serves as the basis for dosage adjustment recommendations in this group of patients. (See DOSAGE AND ADMINISTRATION.)

Hepatic impairment: The pharmacokinetics of Cefepime were unaltered in patients with hepatic impairment who received a single 1 g dose (n=11).

Geriatric patients: Cefepime pharmacokinetics have been investigated in elderly (65 years of age and older) men (n=12) and women (n=12) whose mean (SD) creatinine clearance was 74 (±15) mL/min. There appeared to be a decrease in Cefepime total body clearance as a function of creatinine clearance. Therefore, dosage administration of Cefepime in the elderly should be adjusted as appropriate if the patient's creatinine clearance is 60 mL/min or less. (See DOSAGE AND ADMINISTRATION.)

Pediatric patients: Cefepime pharmacokinetics have been evaluated in pediatric patients from 2 months to 11 years of age following single and multiple doses on every 8 hours (n=29) and every 12 hours (n=13) schedules. Following a single intravenous dose, total body clearance and the steady-state volume of distribution averaged 3.3 (±1) mL/min/kg and 0.3 (±0.1) L/kg, respectively. The urinary recovery of unchanged Cefepime was 60.4 (±30.4)% of the administered dose, and the average renal clearance was 2 (±1.1) mL/min/kg. There were no significant effects of age or gender (25 male vs 17 female) on total body clearance or volume of distribution, corrected for body weight. No accumulation was seen when Cefepime was given at 50 mg per kg every 12 hours (n=13), while Cmax, AUC, and t½ were increased about 15% at steady state after 50 mg per kg every 8 hours. The exposure to Cefepime following a 50 mg per kg intravenous dose in a pediatric patient is comparable to that in an adult treated with a 2 g intravenous dose. The absolute bioavailability of Cefepime after an intramuscular dose of 50 mg per kg was 82.3 (±15)% in eight patients.

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 the INDICATIONS AND USAGE section.

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, e.g., Enterococcus faecalis, and methicillin-resistant staphylococci are resistant to Cefepime.

Aerobic Gram-Negative Microorganisms:

 

Acinetobacter calcoaceticus subsp. lwoffii

 

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.

Susceptibility Tests

Dilution Techniques

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure.

Standardized procedures are based on a dilution method1 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of Cefepime powder. The MIC values should be interpreted according to the following criteria:

Table 4

*NOTE: Isolates from these species should be tested for susceptibility using specialized dilution testing methods.1 Also, isolates of Haemophilus spp. with MICs greater than 2 mcg/mL should be considered equivocal and should be further evaluated.
	MIC (mcg/mL)
Microorganism	Susceptible (S)	Intermediate (I)	Resistant (R)
Microorganisms other than Haemophilus spp.* and Streptococcus pneumoniae*	≤8	16	≥32
Haemophilus spp.*	≤2	---*	---*
S. pneumoniae*	≤0.5	1	≥2

A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of “Intermediate” indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Laboratory control microorganisms are specific strains of microbiological assay organisms with intrinsic biological properties relating to resistance mechanisms and their genetic expression within bacteria; the specific strains are not clinically significant in their current microbiological status. Standard Cefepime powder should provide the following MIC values (Table 5) when tested against the designated quality control strains:

Table 5

Microorganism	ATCC	MIC (mcg/mL)
Escherichia coli	25922	0.016 to 0.12
Staphylococcus aureus	29213	1 to 4
Pseudomonas aeruginosa	27853	1 to 4
Haemophilus influenzae	49247	0.5 to 2
Streptococcus pneumoniae	49619	0.06 to 0.25

Diffusion Techniques

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure2 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 30 mcg of Cefepime to test the susceptibility of microorganisms to Cefepime. Interpretation is identical to that stated above for results using dilution techniques.

Reports from the laboratory providing results of the standard single-disk susceptibility test with a 30-mcg Cefepime disk should be interpreted according to the following criteria:

Table 6

*NOTE: Isolates from these species should be tested for susceptibility using specialized diffusion testing methods.2 Isolates of Haemophilus spp. with zones smaller than 26 mm should be considered equivocal and should be further evaluated. Isolates of S. pneumoniae should be tested against a 1-mcg oxacillin disk; isolates with oxacillin zone sizes larger than or equal to 20 mm may be considered susceptible to Cefepime.
	Zone Diameter (mm)
Microorganism	Susceptible (S)	Intermediate (I)	Resistant (R)
Microorganisms other than Haemophilus spp.* and S. pneumoniae*	≥18	15 to 17	≤14
Haemophilus spp.*	≥26	---*	---*

As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Laboratory control microorganisms are specific strains of microbiological assay organisms with intrinsic biological properties relating to resistance mechanisms and their genetic expression within bacteria; the specific strains are not clinically significant in their current microbiological status. For the diffusion technique, the 30-mcg Cefepime disk should provide the following zone diameters in these laboratory test quality control strains (Table 7):

Table 7

Microorganism	ATCC	Zone Size Range (mm)
Escherichia coli	25922	29 to 35
Staphylococcus aureus	25923	23 to 29
Pseudomonas aeruginosa	27853	24 to 30
Haemophilus influenzae	49247	25 to 31

INDICATIONS AND USAGE

Cefepime for injection, USP is indicated in the treatment of the following infections caused by susceptible strains of the designated microorganisms (see also PRECAUTIONS: Pediatric Use and DOSAGE AND ADMINISTRATION):

Pneumonia (moderate to severe) caused by Streptococcus pneumoniae, including cases associated with concurrent bacteremia, Pseudomonas aeruginosa, Klebsiella pneumoniae, or Enterobacter species.

Empiric Therapy for Febrile Neutropenic Patients. Cefepime as monotherapy is indicated for empiric treatment of febrile neutropenic patients. In patients at high risk for severe infection (including patients with a history of recent bone marrow transplantation, with hypotension at presentation, with an underlying hematologic malignancy, or with severe or prolonged neutropenia), antimicrobial monotherapy may not be appropriate. Insufficient data exist to support the efficacy of Cefepime monotherapy in such patients. (See CLINICAL STUDIES.)

Uncomplicated and Complicated Urinary Tract Infections (including pyelonephritis) caused by Escherichia coli or Klebsiella pneumoniae, when the infection is severe, or caused by Escherichia coli, Klebsiella pneumoniae, or Proteus mirabilis, when the infection is mild to moderate, including cases associated with concurrent bacteremia with these microorganisms.

Uncomplicated Skin and Skin Structure Infections caused by Staphylococcus aureus (methicillin-susceptible strains only) or Streptococcus pyogenes.

Complicated Intra-abdominal Infections (used in combination with metronidazole) caused by Escherichia coli, viridans group streptococci, Pseudomonas aeruginosa, Klebsiella pneumoniae, Enterobacter species, or Bacteroides fragilis. (See CLINICAL STUDIES.)

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Cefepime for injection, USP and other antibacterial drugs, Cefepime for injection, USP should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

CLINICAL STUDIES

Febrile Neutropenic Patients

The safety and efficacy of empiric Cefepime monotherapy of febrile neutropenic patients have been assessed in two multicenter, randomized trials comparing Cefepime monotherapy (at a dose of 2 g intravenously every 8 hours) to ceftazidime monotherapy (at a dose of 2 g intravenously every 8 hours). These studies comprised 317 evaluable patients. Table 8 describes the characteristics of the evaluable patient population.

Table 8: Demographics of Evaluable Patients (First Episodes Only)

ANC = absolute neutrophil count; SBP = systolic blood pressure
Total	Cefepime 164	Ceftazidime 153
Median age (yr)	56 (range, 18 to 82)	55 (range, 16 to 84)
Male	86 (52%)	85 (56%)
Female	78 (48%)	68 (44%)
Leukemia	65 (40%)	52 (34%)
Other hematologic malignancies	43 (26%)	36 (24%)
Solid tumor	54 (33%)	56 (37%)
Median ANC nadir (cells/microliter)	20 (range, 0 to 500)	20 (range, 0 to 500)
Median duration of neutropenia (days)	6 (range, 0 to 39)	6 (range, 0 to 32)
Indwelling venous catheter	97 (59%)	86 (56%)
Prophylactic antibiotics	62 (38%)	64 (42%)
Bone marrow graft	9 (5%)	7 (5%)
SBP less than 90 mm Hg at entry	7 (4%)	2 (1%)

Table 9 describes the clinical response rates observed. For all outcome measures, Cefepime was therapeutically equivalent to ceftazidime.

Table 9: Pooled Response Rates for Empiric Therapy of Febrile Neutropenic Patients

	% Response
Outcome Measures	Cefepime (n=164)	Ceftazidime (n=153)
Primary episode resolved with no treatment modification, no new febrile episodes or infection, and oral antibiotics allowed for completion of treatment	51	55
Primary episode resolved with no treatment modification, no new febrile episodes or infection and no post-treatment oral antibiotics	34	39
Survival, any treatment modification allowed	93	97
Primary episode resolved with no treatment modification and oral antibiotics allowed for completion of treatment	62	67
Primary episode resolved with no treatment modification and no post-treatment oral antibiotics	46	51

Insufficient data exist to support the efficacy of Cefepime monotherapy in patients at high risk for severe infection (including patients with a history of recent bone marrow transplantation, with hypotension at presentation, with an underlying hematologic malignancy, or with severe or prolonged neutropenia). No data are available in patients with septic shock.

Complicated Intra-Abdominal Infections

Patients hospitalized with complicated intra-abdominal infections participated in a randomized, double-blind, multicenter trial comparing the combination of Cefepime (2 g every 12 hours) plus intravenous metronidazole (500 mg every 6 hours) versus imipenem/cilastatin (500 mg every 6 hours) for a maximum duration of 14 days of therapy. The study was designed to demonstrate equivalence of the two therapies. The primary analyses were conducted on the protocol-valid population, which consisted of those with a surgically confirmed complicated infection, at least one pathogen isolated pretreatment, at least 5 days of treatment, and a 4 to 6 week follow-up assessment for cured patients. Subjects in the imipenem/cilastatin arm had higher APACHE II scores at baseline. The treatment groups were otherwise generally comparable with regard to their pretreatment characteristics. The overall clinical cure rate among the protocol-valid patients was 81% (51 cured/63 evaluable patients) in the Cefepime plus metronidazole group and 66% (62/94) in the imipenem/cilastatin group. The observed differences in efficacy may have been due to a greater proportion of patients with high APACHE II scores in the imipenem/cilastatin group.

CONTRAINDICATIONS

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

WARNINGS

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 A HISTORY OF PENICILLIN ALLERGY. IF AN ALLERGIC REACTION TO Cefepime FOR INJECTION 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 for injection 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. (See specific recommendations for dosing adjustment in DOSAGE AND ADMINISTRATION.) 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, and seizures (see ADVERSE REACTIONS: Postmarketing Experience). 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 for injection, 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.

PRECAUTIONS

General

Prescribing Cefepime for injection 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 for injection 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 for injection. 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 for injection 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 for injection. The effect of lower doses is not presently known.

Information for Patients

Patients should be counseled that antibacterial drugs including Cefepime for injection should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Cefepime for injection 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 for injection 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

Phosphotec

Dosage Form: injection, powder, lyophilized, for solution

Phosphotec Description

Each reaction vial contains 40 mg sodium pyrophosphate (equivalent to 23.9 mg anhydrous sodium pyrophosphate) and 0.4 mg stannous fluoride (minimum) and 0.9 mg total tin (maximum) as stannous fluoride; the product does not contain a preservative. The pH of the product is adjusted with sodium hydroxide or hydrochloric acid prior to lyophilization. At the time of manufacture, the air in the vial is replaced with a nitrogen gas atmosphere. The pH of the reconstituted product is 5.5 to 6.9. When sterile, nonpyrogenic sodium pertechnetate Tc 99m solution is added to the vial, a diagnostic agent, technetium Tc 99m pyrophosphate, is formed for intravenous administration; the structure of this radiolabeled complex is unknown.

The product as supplied is sterile and nonpyrogenic.

PHYSICAL CHARACTERISTICS

Technetium Tc 99m decays by isomeric transition with a physical half-life of 6.02 hours.1 The principal photon that is useful for detection and imaging studies is shown in Table 1.

TABLE 1

Principal Radiation Emission Data
Radiation	Mean % per Disintegration	Mean Energy (keV)
Gamma-2	89.07	140.5

1

Kocher, David C. Radioactive Decay Data Tables, DOE/ TIC-11026, 108(1981).

External Radiation

The specific gamma ray constant for Tc 99m is 0.78 R/hour-millicurie at 1 cm. The first half-value layer is 0.017 cm of lead (Pb). A range of values for the relative attenuation of the radiation emitted by this radionuclide that results from interposition of various thicknesses of Pb is shown in Table 2. To facilitate control of the radiation exposure from millicurie amounts of this radionuclide, the use of a 0.25 cm thickness of Pb will attenuate the radiation emitted by a factor of 1,000.

TABLE 2

Radiation Attenuation by Lead Shielding
Shield Thickness (Pb) cm	Attenuation Factor
0.017	0.5
0.08	10-1
0.16	10-2
0.25	10-3
0.33	10-4

To correct for physical decay of technetium Tc 99m, the fractions that remain at selected intervals after the time of calibration are shown in Table 3.

TABLE 3

Physical Decay Chart. Tc 99m half-life 6.02 hours
Hours	Fraction Remaining	Hours	Fraction Remaining
* Calibration Time
0*	1.000	8	0.398
1	0.891	9	0.355
2	0.794	10	0.316
3	0.708	11	0.282
4	0.631	12	0.251
5	0.562	18	0.126
6	0.501	24	0.063
7	0.447

Phosphotec - Clinical Pharmacology

Bone and Cardiac Imaging

Following intravenous administration of the technetium Tc 99m pyrophosphate skeletal uptake occurs as a function of blood flow to bone and bone efficiency in extracting the complex. Bone mineral crystals are generally considered to be hydroxyapatite, and the complex appears to have an affinity for the hydroxyapatite crystals in bone. It is theorized that the complex also reacts with the mitochondrial calcium crystals, produced within infarcted myocardial cells which are believed to be hydroxyapatite; this phenomenon usually does not persist beyond six days after the occurrence of an infarction.

Clearance of the radioactivity from the blood is quite rapid with skeletal uptake and urinary excretion being the principal mechanisms of clearance. At two hours following intravenous injection, approximately 55 percent of the injected dose has localized in bone; at four hours approximately 10 percent of the dose remains in the vascular system, decreasing to about 7 percent at 24 hours. The average urinary excretion was observed to be about 38 percent of the administered dose after eight hours increasing to an average of about 44 percent at 24 hours. A minimum amount of uptake has been observed in soft-tissue organs, most notably the kidneys.

Blood Pool Imaging

The in vivo tagging of Phosphotec results in the radiolabelling of red blood cells. Approximately 76 percent of the injected activity remains in the blood pool between 30 and 60 minutes after injection of sodium pertechnetate Tc 99m, thereby permitting excellent images of the cardiac chambers.

Maximum blood radioactivity levels occur in about 30 minutes; the initial biological half-life is approximately 18 hours. There is virtually no biological elimination of the agent after approximately six hours.

Indications and Usage for Phosphotec

Bone Imaging

Phosphotec (Kit for the Preparation of Technetium Tc 99m Pyrophosphate) may be used as a bone imaging agent to delineate areas of altered osteogenesis.

Cardiac Imaging

Phosphotec is a cardiac imaging agent used as an adjunct in the diagnosis of acute myocardial infarction. The infarction is best visualized one to six days after onset of symptoms. False-negative images can occur if imaging is done too early in the evolutionary phase of the infarct or too late in the resolution phase. The incidence of false-positives may range from 5 to 9 percent and of false-negatives from 6 to 9 percent but may vary even more depending on selection criteria of patient populations.

Blood Pool Imaging

Phosphotec is also a blood pool imaging agent which may be used for gated cardiac blood pool imaging and for the detection of sites of gastrointestinal bleeding. When administered intravenously 15 to 60 minutes prior to intravenous administration of sodium pertechnetate Tc 99m, approximately 75% of the injected activity remains in the blood pool.

Contraindications

None known.

Warnings

Preliminary reports indicate impairment of brain scans using sodium pertechnetate Tc 99m injection which have been preceded by a bone scan using an agent containing stannous ions. The impairment may result in false-positive or false-negative brain scans. It is recommended, where feasible, that brain scans precede bone imaging procedures. Alternatively, a brain-imaging agent such as technetium Tc 99m pentetate may be employed.

Precautions

General

The lyophilized contents of the Phosphotec reaction vial are to be administered to the patient only as an intravenous solution (see PROCEDURES FOR RECONSTITUTION OF Phosphotec).

Any sodium pertechnetate Tc 99m solution which contains an oxidizing agent is not suitable for use with Phosphotec (Kit for the Preparation of Technetium Tc 99m Pyrophosphate).

When reconstituted with sodium pertechnetate Tc 99m, Phosphotec must be used within 6 hours. When reconstituted with Sodium Chloride Injection USP for blood pool imaging, use the solution within 30 minutes.

The imaging of gastrointestinal bleeding is dependent on such factors as the region of imaging, rate and volume of the bleed, efficacy of labeling of the red blood cells and timeliness of imaging. Due to these factors, images should be taken sequentially over a period of time until a positive image is obtained or clinical conditions warrant the discontinuance of the procedure. The period of time for collecting the images may range up to thirty-six hours.

Technetium Tc 99m pyrophosphate as well as other radioactive drugs must be handled with care, and appropriate safety measures should be used to minimize radiation exposure to the patient and occupational workers consistent with proper patient management.

Radiopharmaceuticals should be used only by physicians who are qualified by training and experience in the safe use and handling of radionuclides and whose experience and training have been approved by the appropriate government agency authorized to license the use of radionuclides.

Bone Imaging

Both prior to and following administration of the technetium Tc 99m pyrophosphate, the patient should be encouraged to drink fluids and to void as often as possible thereafter to minimize radiation exposure to the bladder and background interference during imaging.

Cardiac Imaging

The patient's cardiac condition should be stable before beginning the cardiac imaging procedure. If not contraindicated by the patient's cardiac status, patients should be encouraged to drink fluids and to void as often as possible in order to reduce unnecessary radiation exposure to the bladder. Interference from chest wall lesions such as breast tumors and healing rib fractures can be minimized by employing the three recommended projections (see DOSAGE AND ADMINISTRATION). False-positive and false-negative myocardial scans may occur; therefore, the diagnosis of acute myocardial infarction depends on the overall assessment of laboratory and clinical findings.

Blood Pool Imaging

The reconstituted agent should be injected by direct venipuncture. Heparinized catheter systems should be avoided, as interference with red blood cell tagging will result.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No long-term animal studies have been performed to determine any carcinogenic potential or impairment of fertility in males or females.

Teratogenic Effects: Pregnancy Category C

Animal reproduction studies have not been conducted with technetium Tc 99m pyrophosphate. It is also not known whether technetium Tc 99m pyrophosphate can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Technetium Tc 99m pyrophosphate should be administered to a pregnant woman only if clearly needed.

Ideally, examinations using radiopharmaceuticals, especially those elective in nature, in women of childbearing capability should be performed during the first few (approximately 10) days following the onset of menses.

Nursing Mothers

Caution should be exercised when technetium Tc 99m pyrophosphate is administered to a nursing woman. Technetium Tc 99m is excreted in human milk during lactation; therefore, formula-feedings should be substituted for breast-feedings.

Pediatric Use

Safety and effectiveness in children have not been established.

Adverse Reactions

Several adverse reactions due to Phosphotec have been reported. These were usually hypersensitivity reactions characterized by itching, various skin rashes, hypotension, fever, chills, nausea, vomiting and dizziness.

Phosphotec Dosage and Administration

The patient dose should be measured by a suitable radioactivity calibration system immediately prior to administration.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.

Intravenous doses for an average adult (70 kg) are as follows:

Bone Imaging

The suggested dose is 370 to 555 MBq (10 to 15 mCi).

Following reconstitution, Phosphotec is injected intravenously over a 10- to 20-second period. Imaging may be started at one hour after administration; however, for optimal results bone imaging should be performed two to four hours following administration.

Cardiac Imaging

The suggested dose is 370 to 555 MBq (10 to 15 mCi) administered intravenously over 10 to 20 seconds and within 24 hours to six days after the onset of symptoms suggestive of acute myocardial infarction.

Imaging is recommended at 45 to 60 minutes postinjection. It is suggested that scans be obtained in at least three projections (e.g., anterior, lateral, and left anterior oblique).

Blood Pool Imaging

The suggested dose is 41 mg (contents of one reaction vial) of Phosphotec (Kit for the Preparation of Technetium Tc 99m Pyrophosphate) (see PROCEDURE FOR RECONSTITUTION) administered intravenously, followed 15 to 60 minutes later by the intravenous administration of 740 MBq (20 mCi) of sodium pertechnetate Tc 99m. Administration should be made by direct venipuncture and not by heparinized catheter systems. Cardiac pool imaging should be initiated 15 to 30 minutes after the administration of sodium pertechnetate Tc 99m.

Radiation Dosimetry

The effective half-life was assumed to be equal to the physical half-life for all calculated values. The estimated absorbed radiation doses to an average adult (70 kg) from an intravenous injection are shown in Tables 4 and 5.

TABLE 4

Bone and Cardiac Imaging
Estimated Absorbed Radiation Doses
Technetium Tc 99m Sodium Pyrophosphate
Target Organ	(mGy/555 MBq)	(rads/15 mCi)
† lf patient voids frequently after radiopharmaceutical is administered, this dose will be reduced slightly.
* Dose at point of highest uptake may be a factor of 10 higher.
Total Body†	2.3	0.23
Kidneys	7.1	0.71
Bone Marrow	5.7	0.57
Skeleton*	8.1	0.81
Bladder Wall
2 hour void	14.6	1.46
4.8 hour void	34.5	3.45
Testes
2 hour void	1.5	0.15
4.8 hour void	2.3	0.23
Ovaries
2 hour void	1.4	0.14
4.8 hour void	2.3	0.23

TABLE 5

Blood Pool Imaging*
Estimated Absorbed Radiation Doses
Sodium Pertechnetate Tc 99m 30 min. Post Injection with Pyrophosphate
Target Organ	(mGy/740 MBq)	(rads/20 mCi)
* Assume 75% of the Sodium Pertechnetate Tc 99m labels red blood cells and the other 25% remains as pertechnetate.
† If 25% excreted with 1 hour Tb. ——————————————
Total Body	3.2	0.32
Spleen	3.6	0.36
Bladder Wall†	24	2.4
Testes	2.4	0.24
Ovaries	4.6	0.46
Blood	10.4	1.04

Method of Calculation: MIRD Dose Estimate Report

No. 8, J NucI Med 17:74-77, 1976.

How is Phosphotec Supplied

Phosphotec (Kit for the Preparation of Technetium Tc 99m Pyrophosphate) is supplied in a kit containing 10 reaction vials (5 mL size), 10 pressure-sensitive labels, and 1 package insert.

Storage

Store the Phosphotec (Kit for the Preparation of Technetium Tc 99m Pyrophosphate) refrigerated at 2°-8°C (36°-46°F). The reconstituted preparation should be refrigerated since the product does not contain a preservative. When reconstituted with sodium pertechnetate Tc 99m, Phosphotec must be used within 6 hours. When reconstituted with Sodium Chloride Injection USP for blood pool imaging, use the solution within 30 minutes.

PROCEDURES FOR RECONSTITUTION OF Phosphotec

Procedural Precautions

The contents of the Phosphotec reaction vial are sterile and nonpyrogenic. Aseptic procedures should be used during reconstitution of Phosphotec and the withdrawal of doses for intravenous administration. The introduction of air into the vial during the reconstitution step should be avoided.

Reconstitution

Bone and Cardiac Imaging

Technetium Tc 99m pyrophosphate must be used within 6 hours.

1. Waterproof gloves should be worn during the preparation procedure.


2. Allow the contents of the reaction vial to come to room temperature.


3. Place reaction vial in an appropriate lead shield with a fitted cover.


4. Swab the rubber closure of the reaction vial with a germicide.


5. Using a shielded syringe, slowly inject 2 to 4 mL [up to 2775 MBq (75 mCi)] of sterile sodium pertechnetate Tc 99m solution into the reaction vial. In determining the amount of technetium Tc 99m radioactivity to be used, the labeling efficiency, number of patients, administered radioactive dose and radioactive decay must be taken into account. NOTE: If sodium pertechnetate Tc 99m solution must be diluted for use with Phosphotec (Kit for the Preparation of Technetium Tc 99m Pyrophosphate), only Sodium Chloride Injection USP (without preservatives) should be used.


6. Secure the lead shield cover. Shake the vial gently to bring the lyophilized material into solution.


7. Record the time and date of preparation and the radioconcentration and volume of the solution on the pressure-sensitive label.


8. Affix the pressure-sensitive label to the shield.


9. Using proper shielding, examine vial contents. If the solution is not clear and free of particulate matter and discoloration on visual inspection, it should not be used.


10. Maintain adequate shielding of the radioactive preparation including the use of appropriate shielded syringes.


11. Radioassay of technetium Tc 99m pyrophosphate may be accomplished conveniently by using an ionization chamber-type dose calibrator.

Blood Pool Imaging

When reconstituted with Sodium Chloride Injection USP, Phosphotec should be used within 30 minutes.

1. Allow the contents of the reaction vial to come to room temperature. Swab the top of the rubber closure with a germicide.


2. Slowly inject 2 to 5 mL Sodium Chloride Injection USP (without preservatives) into the reaction vial.


3. Shake the vial gently to bring the lyophilized material into solution.


4. If the solution is not clear and free of particulate matter and discoloration on visual inspection it should not be used.

The U.S. Nuclear Regulatory Commission has approved this reagent kit for distribution to persons licensed to use byproduct material identified in §35.200 of 10 CFR Part 35, to persons who hold an equivalent license issued by an Agreement State, and, outside the United States, to persons authorized by the appropriate authority.

Manufactured for

Bracco Diagnostics Inc.

Princeton, NJ 08543

by

Amersham plc,

Little Chalfont,

HP7 9NA,

UK

Revised March 2003

L466302

Phosphotec  sodium pyrophosphate and stannous fluoride  injection, powder, lyophilized, for solution

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0270-0064 Route of Administration INTRAVENOUS DEA Schedule

INGREDIENTS Name (Active Moiety) Type Strength sodium pyrophosphate (sodium pyrophosphate) Active 40 MILLIGRAM  In 1 VIAL stannous fluoride (stannous fluoride) Active 0.4 MILLIGRAM  In 1 VIAL

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 0270-0064-25 10 VIAL In 1 KIT contains a VIAL 1 1 VIAL In 1 VIAL This package is contained within the KIT (0270-0064-25)

Revised: 03/2007Bracco Diagnostics, Inc.

Indometacina Genfar

Indometacina Genfar may be available in the countries listed below.

Ingredient matches for Indometacina Genfar

Indometacin

Indometacin is reported as an ingredient of Indometacina Genfar in the following countries:

• Peru

International Drug Name Search

Vfend

Pronunciation: VOR-i-KON-a-zole
Generic Name: Voriconazole
Brand Name: Vfend

Vfend is used for:

Treating certain fungal infections.

Vfend is an azole antifungal. It works by blocking fungal cell wall growth, which results in the death of the fungus.

Do NOT use Vfend if:

• you are allergic to any ingredient in Vfend


• you have untreated low blood calcium, magnesium, or potassium levels


• you are taking astemizole, a barbiturate (eg, phenobarbital), cabazitaxel, carbamazepine, cisapride, crizotinib, dronedarone, an ergot alkaloid (eg, ergotamine), erythromycin, everolimus, fluconazole, lurasidone, pimozide, quinidine, rifabutin, rifampin, rivaroxaban, sirolimus, St. John's wort, terfenadine, or ticagrelor

Contact your doctor or health care provider right away if any of these apply to you.

Before using Vfend:

Some medical conditions may interact with Vfend. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances


• if you are allergic to other azole antifungals (eg, fluconazole, itraconazole)


• if you have a history of heart problems (eg, cardiomyopathy, irregular heartbeat); an abnormal electrocardiogram (ECG) (a type of heart test); or low blood calcium, magnesium, or potassium levels


• if you have liver problems (eg, cirrhosis), kidney problems, pancreas problems, a weakened immune system, or a blood disease (eg, blood or bone marrow cancer)


• if you have ever been on chemotherapy or have had a stem cell transplant


• if you have taken fluconazole within the last 24 hours


• if you are taking ritonavir. Vfend should not be taken with certain doses of ritonavir

Some MEDICINES MAY INTERACT with Vfend. Tell your health care provider if you are taking any other medicines, especially any of the following:

• Medicines that may harm the kidney because the risk of kidney side effects may be increased. Ask your doctor or pharmacist if you are unsure if any of your medicines might affect the kidney


• Medicines that may increase the risk of a certain type of irregular heartbeat (prolonged QT interval). Check with your doctor or pharmacist if you are unsure if any of your medicines may increase the risk of this type of irregular heartbeat


• Many other prescription and nonprescription medicines (eg, used for aches and pains, anxiety, birth control, blood flow problems, blood thinning, cancer, diabetes, drug dependence, heartburn or reflux, high blood pressure, high cholesterol, HIV, immune system suppression, infections, irregular heartbeat or other heart problems, mental or mood problems, pain, seizures, stomach or bowel problems), multivitamin products, or herbal or dietary supplements (eg, herbal teas, coenzyme Q10, garlic, ginseng, ginkgo, St. John's wort) may interact with Vfend. Ask your doctor or pharmacist if you are unsure if any of your medicines might interact with Vfend

This may not be a complete list of all interactions that may occur. Ask your health care provider if Vfend may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Vfend:

Use Vfend as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• An extra patient leaflet is available with Vfend. Talk to your pharmacist if you have questions about this information.


• Vfend is usually given as an injection at your doctor's office, hospital, or clinic. If you will be using Vfend at home, a health care provider will teach you how to use it. Be sure you understand how to use Vfend. Follow the procedures you are taught when you use a dose. Contact your health care provider if you have any questions.


• Do not use Vfend if it contains particles, is cloudy or discolored, or if the vial is cracked or damaged.


• To clear up your infection completely, use Vfend for the full course of treatment. Keep using it even if you feel better in a few days.


• Keep this product, as well as syringes and needles, out of the reach of children and pets. Do not reuse needles, syringes, or other materials. Ask your health care provider how to dispose of these materials after use. Follow all local rules for disposal.


• If you miss a dose of Vfend, use it as soon as possible. If it is more than 6 hours after the missed dose, skip the missed dose and go back to your regular dosing schedule. Do not use 2 doses at once.

Ask your health care provider any questions you may have about how to use Vfend.

Important safety information:

• Vfend may cause blurred vision or sensitivity to light. These effects may be worse if you take it with alcohol or certain medicines. Use Vfend with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it.


• Avoid driving at night while you are using Vfend.


• Vfend may cause you to become sunburned more easily. Avoid the sun, sunlamps, or tanning booths until you know how you react to Vfend. Use a sunscreen or wear protective clothing if you must be outside for more than a short time.


• Uncommonly, some patients have experienced a reaction while receiving Vfend. Tell your doctor right away if you develop flushing, fever, sweating, fast heartbeat, chest tightness, shortness of breath, faintness, nausea, itching, or rash while you are receiving Vfend.


• Certain types of skin cancers (eg, melanoma, squamous cell) have been reported in patients who became sensitive to sunlight while taking Vfend for a long period of time. Contact your doctor if you notice a change in the appearance of a mole or other unusual skin change or growth. Discuss any questions or concerns with your doctor.


• Vfend may make your eyes more sensitive to sunlight. It may help to wear sunglasses. Avoid strong, direct sunlight.


• Tell your doctor or dentist that you take Vfend before you receive any medical or dental care, emergency care, or surgery.


• If your symptoms do not get better within a few days or if they get worse, check with your doctor.


• Women who may become pregnant should use effective birth control (eg, birth control pills) while using Vfend. Talk with your doctor if you have questions about effective birth control.


• Lab tests, including eye exams, liver and kidney function, and pancreas function, may be performed while you use Vfend. These tests may be used to monitor your condition or check for side effects. Be sure to keep all doctor and lab appointments.


• Vfend should be used with extreme caution in CHILDREN younger than 12 years old; safety and effectiveness in these children have not been confirmed.


• PREGNANCY and BREAST-FEEDING: Vfend may cause harm to the fetus. Do not become pregnant while you are using it. If you think you may be pregnant, contact your doctor. You will need to discuss the benefits and risks of using Vfend while you are pregnant. It is not known if Vfend is found in breast milk. Do not breast-feed while taking Vfend.

Possible side effects of Vfend:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Blurred vision; headache; nausea; sensitivity to light; sensitivity to the sun; vomiting.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing or swallowing; tightness in the chest; swelling of the mouth, face, lips, or tongue; unusual hoarseness); abnormal thoughts; black, tarry stools; bone pain; calf or leg pain, redness, swelling, or tenderness; change in the appearance of a mole; chest, jaw, or arm pain; confusion; decreased urination; fainting; fast, slow, or irregular heartbeat; fever, chills, or persistent sore throat; flushing; hallucinations; mental or mood changes (eg, depression); mouth sores; one-sided weakness; red, swollen, peeling, or blistered skin; seizures; severe or persistent dizziness or headache; shortness of breath; speech changes; sudden, severe nausea or vomiting; suicidal thoughts or actions; swelling of the arms or legs; symptoms of liver problems (eg, yellowing of the skin or eyes; dark urine; pale stools; severe or persistent nausea, vomiting, or stomach pain; loss of appetite; itching); symptoms of pancreatitis (eg, severe stomach or back pain, with or without nausea or vomiting); unusual bruising or bleeding; unusual skin change or skin growth; unusual sweating or weakness; unusual tiredness; unusual vaginal bleeding; vision changes (eg, color vision change, persistent or severe blurred vision or sensitivity to light).

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Vfend side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately.

Proper storage of Vfend:

Vfend is usually handled and stored by a health care provider. If you are using Vfend at home, store Vfend as directed by your pharmacist or health care provider. Keep Vfend out of the reach of children and away from pets.

General information:

• If you have any questions about Vfend, please talk with your doctor, pharmacist, or other health care provider.


• Vfend is to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Vfend. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Vfend resources

• Vfend Side Effects (in more detail)
• Vfend Use in Pregnancy & Breastfeeding
• Drug Images
• Vfend Drug Interactions
• Vfend Support Group
• 1 Review for Vfend - Add your own review/rating

• Vfend Prescribing Information (FDA)


• Vfend Consumer Overview


• Vfend Monograph (AHFS DI)


• Vfend Advanced Consumer (Micromedex) - Includes Dosage Information


• Voriconazole Prescribing Information (FDA)


• Voriconazole Professional Patient Advice (Wolters Kluwer)


• voriconazole Advanced Consumer (Micromedex) - Includes Dosage Information

Compare Vfend with other medications

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Locoid Cream

hydrocortisone butyrate

Dosage Form: cream
Locoid®

(hydrocortisone butyrate 0.1%)

Cream


For Dermatological Use Only

DESCRIPTION

Locoid ® Cream contains the topical corticosteroid hydrocortisone butyrate, a non-fluorinated hydrocortisone ester. It has the chemical name: pregn-4-ene-3,20-dione, 11,21 - dihydroxy-17-[(1-oxobutyl)oxy]-, (11β-;

the molecular formula: C25H36O6;

the molecular weight: 432.54;

and the CAS registry number: 13609-67-1.

Its structural formula is:

Each gram of Locoid ® Cream contains 1.0 mg of hydrocortisone butyrate in a hydrophilic base consisting of cetostearyl alcohol, ceteth-20, mineral oil, white petrolatum, citric acid, sodium citrate, propylparaben and butylparaben (preservatives) and purified water.

CLINICAL PHARMACOLOGY

Topical corticosteroids share anti-inflammatory, anti-pruritic and vasoconstrictive actions. The mechanism of anti-inflammatory activity of the topical corticosteroids is unclear. Various laboratory methods, including vasoconstrictor assays, are used to compare and predict potencies and/or clinical efficacies of the topical corticosteroids. There is some evidence to suggest that a recognizable correlation exists between vasoconstrictor potency and therapeutic efficacy in man.

PHARMACOKINETICS

The extent of percutaneous absorption of topical corticosteroids is determined by many factors including the vehicle, the integrity of the epidermal barrier, and the use of occlusive dressings.

Topical corticosteroids can be absorbed from normal intact skin. Inflammation and/or other disease processes in the skin increase percutaneous absorption. Occlusive dressings substantially increase the percutaneous absorption of topical corticosteroids.

Thus, occlusive dressings may be a valuable therapeutic adjunct for treatment of resistant dermatoses. (See DOSAGE AND ADMINISTRATION.)

Once absorbed through the skin, topical corticosteroids are handled through pharmacokinetic pathways similar to systemically administered corticosteroids. Corticosteroids are bound to plasma proteins in varying degrees. Corticosteroids are metabolized primarily in the liver and are then excreted by the kidneys. Some of the topical corticosteroids and their metabolites are also excreted into the bile.

INDICATIONS AND USAGE

Locoid ® (hydrocortisone butyrate 0.1%) Cream is indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses.

CONTRAINDICATIONS

Topical corticosteroids are contraindicated in those patients with a history of hypersensitivity to any of the components of the preparation.

PRECAUTIONS

General

Systemic absorption of topical corticosteroids has produced reversible hypothalamic-pituitary-adrenal (HPA) axis suppression, manifestations of Cushing's syndrome, hyperglycemia, and glucosuria in some patients. Conditions which augment systemic absorption include the application of the more potent steroids, use over large surface areas, prolonged use, and the addition of occlusive dressings.

Therefore, patients receiving a large dose of a potent topical steroid applied to a large surface area or under an occlusive dressing should be evaluated periodically for evidence of HPA axis suppression by using the urinary free cortisol and ACTH stimulation tests.

If HPA axis suppression is noted, an attempt should be made to withdraw the drug, to reduce the frequency of application, or to substitute a less potent steroid.

Recovery of HPA axis function is generally prompt and complete upon discontinuation of the drug.

Infrequently, signs and symptoms of steroid withdrawal may occur, requiring supplemental systemic corticosteroids.

Children may absorb proportionally larger amounts of topical corticosteroids and thus be more susceptible to systemic toxicity. (See PRECAUTIONS - PEDIATRIC USE).

If irritation develops, topical corticosteroids should be discontinued and appropriate therapy instituted.

In the presence of dermatological infections, the use of an appropriate antifungal or antibacterial agent should be instituted. If a favorable response does not occur promptly, the corticosteroid should be discontinued until the infection has been adequately controlled.

Information for the Patient

Patients using topical corticosteroids should receive the following information and instructions:

1. This medication is to be used as directed by the physician. It is for external use only. Avoid contact with the eyes.


2. Patients should be advised not to use this medication for any disorder other than for which it was prescribed.


3. The treated skin area should not be bandaged or otherwise covered or wrapped as to be occlusive unless directed by the physician.


4. Patients should report any signs of local adverse reactions especially under occlusive dressing.


5. Parents of pediatric patients should be advised not to use tight-fitting diapers or plastic pants on a child being treated in the diaper area, as these garments may constitute occlusive dressings.

Laboratory Tests

The following tests may be helpful in evaluating the HPA axis suppression:

Urinary free cortisol test

ACTH stimulation test

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Long-term animal studies have not been performed to evaluate the carcinogenic potential or the effect on fertility of topical corticosteroids.

Studies to determine mutagenicity with prednisolone and hydrocortisone have revealed negative results.

Pregnancy Category C

Corticosteroids are generally teratogenic in laboratory animals when administered systemically at relatively low dosage levels. The more potent corticosteroids have been shown to be teratogenic after dermal application in laboratory animals. There are no adequate and well-controlled studies in pregnant women on teratogenic effects from topically applied corticosteroids. Therefore, topical corticosteroids should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Drugs of this class should not be used extensively on pregnant patients, in large amounts, or for prolonged periods of time.

Nursing Mothers

It is not known whether topical administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in breast milk. Systemically administered corticosteroids are secreted into breast milk, in quantities not likely to have a deleterious effect on the infant. Nevertheless, caution should be exercised when topical corticosteroids are administered to a nursing woman.

Pediatric Use

Pediatric patients may demonstrate greater susceptibility to topical corticosteroid-induced HPA axis suppression and Cushing's syndrome than mature patients because of a larger skin surface area to body weight ratio.

Hypothalamic-pituitary-adrenal (HPA) axis suppression, Cushing's syndrome, and intracranial hypertension have been reported in children receiving topical corticosteroids.

Manifestations of adrenal suppression in children include linear growth retardation, delayed weight gain, low plasma cortisol levels, and absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema.

Administration of topical corticosteroids to children should be limited to the least amount compatible with an effective therapeutic regimen. Chronic corticosteroid therapy may interfere with the growth and development of children.

ADVERSE REACTIONS

The following local adverse reactions are reported infrequently with topical corticosteroids but may occur more frequently with the use of occlusive dressings. These reactions are listed in an approximate decreasing order of occurrence: burning, itching, irritation, dryness, folliculitis, hypertrichosis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, maceration of the skin, secondary infection, skin atrophy, striae, miliaria.

OVERDOSAGE

Topically applied corticosteroids can be absorbed in sufficient amounts to produce systemic effects. (See PRECAUTIONS.)

DOSAGE AND ADMINISTRATION

Locoid (hydrocortisone butyrate 0.1%) Cream should be applied to the affected area as a thin film two or three times daily depending on the severity of the condition. Occlusive dressings may be used for the management of psoriasis or recalcitrant conditions.

If an infection develops, the use of occlusive dressings should be discontinued and appropriate antimicrobial therapy instituted.

HOW SUPPLIED

Locoid ® (hydrocortisone butyrate 0.1%) Cream is supplied in tubes containing:

15 g          NDC 14290-310-15

45 g          NDC 14290-310-45

STORAGE

Store at controlled temperature between 59° - 77°F (15° - 25°C).

Rx Only.

Manufactured for

Triax Pharmaceuticals, LLC

Cranford, NJ 07016

By Ferndale Laboratories, Inc.

Ferndale, MI 48220

Marketed and Distributed by

Triax Pharmaceuticals, LLC

Cranford, NJ 07016

Locoid ® is a registered trademark

of Astellas Pharma Europe B.V.licensed to

Triax Pharmaceuticals, LLC.

131F000

Rev. 01/08

PRINCIPAL DISPLAY PANEL

NDC 14290-310-15

Locoid®

(hydrocortisone butyrate 0.1%)

Cream

Net Wt. 15 grams

 

LOCOID  hydrocortisone butyrate  cream

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 14290-310 Route of Administration TOPICAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength HYDROCORTISONE BUTYRATE (HYDROCORTISONE) HYDROCORTISONE BUTYRATE 1 mg  in 1 g

Inactive Ingredients Ingredient Name Strength CETOSTEARYL ALCOHOL   CETETH-20   MINERAL OIL   PETROLATUM   CITRIC ACID MONOHYDRATE   SODIUM CITRATE   PROPYLPARABEN   BUTYLPARABEN   WATER

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 14290-310-15 1 TUBE In 1 CARTON contains a TUBE 1 15 g In 1 TUBE This package is contained within the CARTON (14290-310-15) 2 14290-310-45 1 TUBE In 1 CARTON contains a TUBE 2 45 g In 1 TUBE This package is contained within the CARTON (14290-310-45)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA018514	12/01/2008

Labeler - Triax Pharmaceuticals, LLC (194481409)

Establishment
Name	Address	ID/FEI	Operations
Ferndale Laboratories, Inc.		005320536	manufacture

Establishment
Name	Address	ID/FEI	Operations
Pfizer Inc.		829076566	api manufacture

Revised: 01/2008Triax Pharmaceuticals, LLC

More Locoid Cream resources

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