Linezolid Injection - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology
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Linezolid Injection - Scientific Information

Manufacture: Fresenius Kabi USA, LLC
Country: Canada
Condition: Bacteremia, Bacterial Infection, Methicillin-Resistant Staphylococcus Aureus Infection, Nosocomial Pneumonia, Pneumonia, Skin and Structure Infection
Class: Oxazolidinone antibiotics
Form: Liquid solution, Intravenous (IV)
Ingredients: Linezolid

Pharmaceutical Information

Drug Substance

Proper Name: Linezolid
Chemical Name: (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide
Molecular Formula: C16H20FN3O4
Molecular Mass: 337.35
Structural Formula:
Physicohemical Properties:
Physical Form: Crystalline, white-to off-white powder
Solubility: Freely soluble in chloroform and sparingly soluble in methanol
pKa and pH values: The calculated pKa is 1.8 and was determined from solubility versus pH data and confirmed using 1H-NMR. This pKa indicates that linezolid is unionized in aqueous media above pH 4.
Partition Co-efficient: 3.5 (log PC = 0.55) in aqueous buffers (I = 0.1 M) and n-octanol and is independent of pH in the range of pH 3 to 9
Melting Range: 177°C to 182°C

Clinical Trials

Clinical studies have been conducted to establish in adults the safety and efficacy of linezolid for the treatment of infections described in the Indications and Clinical Use Section. This section provides clinical data for the indications of Vancomycin-Resistant Enterococcus faecium (VREF) infections and Complicated Skin and Skin Structure infections, Diabetic Foot infections only.

Vancomycin-Resistant Enterococcal Infections

At the test -of-cure visit patients with vancomycin- resistant Enterococcus faecium (VREF) infections showed the following response rates for the population shown (Table 1):

Table 1. Clinical Cure Rates at Test of Cure visit for Patients with VREF (Pooled VREF data)*
Source of Infection Intent-to-Treat Population n/N (%) Clinically Evaluable Population n/N (%) Microbiologically Evaluable Population n/N (%)
Intra-Abdominal Infection 31/34 (91.2) 30/32 (93.8) 30/32 (93.8)
    Peritonitis @ 13/15 (86.7) 13/14 (92.9) 13/14 (92.9)
    Abdominal Infection @ + 18/19 (94.7) 17/18 (94.4) 17/18 (94.4)
Skin and Skin Structure Infection 14/19 (73.7) 13/15 (86.7) 12/14 (85.7)
Urinary Tract Infection 12/18 (66.7) 10/11 (90.0) 9/10 (90.0)
Pneumonia 3/5 (60.0) 3/3 (100.0) 3/3 (100.0)
Bacteremia of Unknown Origin 16/22 (72.7) 15/20 (75.0) 12/17 (70.6)
Any Site With Associated Bacteremia 28/32 (87.5) 25/26 (96.2) 24/25 (96.0)
Any Site ++ 98/123 (79.9) 85/95 (89.5) 79/89 (88.8)

* 600 mg BID patients only

@ Subsets of Intra-Abdominal Infection

+ Including abdominal abscess, abdominal/intra-abdominal infections, pelvic infections

++ All patients regardless of Source of Infection

Complicated Skin and Skin Structure Infections, Diabetic Foot Infections

Study demographics and trial design

Table 2. Summary of trial design and patient demographics for Study 113, linezolid in the treatment of adult diabetic patients with clinically documented complicated skin and skin structure infections (“diabetic foot infections”)
Study # Trial Design Dosage, Route of Administration and Duration* Study Subjects (Intent-to-Treat) Mean Age (Range) Gender (% M/F)
766-INF-0026-113 Randomized (2:1 ratio), multi-center, open-label, comparator-controlled trial Linezolid IV or oral – 600 mg BID, 7 to 28 consecutive days 241 63 (30 - 86) 71/29
Ampicillin/sulbactam IV (1.5 to 3 g QID) or Amoxicillin/clavulanate IV (500 mg to 2 g QID) or oral (500 to 875 mg TID or BID) 7 to 28 consecutive days 120 62 (28 - 88) 71.7/28.3

* Patients in the comparator group could also be treated with vancomycin IV 1 g q12h if MRSA was isolated from the foot infection. Patients in either treatment group who had Gram-negative bacilli isolated from the infection site could also receive aztreonam IV (1 to 2 g q8-12h). All patients were eligible to receive appropriate adjunctive treatment methods, such as debridement and off-loading, as typically required in the treatment of diabetic foot infections, and most patients received these treatments.

Demographic Characteristics

Treatment groups were similar with regard to disposition of patients by age, weight, race, sex and ethnicity. Diabetic patients in each treatment group were mostly white, male, and over 45 years of age.

Study Results

Table 3. Clinical Cure Rates at Test of Cure Visit for ITT, MITT, CE and ME Populations in Study 113, linezolid in the treatment of adult diabetic patients with clinically documented complicated skin and skin structure infections (“diabetic foot infections”)
Endpoints Study Population Assessment Linezolid N = 241 n (%)* Comparator N = 120 n (%)* 95% CI§
Patient clinical outcome [clinical cure rate at follow-up (test of cure)] ITT Success (cured) 165 (81.3) 77 (71.3) - 0.1, 20.1
Number Assessed 203 (100) 108 (100)
Total 239 119
MITT Success (cured) 124 (79.5) 61 (70.9) - 2.9, 20.1
Number Assessed 156 (100) 86 (100)
Total 180 92
CE Success (cured) 159 (82.8) 74 (73.3) - 0.6, 19.7
Number Assessed 192 (100) 101 (100)
Total 212 105
ME Success (cured) 119 (81.0) 36 (66.7) 0.2, 28.4
Number Assessed 147 (100) 54 (100)
Total 161 55

Abbreviations: ITT = intent-to-treat, MTT = modified intent-to-treat, CE = clinically evaluable, ME = microbiologically evaluable

* All percentages are based on the number of patients assessed.

§ Confidence interval for the difference in cure rates based on normal approximation, expressed as a percentage

¶ Excludes patients with Indeterminate or Missing outcomes

The cure rates by pathogen for microbiologically evaluable patients are presented in Table 4.

Table 4. Cure Rates at the Test-of-Cure Visit for Microbiologically Evaluable Adult Patients with Diabetic Foot Infections [Study 113, linezolid in the treatment of adult diabetic patients with clinically documented complicated skin and skin structure infections (“diabetic foot infection”)]
Pathogen Cured
Linezolid n/N (%) Comparator n/N (%)
Staphylococcus aureus 49/64 (77) 20/30 (67)
Methicillin-resistant S. aureus 12/17 (71) 2/3 (67)
Streptococcus agalactiae 25/30 (83) 9/17 (53)
Streptococcus pyogenes 2/2 (100) --

Detailed Pharmacology

Animal Pharmacology

Linezolid has been studied in in vitro and in vivo animal models to evaluate the efficacy and safety profile. The intravenous and oral pharmacokinetic profiles are similar due to 100% oral bioavailability.

In animals the general pharmacological properties of linezolid were investigated to evaluate its effects on major physiological systems.

Central Nervous System Effects

No biologically relevant effects were noted in the functional observational battery up to a single oral dose of 100 mg/kg in rats. At a single intravenous dose of 125 mg/kg, moderate decreases in activity parameters and urine and fecal output in females were noted 5 minutes postdose, and an increase in urine output was seen in females 3 hours postdose.

Cardiovascular Effects

Intravenous 10 or 30 mg/kg doses of linezolid in anesthetized dogs produced no significant cardiovascular or respiratory changes.

Gastrointestinal and Renal System Effects

Gastrointestinal effects of linezolid in rats were limited to a reduction in gastric emptying at single oral doses of 62.5 and 100 mg/kg. When administered intravenously, reduced gastric secretion and gastric emptying were noted at a dose of 125 mg/kg. No effects on urine volume or urinary excretion of sodium, potassium, or chloride were seen with intravenous doses of up to 125 mg/kg; increases in water consumption were observed in females with 30 and 125 mg/kg intravenous doses. No effects on intestinal contraction were observed in studies of isolated guinea pig ileum.

Monoamine Oxidase (MAO) Inhibition

In vitro studies showed that linezolid is a weak and reversible (competitive) inhibitor of human MAO A and B with Ki values of 56 µM and 0.71 µM, respectively. The major metabolites had reduced affinity for MAO A and B, and also had reversible kinetics.

Large oral doses of crystalline tyramine, coadministered with 50 mg/kg oral doses of linezolid, were required to increase blood pressure in a rat model.

Administration of oral pseudoephedrine and phenylpropanolamine at 3-times the recommended clinical dose did not produce a clinically relevant vasopressor response in conscious, linezolid-pretreated dogs.

Linezolid was a weak inhibitor of serotonin and dopamine turnover in conscious rats. The magnitude of the changes induced by high doses of linezolid was small, compared to the irreversible MAO inhibitor clorgyline.

The physiologic and behavioral effects of linezolid in a rabbit model of the serotonin syndrome were determined. At 150 mg/Kg, linezolid did not induce hyperthermia in the presence of a meperidine challenge, unlike the positive control, clorgyline.

Microbiology

Linezolid belongs to a relatively new class of antimicrobial agents which possess a unique mechanism of bacterial protein synthesis inhibition. Linezolid targets the initiation phase of bacterial translation by preventing the formation of a functional 70S initiation complex. The action of linezolid is distinct from that of other protein synthesis inhibitors that inhibit elongation or termination. No inhibition of eukaryotic translation was observed in a cell-free mammalian translation system.

Linezolid has been shown to be active in vitro against most isolates of the organisms listed in Table 5.

Table 5. In vitro Activity of Linezolid Against Aerobic and Facultative Gram-positive Microorganisms
Organism No. Studies No. Isolates Weighted Average
MIC50 MIC90
Staphylococcus aureus (methicillin-susceptible) 9 916 1.8 2.5
Staphylococcus aureus (methicillin-resistant) 9 973 1.7 3.2
Staphylococcus epidermidis (methicillin-susceptible) 6 183 1.3 2.4
Staphylococcus epidermidis (methicillin-resistant) 6 216 1.2 2.1
Enterococcus faecalis (vancomycin-susceptible) 4 476 1.2 2.0
Enterococcus faecalis (vancomycin-resistant) 7 148 1.7 3.1
Enterococcus faecium (vancomycin-susceptible) 4 68 1.9 2.0
Enterococcus faecium (vancomycin-resistant) 6 252 1.3 2.4
Streptococcus pneumoniae (penicillin-susceptible) 5 303 0.6 1.0
Streptococcus pneumoniae (penicillin-intermediate) 4 242 0.6 1.0
Streptococcus pneumoniae (penicillin-resistant) 6 266 0.6 0.9
Streptococcus agalactiae 2 164 1.9 2.0
Streptococcus pyogenes 3 182 1.1 2.2

The following in vitro data are available, but their clinical significance is unknown. At least 90% of the following microorganisms exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for linezolid. However, the safety and effectiveness of linezolid in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

Aerobic and Facultative Gram-positive Microorganisms

Corynebacterium jeikeium

Enterococcus casseliflavus

Enterococcus gallinarum

Listeria monocytogenes

Staphylococcus aureus (vancomycin-intermediate strains)

Staphylococcus haemolyticus

Staphylococcus lugdunensis

Streptococcus intermedius

Viridans group streptococci

Group C streptococci

Group G streptococci

Aerobic and Facultative Gram-negative Microorganisms

Pasteurella canis

Pasteurella multocida

Anaerobic Microorganisms

Peptostreptococcus anaerobius

“Other” Microorganisms

Chlamydia pneumoniae

In clinical trials, resistance to linezolid developed in 6 patients infected with E. faecium (4 patients received 200 mg q12h, lower than the recommended dose, and 2 patients received 600 mg q12h). In a compassionate use program, resistance to linezolid developed in 8 patients with E. faecium and in 1 patient with E. faecalis. All patients had either unremoved prosthetic devices or undrained abscesses. Resistance to linezolid occurs in vitro at a frequency of 1 x 10-9 to 1 x 10-11. In vitro studies have shown that point mutations in the 23S rRNA are associated with linezolid resistance. Resistance to linezolid has not been seen in clinical trials in patients infected with Staphylococcus spp. or Streptococcus spp., including S. pneumoniae.

Susceptibility Testing Methods

Note: Susceptibility testing by dilution methods requires the use of linezolid susceptibility powder. Linezolid should not be used for susceptibility testing.

When available, the results of in vitro susceptibility test results for antimicrobial drugs used in the resident hospitals should be provided to the physician as periodic reports which describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting the most effective antimicrobial.

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 method (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of linezolid powder. The MIC values should be interpreted according to criteria provided in Table 6.

Table 6. Susceptibility Interpretive Criteria for Linezolid
Pathogen Susceptibility Interpretive Criteria
Minimal Inhibitory Concentrations (MIC in μg/mL) Disk Diffusion (Zone Diameters in mm)
S I R S I R
Enterococcus spp ≤ 2 4 ≥ 8 ≥ 23 21 - 22 ≤ 20
Enterococcus sppa ≤ 4 --- --- ≥ 21 --- ---
Streptococcus pneumoniaea ≤ 2b --- --- ≥ 23c --- ---
Streptococcus spp other than S pneumoniaea ≤ 2b --- --- ≥ 23c --- ---

a The current absence of data on resistant strains precludes defining any categories other than “Susceptible”. Strains yielding test results suggestive of a “nonsusceptible” category should be retested, and if the result is confirmed, the isolate should be submitted to a reference laboratory for further testing.
b These interpretive standards for S. pneumoniae and Streptococcus spp. other than S. pneumoniae are applicable only to tests performed by broth microdilution using cation-adjusted Mueller-Hinton broth with 2 to 5% lysed horse blood inoculated with a direct colony suspension and incubated in ambient air at 35°C for 20 to 24 hours.
c These zone diameter interpretive standards are applicable only to tests performed using Mueller-Hinton agar supplemented with 5% defibrinated sheep blood inoculated with a direct colony suspension and incubated in 5% CO2 at 35°C for 20 to 24 hours.

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 procedure requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 30 μg of linezolid to test the susceptibility of microorganisms to linezolid. The disc diffusion interpretive criteria are provided in Table 6.

Anaerobic Techniques

For anaerobic bacteria, the susceptibility to linezolid as MICs can be determined by standardized test methods. Interpretive criteria for linezolid and anaerobic microorganisms have not been defined.

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.

Quality Control

Standardized susceptibility test procedures require the use of quality control microorganisms to control the technical aspects of the test procedures. Standard linezolid powder should provide the following range of values noted in Table 7. NOTE: Quality control microorganisms are specific strains of organisms with intrinsic biological properties relating to resistance mechanisms and their genetic expression within bacteria; the specific strains used for microbiological quality control are not clinically significant.

Table 7. Acceptable Quality Control Ranges for Linezolid to be Used in Validation of Susceptibility Test Results
QC Strain Acceptable Quality Control Ranges
Minimum Inhibitory Concentration (MIC in μg/mL) Disk Diffusion (Zone Diameters in mm)
Enterococcus faecalis ATCC 29212 1 - 4 Not applicable
Staphylococcus aureus ATCC 29213 1 - 4 Not applicable
Staphylococcus aureus ATCC 25923 Not applicable 27 - 31
Streptococcus pneumoniae ATCC 49619 0.5 - 2 28 - 34

Toxicology

The toxicity of linezolid was evaluated in acute oral and IV toxicity studies in rats and an acute oral toxicity study in dogs, repeated-dose oral toxicity studies up to 6 months in duration in rats and 3 months in duration in dogs, a 4-week oral toxicity study in juvenile rats, repeated-dose IV toxicity studies up to 1 month in duration in rats and dogs, developmental and reproductive toxicity studies in mice and adult and juvenile rats, mutagenic potential studies in vitro and invivo, and special toxicology studies (handler safety [ocular and dermal irritation] studies and MAO inhibition studies).

Acute Toxicity

Rat

When the acute oral toxicity of linezolid was evaluated in rats given two equally divided doses of drug on one day, the minimum lethal oral dose was between 1000 - 3000 mg/kg/day. Clinical signs in surviving and moribund animals included decreased activity, ataxia, salivation, alopecia, and soiled face and urogenitalia. Suppressed or decreased body weight gain, which returned to normal by the end of the study, was observed at doses of 3000 and 5000 mg/kg/day. In surviving rats, the main gross findings consisted of enlarged cecum (a common effect in rats treated with antibiotics) and alopecia. No toxic signs or adverse effects were seen in acute IV toxicity studies when rats were administered dose levels of up to 400 mg/kg/day.

Dog

In male dogs given two equally divided doses of linezolid orally on one day, the minimum lethal dose was greater than 2000 mg/kg/day. Vomiting, tremors, and decreased activity were the primary clinical observations. No symptoms were observed twenty- four hours after the evening (PM) dose. Food consumption and body weight gains in dogs given 500 and 2000 mg/kg/day were suppressed slightly in the early phase of the observation period and returned to normal thereafter. Slight, transient elevations in serum alanine aminotransferase (ALT) were seen in one dog given 2000 mg/kg/day.

Repeated-Dose Toxicity

Studies performed to assess the toxicity of linezolid after repeated dosing indicated that the primary target organs of toxicity were the hematopoietic and gastrointestinal systems in rats and dogs, and the reproductive system in rats. The NOAELs were 40 mg/kg/day in the 6-month oral rat study, 10 mg/kg/day in the 3-month oral rat study, 20 mg/kg/day in the 1-month oral rat study, and 20 mg/kg/day in the 1- and 3-month oral dog studies.

Hematopoietic Effects

Linezolid produced myelosuppression in rats and dogs that was time- and dose-dependent, and reversible. Findings included mild bone marrow hypocellularity and moderate decreases in red blood cell, white blood cell, and platelet counts. A 1- month recovery period was sufficient for the reversal of myelosuppression in most studies, and in the case of the 3-month oral dose study in dogs, reversal of effects was observed during the dosing phase of the study when the dose was reduced from 40 to 30 mg/kg/day.

Gastrointestinal Effects

Gastrointestinal effects were observed in rats and dogs that were likely primarily related to antibiotic-induced alterations in intestinal microflora. Findings in rats included decreased food consumption and diarrhea, which resulted in decreased weight gain, and histological changes in the large and small intestines (atrophy of intestinal mucosa and necrosis of epithelial cells in the intestinal crypts) in the 2-week study at high doses of 200 and 1000 mg/kg/day. In the longer term definitive studies in rats, treatment-related decreases in body weight gain and food consumption were not accompanied by microscopic findings. Reduced gastric emptying, noted in the safety pharmacology studies in rats, may have been a contributing factor to the inappetence. In dogs, anorexia, vomiting, and mucous stools accompanied weight loss. The gastrointestinal findings were note related to oral administration of linezolid, as they were also observed in the intravenous studies. All effects reversed with cessation of treatment.

Other Effects

In rats administered linezolid orally for 6 months, non-reversible, minimal to mild axonal degeneration of sciatic nerves was observed at 80 mg/kg/day; minimal degeneration of the sciatic nerve was also observed in 1 male at this dose level at a 3-month interim necropsy. Sensitive morphologic evaluation of perfusion-fixed tissues was conducted to investigate evidence of optic nerve degeneration. Minimal to moderate optic nerve degeneration was evident in 2 male rats administered linezolid at 80 mg/kg/day for 6 months, but the direct relationship to drug was equivocal because of t he acute nature of the finding and its asymmetrical distribution. The optic nerve degeneration observed was microscopically comparable to a spontaneous unilateral optic nerve degeneration reported in aging rats and may be an exacerbation of a common background change.

Carcinogenicity

Linezolid will be used for short-term therapy. Therefore carcinogenicity bioassay studies have not been conducted.

Mutagenicity

Linezolid is considered to be nonmutagenic and nonclastogenic, based on negative results in a battery of tests including those designed to measure chemically induced gene mutation in bacterial and mammalian cells (the Ames and AS52 assays, respectively) and those designed to measure chromosome aberrations in human lymphocytes in vitro and micronuclei in mouse bone marrow cells in vivo. In addition, linezolid did not induce unscheduled DNA synthesis (UDS) invitro, a measure of DNA repair following chemically induced DNA damage.

Reproduction and Teratology

Linezolid did not affect the fertility or reproductive performance of adult female rats, while it reversibly decreased fertility in adult male rats when given orally at doses ≥ 50 mg/kg/day for 4 to 10 weeks with exposures approximately equal to or greater than the expected human exposure level (exposure comparisons are based on AUC0- 24 in animals vs (2 x AUC0-τ) in humans given 600 mg twice daily). Epithelial cell hypertrophy in the epididymis may have contributed to the decreased fertility be affecting sperm maturation. Similar epididymal changes were not seen in dogs. Light microscopic examination of the testes did not show overt drug-induced effects, although an effect on spermatogenesis cannot be excluded. Although the concentrations of sperm in the testes were in the normal range, the concentrations in the cauda epididymis were decreased, and sperm from the vas deferens had decreased motility.

Mildly decreased fertility occurred in juvenile male rats treated with linezolid orally through most of their period of sexual development (50 mg/kg/day from days 7 to 36 of age, and

100 mg/kg/day from days 37 to 55 of age, with exposures ranging from 0.4-fold to 1.2-fold that expected in humans based on AUC). No histopathological evidence of adverse effects was observed in the male reproductive tract.

In mice, embryo and fetal toxicity was seen only at doses that caused maternal toxicity (clinical signs and reduced body weight again). An oral dose of 450 mg/kg/day (6.5-fold the estimated human exposure level based on AUC) correlated with increased postimplantational embryo death, including total litter loss; decreased fetal body weights and an exacerbation of a normal genetic predisposition to sternal variations in the strain of mice used, in the form of an increased incidence of costal cartilage fusion.

In rats, mild fetal toxicity was observed at oral doses of 15 and 50 mg/kg/day (exposure levels 0.22-fold to approximately equivalent to the estimated human exposure, respectively, based on AUC). The effects consisted of decreased fetal body weights and reduced ossification of sternebrae, a finding often seen in association with decreased fetal body weights. Slight maternal toxicity, in the form of reduced body weight gain, was seen at 50 mg/kg/day.

In rabbits, reduced fetal body weight occurred only in the presence of maternal toxicity (clinical signs, reduced body weight gain and food consumption) when administered twice daily at total oral daily doses of 15 mg/kg/day (0.06-fold the estimated human exposure based on AUCs).

Linezolid was not teratogenic in mice, rats, or rabbits at exposure levels 6.5-fold (in mice), equivalent to (in rats), or 0.06-fold (in rabbits) the expected human exposure level, based on AUCs. However, embryo and fetal toxicities were seen.

When female rats were treated orally with 50 mg/kg/day of linezolid during pregnancy and lactation, survival of pups was decreased on postnatal days 1 to 4, and mild delays in maturational milestones were observed. Pups permitted to mature to reproductive age, when mated, showed evidence of a dose-related increase in preimplantation loss at maternal doses ≥ 2.5 mg/kg/day, with exposures below those expected in humans.

Other Studies

In ocular and dermal irritation studies in albino rabbits, linezolid caused minimal and transient irritation when administered as a single dose of 100 mg/eye and was slightly irritating to abraded skin when applied at a dose of 100 mg/site/day for 5 days.