Levaquin

[Levofloxacin]

Since only limited data are available on the compatibility of levofloxacin intravenous injection with other intravenous substances, additives or other medications should not be added to LEVAQUIN Injection in single-use vials or infused simultaneously through the same intravenous line. If the same intravenous line is used for sequential infusion of several different drugs, the line should be flushed before and after infusion of LEVAQUIN Injection with an infusion solution compati-ble with LEVAQUIN Injection and with any other drug( s) administered via this common line.

Prepare the desired dosage of levofloxacin according to the following chart:
Desired From Appropriate Vial, Volume of Infusion Dosage Strength Withdraw Volume Diluent Time
250 mg 10 mL (20 mL Vial) 40 mL 60 min
500 mg 20 mL (20 mL Vial) 80 mL 60 min
750 mg 30 mL (30 mL Vial) 120 mL 90 min
For example, to prepare a 500 mg dose using the 20 mL vial (25 mg/ mL), withdraw 20 mL and dilute with a compatible intravenous solution to a

total volume of 100 mL.
Compatible Intravenous Solutions: Any of the following intravenous solutions may be used to prepare a 5 mg/ mL levofloxacin solution with the approximate pH values:
Final pH of Intravenous Fluids LEVAQUIN Solution

Text Continues Below

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0.9% Sodium Chloride Injection, USP 4. 71 5% Dextrose Injection, USP 4.58
5% Dextrose/ 0.9% NaCl Injection 4.62 5% Dextrose in Lactated Ringers 4.92
Plasma-Lyte ® 56/ 5% Dextrose Injection 5.03 5% Dextrose, 0.45% Sodium Chloride, 4.61
and 0.15% Potassium Chloride Injection Sodium Lactate Injection (M/ 6) 5.54

LEVAQUIN Injection Premix in Single-Use Flexible Containers:

LEVAQUIN Injection is also supplied in flexible containers containing a premixed, ready-to-use levofloxacin solution in D5 W for single-use. The fill volume is either 50 or 100 mL for the 100 mL flexible container or 150 mL for the 150 mL container. NO FURTHER DILUTION OF THESE PREPARATIONS ARE NECESSARY. Consequently each 50 mL, 100 mL, and 150 mL premix flexible container already contains a dilute solution with the equivalent of 250 mg, 500 mg, and 750 mg of levofloxacin, respectively (5 mg/ mL) in 5% Dextrose (D5W). This parenteral drug product should be inspected visually for particulate matter prior to administration. Samples containing visible particles should be discarded. Since the premix flexible containers are for single-use only, any unused portion should be discarded.

Since only limited data are available on the compatibility of levofloxacin intravenous injection with other intravenous substances, additives or other medications should not be added to LEVAQUIN Injection in flexible containers or infused simultaneously through the same intravenous line. If the same intravenous line is used for sequential infusion of several different drugs, the line should be flushed before and after infusion of LEVAQUIN Injection with an infusion solution compati-ble with LEVAQUIN Injection and with any other drug( s) administered via this common line.

Instructions for the Use of LEVAQUIN Injection Premix in Flexible Containers
To open:

1. Tear outer wrap at the notch and remove solution container.
2. Check the container for minute leaks by squeezing the inner bag firmly. If leaks are found, or if the seal is not intact, discard the solution, as
the sterility may be compromised.
3. Do not use if the solution is cloudy or a precipitate is present.
4. Use sterile equipment.
5. WARNING: Do not use flexible containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is complete.

Preparation for administration:

1. Close flow control clamp of administration set.
2. Remove cover from port at bottom of container.
3. Insert piercing pin of administration set into port with a twisting motion until the pin is firmly seated.
NOTE: See full directions on administration set carton.
4. Suspend container from hanger.
5. Squeeze and release drip chamber to establish proper fluid level in chamber during infusion of LEVAQUIN Injection in Premix Flexible Containers.
6. Open flow control clamp to expel air from set. Close clamp.
7. Regulate rate of administration with flow control clamp.

Stability of LEVAQUIN Injection as Supplied When stored under recommended conditions, LEVAQUIN Injection, as supplied in 20 mL and 30 mL vials, or 100 mL and 150 mL flexible containers, is stable through the expiration date printed on the label.

Stability of LEVAQUIN Injection Following Dilution LEVAQUIN Injection, when diluted in a compatible intravenous fluid to a concentration of 5 mg/ mL, is stable for 72 hours when stored at or below 25° C (77° F) and for 14 days when stored under refrigeration at 5° C (41° F) in plastic intravenous containers. Solutions that are diluted in a com-patible intravenous solution and frozen in glass bottles or plastic intra-venous containers are stable for 6 months when stored at -20° C (-4° F). THAW FROZEN SOLUTIONS AT ROOM TEMPERATURE 25° C (77° F) OR IN A REFRIGERATOR 8° C (46° F). DO NOT FORCE THAW BY MICROWAVE IRRADIATION OR WATER BATH IMMERSION. DO NOT REFREEZE AFTER INITIAL THAWING.

HOW SUPPLIED

LEVAQUIN Tablets
LEVAQUIN (levofloxacin) Tablets are supplied as 250, 500, and 750 mg modified rectangular, film-coated tablets. LEVAQUIN Tablets are packaged in bottles and in unit-dose blister strips in the following configurations:

250 mg tablets: color: terra cotta pink debossing: "LEVAQUIN" on side 1 and "250" on side 2
bottles of 50 (NDC 0045-1520-50) unit-dose/ 100 tablets (NDC 0045-1520-10)
500 mg tablets: color: peach debossing: "LEVAQUIN" on side 1 and "500" on side 2
bottles of 50 (NDC 0045-1525-50) unit-dose/ 100 tablets (NDC 0045-1525-10)
750 mg tablets: color: white debossing: "LEVAQUIN" on side 1 and "750" on side 2
bottles of 50 (NDC 0045-1530-50) unit-dose/ 100 tablets (NDC 0045-1530-10)
LEVA-Pak unit-dose/ 5 tablets (NDC 0045-1530-05)
LEVAQUIN Tablets should be stored at 15° to 30° C (59° to 86° F) in well-closed containers.

LEVAQUIN Tablets are manufactured for OMP DIVISION, ORTHO-McNEIL PHARMACEUTICAL, INC. by Janssen Ortho LLC, Gurabo, Puerto Rico
00778.
LEVAQUIN Injection Single-Use Vials: LEVAQUIN (levofloxacin) Injection is supplied in single-use vials. Each vial contains a concentrated solution with the equiv-alent of 500 mg of levofloxacin in 20 mL vials and 750 mg of levofloxacin
in 30 mL vials.
25 mg/ mL, 20 mL vials (NDC 0045-0069-51)
25 mg/ mL, 30 mL vials (NDC 0045-0065-55)

LEVAQUIN Injection in Single-Use Vials should be stored at controlled room temperature and protected from light.

LEVAQUIN Injection in Single-Use Vials is manufactured for OMP DIVISION, ORTHO-McNEIL PHARMACEUTICAL, INC. by OMJ Pharmaceuticals, Inc.,
San German, Puerto Rico 00683.

Premix in Flexible Containers: LEVAQUIN (levofloxacin in 5% dextrose) Injection is supplied as a single-use, premixed solution in flexible containers. Each bag contains a dilute solution with the equivalent of 250, 500, or 750 mg of levofloxacin, respectively, in 5% Dextrose (D5 W).

5 mg/ mL (250 mg), 50 mL flexible container (NDC 0045-0067-01)
5 mg/ mL (500 mg), 100 mL flexible container (NDC 0045-0068-01)
5 mg/ mL (750 mg), 150 mL flexible container (NDC 0045-0066-01)

LEVAQUIN Injection Premix in Flexible Containers should be stored at or below 25° C (77° F); however, brief exposure up to 40° C (104° F) does not adversely affect the product. Avoid excessive heat and protect from freezing and light.

LEVAQUIN Injection Premix in Flexible Containers is manufactured for OMP DIVISION, ORTHO-McNEIL PHARMACEUTICAL, INC. by ABBOTT
Laboratories, North Chicago, IL 60064.
CLINICAL STUDIES Nosocomial Pneumonia

Adult patients with clinically and radiologically documented nosocomial pneumonia were enrolled in a multicenter, randomized, open-label study comparing intravenous levofloxacin (750 mg once daily) followed by oral levofloxacin (750 mg once daily) for a total of 7-15 days to intravenous imipenem/ cilastatin (500-1000 mg q6-8 hours daily) followed by oral ciprofloxacin (750 mg q12 hours daily) for a total of 7-15 days.
Levofloxacin-treated patients received an average of 7 days of intra-venous therapy (range: 1-16 days); comparator-treated patients received
an average of 8 days of intravenous therapy (range: 1-19 days).

Overall, in the clinically and microbiologically evaluable population, adjunctive therapy was empirically initiated at study entry in 56 of 93 (60.2%) patients in the levofloxacin arm and 53 of 94 (56.4%) patients in the comparator arm. The average duration of adjunctive therapy was 7 days in the levofloxacin arm and 7 days in the comparator.

In clinically and microbiologically evaluable patients with documented Pseudomonas aeruginosa infection, 15 of 17 (88.2%) received ceftazidime (N= 11) or piperacillin/ tazobactam (N= 4) in the levofloxacin arm and 16 of 17 (94.1%) received an aminoglycoside in the comparator arm. Overall, in clinically and microbiologically evaluable patients, vancomycin was added to the treatment regimen of 37 of 93 (39.8%) patients in the lev-ofloxacin arm and 28 of 94 (29.8%) patients in the comparator arm for suspected methicillin-resistant S. aureus infection.

Clinical success rates in clinically and microbiologically evaluable patients at the posttherapy visit (primary study endpoint assessed on day 3-15 after completing therapy) were 58.1% for levofloxacin and 60.6% for comparator. The 95% CI for the difference of response rates (levofloxacin minus comparator) was [-17.2, 12.0]. The microbiological eradication rates at the posttherapy visit were 66.7% for levofloxacin and 60.6% for comparator. The 95% CI for the difference of eradication rates (levofloxacin minus comparator) was [-8.3, 20.3]. Clinical success and microbiological eradication rates by pathogen were as follows:
Levofloxacin Imipenem/ Cilastatin
No. (%) of Patients No. (%) of Patients
Pathogen N Microbiologic / Clinical N Microbiologic / Clinical
Outcomes Outcomes
MSSA a 21 14 (66.7) / 13 (61.9) 19 13 (68.4) / 15 (78. 9)
P. aeruginosa b 17 10 (58.8) / 11 (64.7) 17 5 (29.4) / 7 (41. 2)
S. marcescens 11 9 (81.8) / 7 (63.6) 7 2 (28.6) / 3 (42. 9)
E. coli 12 10 (83.3) / 7 (58.3) 11 7 (63.6) / 8 (72. 7)
K. pneumoniae c 11 9 (81.8) / 5 (45.5) 7 6 (85.7) / 3 (42. 9)
H. influenzae 16 13 (81.3) / 10 (62.5) 15 14 (93.3) / 11 (73. 3)
S. pneumoniae 4 3 (75.0) / 3 (75.0) 7 5 (71.4) / 4 (57. 1)

a Methicillin-susceptible S. aureus.
b See above text for use of combination therapy.
c The observed differences in rates for the clinical and microbiological outcomes may reflect other factors that were not accounted for in the study.

Community-Acquired Bacterial Pneumonia 7 to 14 Day Treatment Regimen

Adult inpatients and outpatients with a diagnosis of community-acquired bacterial pneumonia were evaluated in two pivotal clinical studies. In the first study, 590 patients were enrolled in a prospective, multi-center, unblinded randomized trial comparing levofloxacin 500 mg once daily orally or intravenously for 7 to 14 days to ceftriaxone 1 to 2 grams intravenously once or in equally divided doses twice daily followed by cefuroxime axetil 500 mg orally twice daily for a total of 7 to 14 days.

Patients assigned to treatment with the control regimen were allowed to receive erythromycin (or doxycycline if intolerant of erythromycin) if an infection due to atypical pathogens was suspected or proven. Clinical and microbiologic evaluations were performed during treatment, 5 to 7 days posttherapy, and 3 to 4 weeks posttherapy. Clinical success (cure plus improvement) with levofloxacin at 5 to 7 days posttherapy, the primary efficacy variable in this study, was superior (95%) to the control group (83%).

The 95% CI for the difference of response rates (levofloxacin minus comparator) was [-6, 19]. In the second study, 264 patients were enrolled in a prospective, multi-center, non-comparative trial of 500 mg levofloxacin administered orally or intravenously once daily for 7 to 14 days. Clinical success for clinically evaluable patients was 93%. For both studies, the clinical success rate in patients with atypical pneumonia due to Chlamydia pneumoniae, Mycoplasma pneumoniae, and Legionella pneumophila were 96%, 96%, and 70%, respectively. Microbiologic eradication rates across both studies were as follows:

Pathogen No. Pathogens Microbiologic Eradication Rate (%)
H. influenzae 55 98 S. pneumoniae 83 95

S. aureus 17 88 M. catarrhalis 18 94
H. parainfluenzae 19 95 K. pneumoniae 10 100.0

Additional studies were initiated to evaluate the utility of LEVAQUIN in community-acquired pneumonia due to S. pneumoniae, with particular interest in penicillin-resistant strains (MIC value for penicillin 2 µg/ mL). In addition to the studies previously discussed, inpatients and outpatients with mild to severe community-acquired pneumonia were evaluated in six additional clinical studies; one double-blind study, two open label randomized studies, and three open label non-comparative studies. The total number of clinically evaluable patients with S. pneumoniae across all 8 studies was 250 for levofloxacin and 41 for comparators.

The clinical success rate (cured or improved) among the 250 levofloxacin-treated patients with S. pneumoniae was 245/ 250 (98%). The clinical success rate among the 41 comparator-treated patients with S. pneumoniae was 39/ 41 (95%). Across these 8 studies, 18 levofloxacin-treated and 4 non-quinolone comparator-treated patients with community-acquired pneumonia due to penicillin-resistant S. pneumoniae (MIC value for penicillin 2 µg/ mL) were identified. Of the 18 levofloxacin-treated patients, 15 were evalu-able following the completion of therapy.

Fifteen out of the 15 evaluable levofloxacin-treated patients with community-acquired pneumonia due to penicillin-resistant S. pneumoniae achieved clinical success (cure or improvement). Of these 15 patients, 6 were bacteremic and 5 were classified as having severe disease. Of the 4 comparator-treated patients with community-acquired pneumonia due to penicillin-resistant S. pneumoniae, 3 were evaluable for clinical efficacy. Three out of the 3 evaluable comparator-treated patients achieved clinical success. All three of the comparator-treated patients were bacteremic and had disease classified as severe.

Community-Acquired Bacterial Pneumonia 5-Day Treatment Regimen
To evaluate the safety and efficacy of higher dose and shorter course of levofloxacin, 528 outpatient and hospitalized adults with clinically and radiologically determined mild to severe community-acquired pneumonia were evaluated in a double-blind, randomized, prospective, multicenter study comparing levofloxacin 750 mg, i. v. or p. o., q. d. for five days or levofloxacin 500 mg i. v. or p. o., q. d. for 10 days.

Clinical success rates (cure plus improvement) in the clinically evalu-able population were 90.9% in the levofloxacin 750mg group and 91.1% in the levofloxacin 500 mg group. The 95% CI for the difference of response rates (levofloxacin 750 minus levofloxacin 500) was [-5.9, 5.4]. In the clinically evaluable population (31-38 days after enrollment) pneumonia was observed in 7 out of 151 patients in the levofloxacin 750 mg group and 2 out of 147 patients in the levofloxacin 500 mg group. Given the small numbers observed, the significance of this finding can not be determined statistically. The microbiological efficacy of the 5-day regimen was documented for infections listed in the table below.

Eradication rate
Penicillin susceptible S. pneumoniae 19/ 20 Haemophilus influenzae 12/ 12

Haemophilus parainfluenzae 10/ 10 Mycoplasma pneumoniae 26/ 27
Chlamydia pneumoniae 13/ 15
Complicated Skin and Skin Structure Infections Three hundred ninety-nine patients were enrolled in an open-label, randomized, comparative study for complicated skin and skin structure infections. The patients were randomized to receive either levofloxacin 750 mg QD (IV followed by oral), or an approved comparator for a median of 10 ± 4.7 days.

As is expected in complicated skin and skin structure infections, surgical procedures were performed in the levofloxacin and comparator groups. Surgery (incision and drainage or debridement) was performed on 45% of the levofloxacin treated patients and 44% of the comparator treated patients, either shortly before or during antibiotic treatment and formed an integral part of therapy for this indication.

Among those who could be evaluated clinically 2-5 days after comple-tion of study drug, overall success rates (improved or cured) were 116/ 138 (84.1%) for patients treated with levofloxacin and 106/ 132 (80.3%) for patients treated with the comparator.

Success rates varied with the type of diagnosis ranging from 68% in patients with infected ulcers to 90% in patients with infected wounds and abscesses. These rates were equivalent to those seen with comparator drugs.

Chronic Bacterial Prostatitis

Adult patients with a clinical diagnosis of prostatitis and microbiological culture results from urine sample collected after prostatic massage (VB3 ) or expressed prostatic secretion (EPS) specimens obtained via the Meares-Stamey procedure were enrolled in a multicenter, randomized, double-blind study comparing oral levofloxacin 500 mg, once daily for a total of 28 days to oral ciprofloxacin 500 mg, twice daily for a total of 28 days. The primary efficacy endpoint was microbiologic efficacy in microbiologically evaluable patients.

A total of 136 and 125 microbio-logically evaluable patients were enrolled in the levofloxacin and ciprofloxacin groups, respectively. The microbiologic eradication rate by patient infection at 5-18 days after completion of therapy was 75.0% in the levofloxacin group and 76.8% in the ciprofloxacin group (95% CI [-12.58, 8.98] for levofloxacin minus ciprofloxacin). The overall eradication rates for pathogens of interest are presented below:
Levofloxacin (N= 136) Ciprofloxacin (N= 125)
Pathogen N Eradication N Eradication
E. coli 15 14 (93.3%) 11 9 (81.8%)
E. faecalis 54 39 (72.2%) 44 33 (75.0%)
*S. epidermidis 11 9 (81.8%) 14 11 (78.6%)

*Eradication rates shown are for patients who had a sole pathogen only; mixed cultures were excluded.

Eradication rates for S. epidermidis when found with other co-pathogens are consistent with rates seen in pure isolates.
Clinical success (cure + improvement with no need for further antibi-otic therapy) rates in microbiologically evaluable population 5-18 days after completion of therapy were 75.0% for levofloxacin-treated patients and 72.8% for ciprofloxacin-treated patients (95% CI [-8.87, 13.27] for levofloxacin minus ciprofloxacin). Clinical long-term success (24-45 days after completion of therapy) rates were 66.7% for the levofloxacin-treated patients and 76.9% for the ciprofloxacin-treated patients (95% CI [-23.40, 2.89] for levofloxacin minus ciprofloxacin).

ANIMAL PHARMACOLOGY

Levofloxacin and other quinolones have been shown to cause arthropa-thy in immature animals of most species tested. (See WARNINGS.) In immature dogs (4-5 months old), oral doses of 10 mg/ kg/ day for 7 days and intravenous doses of 4 mg/ kg/ day for 14 days of levofloxacin resulted in arthropathic lesions. Administration at oral doses of 300 mg/ kg/ day for 7 days and intravenous doses of 60 mg/ kg/ day for 4 weeks produced arthropathy in juvenile rats.

When tested in a mouse ear swelling bioassay, levofloxacin exhibited phototoxicity similar in magnitude to ofloxacin, but less phototoxicity than other quinolones. While crystalluria has been observed in some intravenous rat studies, urinary crystals are not formed in the bladder, being present only after micturition and are not associated with nephrotoxicity.

In mice, the CNS stimulatory effect of quinolones is enhanced by concomitant administration of non-steroidal anti-inflammatory drugs. In dogs, levofloxacin administered at 6 mg/ kg or higher by rapid intravenous injection produced hypotensive effects. These effects were considered to be related to histamine release. In vitro and in vivo studies in animals indicate that levofloxacin is neither an enzyme inducer or inhibitor in the human therapeutic plasma concentration range; therefore, no drug metabolizing enzyme-related interactions with other drugs or agents are anticipated.

REFERENCES

1. National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically Sixth Edition. Approved Standard NCCLS Document M7-A6, Vol. 23, No. 2, NCCLS, Wayne, PA, January, 2003.

2. National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Disk Susceptibility Tests Eighth Edition.

Approved Standard NCCLS Document M2-A8, Vol. 23, No. 1, NCCLS, Wayne, PA, January, 2003.

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