LEVAQUIN 500 MG Oral Tablet
DRUG INTERACTIONS
7 Interacting Drug Interaction Multivalent cation-containing products including antacids, metal cations or didanosine Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products.
Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1) Warfarin Effect may be enhanced.
Monitor prothrombin time, INR, watch for bleeding (7.2) Antidiabetic agents Carefully monitor blood glucose (5.10, 7.3) 7.1 Chelation Agents: Antacids, Sucralfate, Metal Cations, Multivitamins LEVAQUIN® Tablets and Oral Solution While the chelation by divalent cations is less marked than with other fluoroquinolones, concurrent administration of LEVAQUIN® Tablets and Oral Solution with antacids containing magnesium, or aluminum, as well as sucralfate, metal cations such as iron, and multivitamin preparations with zinc may interfere with the gastrointestinal absorption of levofloxacin, resulting in systemic levels considerably lower than desired.
Tablets with antacids containing magnesium, aluminum, as well as sucralfate, metal cations such as iron, and multivitamins preparations with zinc or didanosine may substantially interfere with the gastrointestinal absorption of levofloxacin, resulting in systemic levels considerably lower than desired.
These agents should be taken at least two hours before or two hours after oral LEVAQUIN® administration.
LEVAQUIN® Injection There are no data concerning an interaction of intravenous fluoroquinolones with oral antacids, sucralfate, multivitamins, didanosine, or metal cations.
However, no fluoroquinolone should be co-administered with any solution containing multivalent cations, e.g., magnesium, through the same intravenous line [see Dosage and Administration (2.5)].
7.2 Warfarin No significant effect of LEVAQUIN® on the peak plasma concentrations, AUC, and other disposition parameters for R- and S- warfarin was detected in a clinical study involving healthy volunteers.
Similarly, no apparent effect of warfarin on levofloxacin absorption and disposition was observed.
However, there have been reports during the postmarketing experience in patients that LEVAQUIN® enhances the effects of warfarin.
Elevations of the prothrombin time in the setting of concurrent warfarin and LEVAQUIN® use have been associated with episodes of bleeding.
Prothrombin time, International Normalized Ratio (INR), or other suitable anticoagulation tests should be closely monitored if LEVAQUIN® is administered concomitantly with warfarin.
Patients should also be monitored for evidence of bleeding [see Adverse Reactions (6.3); Patient Counseling Information (17.4)].
7.3 Antidiabetic Agents Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with fluoroquinolones and an antidiabetic agent.
Therefore, careful monitoring of blood glucose is recommended when these agents are co-administered [see Warnings and Precautions (5.10); Adverse Reactions (6.2), Patient Counseling Information (17.4)].
7.4 Non-Steroidal Anti-Inflammatory Drugs The concomitant administration of a non-steroidal anti-inflammatory drug with a fluoroquinolone, including LEVAQUIN®, may increase the risk of CNS stimulation and convulsive seizures [see Warnings and Precautions (5.5)].
7.5 Theophylline No significant effect of LEVAQUIN® on the plasma concentrations, AUC, and other disposition parameters for theophylline was detected in a clinical study involving healthy volunteers.
Similarly, no apparent effect of theophylline on levofloxacin absorption and disposition was observed.
However, concomitant administration of other fluoroquinolones with theophylline has resulted in prolonged elimination half-life, elevated serum theophylline levels, and a subsequent increase in the risk of theophylline-related adverse reactions in the patient population.
Therefore, theophylline levels should be closely monitored and appropriate dosage adjustments made when LEVAQUIN® is co-administered.
Adverse reactions, including seizures, may occur with or without an elevation in serum theophylline levels [see Warnings and Precautions (5.5)].
7.6 Cyclosporine No significant effect of LEVAQUIN® on the peak plasma concentrations, AUC, and other disposition parameters for cyclosporine was detected in a clinical study involving healthy volunteers.
However, elevated serum levels of cyclosporine have been reported in the patient population when co-administered with some other fluoroquinolones.
Levofloxacin Cmax and ke were slightly lower while Tmax and t½ were slightly longer in the presence of cyclosporine than those observed in other studies without concomitant medication.
The differences, however, are not considered to be clinically significant.
Therefore, no dosage adjustment is required for LEVAQUIN® or cyclosporine when administered concomitantly.
7.7 Digoxin No significant effect of LEVAQUIN® on the peak plasma concentrations, AUC, and other disposition parameters for digoxin was detected in a clinical study involving healthy volunteers.
Levofloxacin absorption and disposition kinetics were similar in the presence or absence of digoxin.
Therefore, no dosage adjustment for LEVAQUIN® or digoxin is required when administered concomitantly.
7.8 Probenecid and Cimetidine No significant effect of probenecid or cimetidine on the Cmax of levofloxacin was observed in a clinical study involving healthy volunteers.
The AUC and t½ of levofloxacin were higher while CL/F and CLR were lower during concomitant treatment of LEVAQUIN® with probenecid or cimetidine compared to LEVAQUIN® alone.
However, these changes do not warrant dosage adjustment for LEVAQUIN® when probenecid or cimetidine is co-administered.
7.9 Interactions with Laboratory or Diagnostic Testing Some fluoroquinolones, including LEVAQUIN®, may produce false-positive urine screening results for opiates using commercially available immunoassay kits.
Confirmation of positive opiate screens by more specific methods may be necessary.
OVERDOSAGE
10 In the event of an acute overdosage, the stomach should be emptied.
The patient should be observed and appropriate hydration maintained.
Levofloxacin is not efficiently removed by hemodialysis or peritoneal dialysis.
LEVAQUIN® exhibits a low potential for acute toxicity.
Mice, rats, dogs and monkeys exhibited the following clinical signs after receiving a single high dose of LEVAQUIN®: ataxia, ptosis, decreased locomotor activity, dyspnea, prostration, tremors, and convulsions.
Doses in excess of 1500 mg/kg orally and 250 mg/kg IV produced significant mortality in rodents.
DESCRIPTION
11 LEVAQUIN® is a synthetic broad-spectrum antibacterial agent for oral and intravenous administration.
Chemically, levofloxacin, a chiral fluorinated carboxyquinolone, is the pure (-)-(S)-enantiomer of the racemic drug substance ofloxacin.
The chemical name is (-)-(S)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid hemihydrate.
Figure 1: The Chemical Structure of Levofloxacin The empirical formula is C18H20FN3O4 • ½ H2O and the molecular weight is 370.38.
Levofloxacin is a light yellowish-white to yellow-white crystal or crystalline powder.
The molecule exists as a zwitterion at the pH conditions in the small intestine.
The data demonstrate that from pH 0.6 to 5.8, the solubility of levofloxacin is essentially constant (approximately 100 mg/mL).
Levofloxacin is considered soluble to freely soluble in this pH range, as defined by USP nomenclature.
Above pH 5.8, the solubility increases rapidly to its maximum at pH 6.7 (272 mg/mL) and is considered freely soluble in this range.
Above pH 6.7, the solubility decreases and reaches a minimum value (about 50 mg/mL) at a pH of approximately 6.9.
Levofloxacin has the potential to form stable coordination compounds with many metal ions.
This in vitro chelation potential has the following formation order: Al+3>Cu+2>Zn+2>Mg+2>Ca+2.
Excipients and Description of Dosage Forms LEVAQUIN® Tablets LEVAQUIN® Tablets are available as film-coated tablets and contain the following inactive ingredients: •250 mg (as expressed in the anhydrous form): hypromellose, crospovidone, microcrystalline cellulose, magnesium stearate, polyethylene glycol, titanium dioxide, polysorbate 80 and synthetic red iron oxide.
•500 mg (as expressed in the anhydrous form): hypromellose, crospovidone, microcrystalline cellulose, magnesium stearate, polyethylene glycol, titanium dioxide, polysorbate 80 and synthetic red and yellow iron oxides.
•750 mg (as expressed in the anhydrous form): hypromellose, crospovidone, microcrystalline cellulose, magnesium stearate, polyethylene glycol, titanium dioxide, polysorbate 80.
LEVAQUIN® Oral Solution LEVAQUIN® Oral Solution, 25 mg/mL, is a multi-use self-preserving aqueous solution of levofloxacin with pH ranging from 5.0 – 6.0.
The appearance of LEVAQUIN® Oral Solution may range from clear yellow to clear greenish-yellow.
This does not adversely affect product potency.
LEVAQUIN® Oral Solution contains the following inactive ingredients: sucrose, glycerin, sucralose, hydrochloric acid, purified water, propylene glycol, artificial and natural flavors, benzyl alcohol, ascorbic acid, and caramel color.
It may also contain a solution of sodium hydroxide for pH adjustment.
LEVAQUIN® Injection The appearance of LEVAQUIN® Injection may range from a clear yellow to a greenish-yellow solution.
This does not adversely affect product potency.
LEVAQUIN ® Injection in Single-Use Vials is a sterile, preservative-free aqueous solution of levofloxacin in Water for Injection, with pH ranging from 3.8 to 5.8.
LEVAQUIN ® Injection Premix in Single-Use Flexible Containers is a sterile, preservative-free aqueous solution of levofloxacin with pH ranging from 3.8 to 5.8.
This is a dilute, non-pyrogenic, nearly isotonic premixed solution that contains levofloxacin in 5% Dextrose (D5W).
Solutions of hydrochloric acid and sodium hydroxide may have been added to adjust the pH.
The flexible container is fabricated from a specially formulated non-plasticized, thermoplastic copolyester (CR3).
The amount of water that can permeate from the container into the overwrap is insufficient to affect the solution significantly.
Solutions in contact with the flexible container can leach out certain of the container’s chemical components in very small amounts within the expiration period.
The suitability of the container material has been confirmed by tests in animals according to USP biological tests for plastic containers.
Chemical Structure
CLINICAL STUDIES
14 14.1 Nosocomial Pneumonia Adult patients with clinically and radiologically documented nosocomial pneumonia were enrolled in a multicenter, randomized, open-label study comparing intravenous LEVAQUIN® (750 mg once daily) followed by oral LEVAQUIN® (750 mg once daily) for a total of 7–15 days to intravenous imipenem/cilastatin (500–1000 mg every 6–8 hours daily) followed by oral ciprofloxacin (750 mg every 12 hours daily) for a total of 7–15 days.
LEVAQUIN®-treated patients received an average of 7 days of intravenous 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 LEVAQUIN® arm and 53 of 94 (56.4%) patients in the comparator arm.
The average duration of adjunctive therapy was 7 days in the LEVAQUIN® 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 LEVAQUIN® 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 LEVAQUIN® 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 LEVAQUIN® and 60.6% for comparator.
The 95% CI for the difference of response rates (LEVAQUIN® minus comparator) was [-17.2, 12.0].
The microbiological eradication rates at the posttherapy visit were 66.7% for LEVAQUIN® and 60.6% for comparator.
The 95% CI for the difference of eradication rates (LEVAQUIN® minus comparator) was [-8.3, 20.3].
Clinical success and microbiological eradication rates by pathogen are detailed in Table 13.
Table 13: Clinical Success Rates and Microbiological Eradication Rates (Nosocomial Pneumonia) Pathogen N LEVAQUIN® No.
(%) of Patients Microbiologic/Clinical Outcomes N Imipenem/Cilastatin No.
(%) of Patients Microbiologic/Clinical Outcomes MSSAMethicillin-susceptible S.
aureus 21 14 (66.7)/13 (61.9) 19 13 (68.4)/15 (78.9) P.
aeruginosa See above text for use of combination therapy 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 The observed differences in rates for the clinical and microbiological outcomes may reflect other factors that were not accounted for in the study 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) 14.2 Community-Acquired Pneumonia: 7–14 day Treatment Regimen Adult inpatients and outpatients with a diagnosis of community-acquired bacterial pneumonia were evaluated in 2 pivotal clinical studies.
In the first study, 590 patients were enrolled in a prospective, multi-center, unblinded randomized trial comparing LEVAQUIN® 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 LEVAQUIN® 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 (LEVAQUIN® minus comparator) was [-6, 19].
In the second study, 264 patients were enrolled in a prospective, multi-center, non-comparative trial of 500 mg LEVAQUIN® 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 Chlamydophila pneumoniae, Mycoplasma pneumoniae, and Legionella pneumophila were 96%, 96%, and 70%, respectively.
Microbiologic eradication rates across both studies are presented in Table 14.
Table 14: Microbiologic Eradication Rates Across 2 Community Acquired Pneumonia Clinical Studies 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 Community-Acquired Pneumonia Due to Multi-Drug Resistant Streptococcus pneumoniae LEVAQUIN® was effective for the treatment of community-acquired pneumonia caused by multi-drug resistant Streptococcus pneumoniae (MDRSP).
MDRSP isolates are strains resistant to two or more of the following antibacterials: penicillin (MIC ≥2 mcg/ml), 2nd generation cephalosporins (e.g., cefuroxime, macrolides, tetracyclines and trimethoprim/sulfamethoxazole).
Of 40 microbiologically evaluable patients with MDRSP isolates, 38 patients (95.0%) achieved clinical and bacteriologic success at post-therapy.
The clinical and bacterial success rates are shown in Table 15.
Table 15: Clinical and Bacterial Success Rates for LEVAQUIN®-Treated MDRSP in Community Acquired Pneumonia Patients (Population Valid for Efficacy) Screening Susceptibility Clinical Success Bacteriological Success One patient had a respiratory isolate that was resistant to tetracycline, cefuroxime, macrolides and TMP/SMX and intermediate to penicillin and a blood isolate that was intermediate to penicillin and cefuroxime and resistant to the other classes.
The patient is included in the database based on respiratory isolate.
n/N n=the number of microbiologically evaluable patients who were clinical successes; N=number of microbiologically evaluable patients in the designated resistance group.
% n/N n=the number of MDRSP isolates eradicated or presumed eradicated in microbiologically evaluable patients; N=number of MDRSP isolates in a designated resistance group.
% Penicillin-resistant 16/17 94.1 16/17 94.1 2nd generation Cephalosporin resistant 31/32 96.9 31/32 96.9 Macrolide-resistant 28/29 96.6 28/29 96.6 Trimethoprim/ Sulfamethoxazole resistant 17/19 89.5 17/19 89.5 Tetracycline-resistant 12/12 100 12/12 100 Not all isolates were resistant to all antimicrobial classes tested.
Success and eradication rates are summarized in Table 16.
Table 16: Clinical Success and Bacteriologic Eradication Rates for Resistant Streptococcus pneumoniae (Community Acquired Pneumonia) Type of Resistance Clinical Success Bacteriologic Eradication Resistant to 2 antibacterials 17/18 (94.4%) 17/18 (94.4%) Resistant to 3 antibacterials 14/15 (93.3%) 14/15 (93.3%) Resistant to 4 antibacterials 7/7 (100%) 7/7 (100%) Resistant to 5 antibacterials 0 0 Bacteremia with MDRSP 8/9 (89%) 8/9 (89%) 14.3 Community-Acquired Pneumonia: 5-Day Treatment Regimen To evaluate the safety and efficacy of higher dose and shorter course of LEVAQUIN®, 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 LEVAQUIN® 750 mg, IV or orally, every day for five days or LEVAQUIN® 500 mg IV or orally, every day for 10 days.
Clinical success rates (cure plus improvement) in the clinically evaluable population were 90.9% in the LEVAQUIN® 750 mg group and 91.1% in the LEVAQUIN® 500 mg group.
The 95% CI for the difference of response rates (LEVAQUIN® 750 minus LEVAQUIN® 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 LEVAQUIN® 750 mg group and 2 out of 147 patients in the LEVAQUIN® 500 mg group.
Given the small numbers observed, the significance of this finding cannot be determined statistically.
The microbiological efficacy of the 5-day regimen was documented for infections listed in Table 17.
Table 17: Microbiological Eradication Rates (Community-Acquired Pneumonia) Penicillin susceptible S.
pneumoniae 19/20 Haemophilus influenzae 12/12 Haemophilus parainfluenzae 10/10 Mycoplasma pneumoniae 26/27 Chlamydophila pneumoniae 13/15 14.4 Acute Bacterial Sinusitis: 5-day and 10–14 day Treatment Regimens LEVAQUIN® is approved for the treatment of acute bacterial sinusitis (ABS) using either 750 mg by mouth × 5 days or 500 mg by mouth once daily × 10–14 days.
To evaluate the safety and efficacy of a high dose short course of LEVAQUIN®, 780 outpatient adults with clinically and radiologically determined acute bacterial sinusitis were evaluated in a double-blind, randomized, prospective, multicenter study comparing LEVAQUIN® 750 mg by mouth once daily for five days to LEVAQUIN® 500 mg by mouth once daily for 10 days.
Clinical success rates (defined as complete or partial resolution of the pre-treatment signs and symptoms of ABS to such an extent that no further antibiotic treatment was deemed necessary) in the microbiologically evaluable population were 91.4% (139/152) in the LEVAQUIN® 750 mg group and 88.6% (132/149) in the LEVAQUIN® 500 mg group at the test-of-cure (TOC) visit (95% CI [-4.2, 10.0] for LEVAQUIN® 750 mg minus LEVAQUIN® 500 mg).
Rates of clinical success by pathogen in the microbiologically evaluable population who had specimens obtained by antral tap at study entry showed comparable results for the five- and ten-day regimens at the test-of-cure visit 22 days post treatment.
Table 18: Clinical Success Rate by Pathogen at the TOC in Microbiologically Evaluable Subjects Who Underwent Antral Puncture (Acute Bacterial Sinusitis) Pathogen LEVAQUIN® 750 mg × 5 days LEVAQUIN® 500 mg × 10 days Streptococcus pneumoniae Note: Forty percent of the subjects in this trial had specimens obtained by sinus endoscopy.
The efficacy data for subjects whose specimen was obtained endoscopically were comparable to those presented in the above table 25/27 (92.6%) 26/27 (96.3%) Haemophilus influenzae 19/21 (90.5%) 25/27 (92.6%) Moraxella catarrhalis 10/11 (90.9%) 13/13 (100%) 14.5 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 LEVAQUIN® 750 mg once daily (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 LEVAQUIN® and comparator groups.
Surgery (incision and drainage or debridement) was performed on 45% of the LEVAQUIN®-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 completion of study drug, overall success rates (improved or cured) were 116/138 (84.1%) for patients treated with LEVAQUIN® 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.
14.6 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 LEVAQUIN® 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 microbiologically evaluable patients were enrolled in the LEVAQUIN® and ciprofloxacin groups, respectively.
The microbiologic eradication rate by patient infection at 5–18 days after completion of therapy was 75.0% in the LEVAQUIN® group and 76.8% in the ciprofloxacin group (95% CI [-12.58, 8.98] for LEVAQUIN® minus ciprofloxacin).
The overall eradication rates for pathogens of interest are presented in Table 19.
Table 19: Microbiological Eradication Rates (Chronic Bacterial Prostatitis) LEVAQUIN® (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 Eradication rates shown are for patients who had a sole pathogen only; mixed cultures were excluded.
11 9 (81.8%) 14 11 (78.6%) 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 antibiotic therapy) rates in microbiologically evaluable population 5–18 days after completion of therapy were 75.0% for LEVAQUIN®-treated patients and 72.8% for ciprofloxacin-treated patients (95% CI [-8.87, 13.27] for LEVAQUIN® minus ciprofloxacin).
Clinical long-term success (24–45 days after completion of therapy) rates were 66.7% for the LEVAQUIN®-treated patients and 76.9% for the ciprofloxacin-treated patients (95% CI [-23.40, 2.89] for LEVAQUIN® minus ciprofloxacin).
14.7 Complicated Urinary Tract Infections and Acute Pyelonephritis: 5-day Treatment Regimen To evaluate the safety and efficacy of the higher dose and shorter course of LEVAQUIN®, 1109 patients with cUTI and AP were enrolled in a randomized, double-blind, multicenter clinical trial conducted in the US from November 2004 to April 2006 comparing LEVAQUIN® 750 mg IV or orally once daily for 5 days (546 patients) with ciprofloxacin 400 mg IV or 500 mg orally twice daily for 10 days (563 patients).
Patients with AP complicated by underlying renal diseases or conditions such as complete obstruction, surgery, transplantation, concurrent infection or congenital malformation were excluded.
Efficacy was measured by bacteriologic eradication of the baseline organism(s) at the post-therapy visit in patients with a pathogen identified at baseline.
The post-therapy (test-of-cure) visit occurred 10 to 14 days after the last active dose of LEVAQUIN® and 5 to 9 days after the last dose of active ciprofloxacin.
The bacteriologic cure rates overall for LEVAQUIN® and control at the test-of-cure (TOC) visit for the group of all patients with a documented pathogen at baseline (modified intent to treat or mITT) and the group of patients in the mITT population who closely followed the protocol (Microbiologically Evaluable) are summarized in Table 20.
Table 20: Bacteriologic Eradication at Test-of-Cure LEVAQUIN® 750 mg orally or IV once daily for 5 days Ciprofloxacin 400 mg IV/500 mg orally twice daily for 10 days Overall Difference [95% CI] n/N % n/N % LEVAQUIN®-Ciprofloxacin mITT Population The mITT population included patients who received study medication and who had a positive (≥105 CFU/mL) urine culture with no more than 2 uropathogens at baseline.
Patients with missing response were counted as failures in this analysis.
Overall (cUTI or AP) 252/333 75.7 239/318 75.2 0.5 (-6.1, 7.1) cUTI 168/230 73.0 157/213 73.7 AP 84/103 81.6 82/105 78.1 Microbiologically Evaluable Population The Microbiologically Evaluable population included patients with a confirmed diagnosis of cUTI or AP, a causative organism(s) at baseline present at ≥ 105 CFU/mL, a valid test-of-cure urine culture, no pathogen isolated from blood resistant to study drug, no premature discontinuation or loss to follow-up, and compliance with treatment (among other criteria).
Overall (cUTI or AP) 228/265 86.0 215/241 89.2 -3.2 [-8.9, 2.5] cUTI 154/185 83.2 144/165 87.3 AP 74/80 92.5 71/76 93.4 Microbiologic eradication rates in the Microbiologically Evaluable population at TOC for individual pathogens recovered from patients randomized to LEVAQUIN® treatment are presented in Table 21.
Table 21: Microbiological Eradication Rates for Individual Pathogens Recovered From Patients Randomized to LEVAQUIN® 750 mg QD for 5 Days Treatment Pathogen Microbiologic Eradication Rate (n/N) % Escherichia coli The predominant organism isolated from patients with AP was E.
coli: 91% (63/69) eradication in AP and 89% (92/103) in patients with cUTI.
155/172 90 Klebsiella pneumoniae 20/23 87 Proteus mirabilis 12/12 100 14.8 Complicated Urinary Tract Infections and Acute Pyelonephritis: 10-day Treatment Regimen To evaluate the safety and efficacy of the 250 mg dose, 10 day regimen of LEVAQUIN®, 567 patients with uncomplicated UTI, mild-to-moderate cUTI, and mild-to-moderate AP were enrolled in a randomized, double-blind, multicenter clinical trial conducted in the US from June 1993 to January 1995 comparing LEVAQUIN® 250 orally once daily for 10 days (285 patients) with ciprofloxacin 500 mg orally twice daily for 10 days (282 patients).
Patients with a resistant pathogen, recurrent UTI, women over age 55 years, and with an indwelling catheter were initially excluded, prior to protocol amendment which took place after 30% of enrollment.
Microbiological efficacy was measured by bacteriologic eradication of the baseline organism(s) at 1–12 days post-therapy in patients with a pathogen identified at baseline.
The bacteriologic cure rates overall for LEVAQUIN® and control at the test-of-cure (TOC) visit for the group of all patients with a documented pathogen at baseline (modified intent to treat or mITT) and the group of patients in the mITT population who closely followed the protocol (Microbiologically Evaluable) are summarized in Table 22.
Table 22.
Bacteriologic Eradication Overall (cUTI or AP) at Test-Of-Cure1–9 days posttherapy for 30% of subjects enrolled prior to a protocol amendment; 5–12 days posttherapy for 70% of subjects.
LEVAQUIN® 250 mg once daily for 10 days Ciprofloxacin 500 mg twice daily for 10 days n/N % n/N % mITT Population The mITT population included patients who had a pathogen isolated at baseline.
Patients with missing response were counted as failures in this analysis.
174/209 83.3 184/219 84.0 Microbiologically Evaluable Population The Microbiologically Evaluable population included mITT patients who met protocol-specified evaluability criteria.
164/177 92.7 159/171 93.0 14.9 Inhalational Anthrax (Post-Exposure) The effectiveness of LEVAQUIN® for this indication is based on plasma concentrations achieved in humans, a surrogate endpoint reasonably likely to predict clinical benefit.
LEVAQUIN® has not been tested in humans for the post-exposure prevention of inhalation anthrax.
The mean plasma concentrations of LEVAQUIN® associated with a statistically significant improvement in survival over placebo in the rhesus monkey model of inhalational anthrax are reached or exceeded in adult and pediatric patients receiving the recommended oral and intravenous dosage regimens [see Indications and Usage (1.13); Dosage and Administration (2.1), (2.2)].
Levofloxacin pharmacokinetics have been evaluated in adult and pediatric patients.
The mean (± SD) steady state peak plasma concentration in human adults receiving 500 mg orally or intravenously once daily is 5.7 ± 1.4 and 6.4 ± 0.8 mcg/mL, respectively; and the corresponding total plasma exposure (AUC0–24) is 47.5 ± 6.7 and 54.6 ± 11.1 mcg.h/mL, respectively.
The predicted steady-state pharmacokinetic parameters in pediatric patients ranging in age from 6 months to 17 years receiving 8 mg/kg orally every 12 hours (not to exceed 250 mg per dose) were calculated to be comparable to those observed in adults receiving 500 mg orally once daily [see Clinical Pharmacology (12.3)].
In adults, the safety of LEVAQUIN® for treatment durations of up to 28 days is well characterized.
However, information pertaining to extended use at 500 mg daily up to 60 days is limited.
Prolonged LEVAQUIN® therapy in adults should only be used when the benefit outweighs the risk.
In pediatric patients, the safety of levofloxacin for treatment durations of more than 14 days has not been studied.
An increased incidence of musculoskeletal adverse events (arthralgia, arthritis, tendonopathy, gait abnormality) compared to controls has been observed in clinical studies with treatment duration of up to 14 days.
Long-term safety data, including effects on cartilage, following the administration of levofloxacin to pediatric patients is limited [see Warnings and Precautions (5.9), Use in Specific Populations (8.4)].
A placebo-controlled animal study in rhesus monkeys exposed to an inhaled mean dose of 49 LD50 (~2.7 × 106) spores (range 17 – 118 LD50) of B.
anthracis (Ames strain) was conducted.
The minimal inhibitory concentration (MIC) of levofloxacin for the anthrax strain used in this study was 0.125 mcg/mL.
In the animals studied, mean plasma concentrations of levofloxacin achieved at expected Tmax (1 hour post-dose) following oral dosing to steady state ranged from 2.79 to 4.87 mcg/mL.
Steady state trough concentrations at 24 hours post-dose ranged from 0.107 to 0.164 mcg/mL.
Mean (SD) steady state AUC0–24 was 33.4 ± 3.2 mcg.h/mL (range 30.4 to 36.0 mcg.h/mL).
Mortality due to anthrax for animals that received a 30 day regimen of oral LEVAQUIN® beginning 24 hrs post exposure was significantly lower (1/10), compared to the placebo group (9/10) [P=0.0011, 2-sided Fisher’s Exact Test].
The one levofloxacin treated animal that died of anthrax did so following the 30-day drug administration period.
HOW SUPPLIED
16 /STORAGE AND HANDLING 16.1 LEVAQUIN® Tablets LEVAQUIN® Tablets are supplied as 250, 500, and 750 mg capsule-shaped, coated tablets.
LEVAQUIN® Tablets are packaged in bottles and in unit-dose blister strips in the following configurations: •250 mg tablets are terra cotta pink and are imprinted: “LEVAQUIN” on one side and “250” on the other side.
•–bottles of 50 (NDC 50458-920-50) •–unit-dose/100 tablets (NDC 50458-920-10) •500 mg tablets are peach and are imprinted: “LEVAQUIN” on one side and “500” on the other side •–bottles of 50 (NDC 50458-925-50) •–unit-dose/100 tablets (NDC 50458-925-10) •750 mg tablets are white and are imprinted “LEVAQUIN” on one side and “750” on the other side •–bottles of 20 (NDC 50458-930-20) •–unit-dose/100 tablets (NDC 50458-930-10) LEVAQUIN® Tablets should be stored at 15° to 30°C (59° to 86°F) in well-closed containers.
LEVAQUIN® Tablets are manufactured for PriCara, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc.
Raritan, NJ 08869 by Janssen Ortho LLC, Gurabo, Puerto Rico 00778.
16.2 LEVAQUIN® Oral Solution LEVAQUIN® Oral Solution is supplied in a 16 oz.
multi-use bottle (NDC 50458-170-01).
Each bottle contains 480 mL of the 25 mg/mL levofloxacin oral solution LEVAQUIN® Oral Solution should be stored at 25°C (77°F); excursions permitted to 15° – 30°C (59° to 86°F) [refer to USP controlled room temperature].
LEVAQUIN® Oral Solution is manufactured for PriCara, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc.
Raritan, NJ 08869 by Janssen Pharmaceutica N.V, Beerse, Belgium.
16.3 LEVAQUIN® Injection, Single-Use Vials LEVAQUIN® Injection is supplied in single-use vials.
Each vial contains a concentrated solution with the equivalent 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 50458-164-20) •25 mg/mL, 30 mL vials (NDC 50458-165-30) 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 Ortho-McNeil, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc.
Raritan, NJ 08869 by Janssen Pharmaceutica N.V., Beerse, Belgium.
16.4 LEVAQUIN® Injection Pre-Mixed Solution, Single-Use in Flexible Container 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 (D5W).
•5 mg/mL (250 mg), 100 mL flexible container, 50 mL fill (NDC 50458-167-01) •5 mg/mL (500 mg), 100 mL flexible container, 100 mL fill (NDC 50458-168-01) •5 mg/mL (750 mg), 150 mL flexible container, 150 mL fill (NDC 50458-166-01) 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 Ortho-McNeil, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc.
Raritan, NJ 08869 by Hospira, Inc., Lake Forest, IL 60045.
RECENT MAJOR CHANGES
Warnings and Precautions •Tendinopathy and Tendon Rupture (5.1) 9/2008
GERIATRIC USE
8.5 Geriatric Use Geriatric patients are at increased risk for developing severe tendon disorders including tendon rupture when being treated with a fluoroquinolone such as LEVAQUIN®.
This risk is further increased in patients receiving concomitant corticosteroid therapy.
Tendinitis or tendon rupture can involve the Achilles, hand, shoulder, or other tendon sites and can occur during or after completion of therapy; cases occurring up to several months after fluoroquinolone treatment have been reported.
Caution should be used when prescribing LEVAQUIN® to elderly patients especially those on corticosteroids.
Patients should be informed of this potential side effect and advised to discontinue LEVAQUIN® and contact their healthcare provider if any symptoms of tendinitis or tendon rupture occur [see Boxed Warning; Warnings and Precautions (5.1); and Adverse Reactions (6.3)].
In phase 3 clinical trials, 1,945 LEVAQUIN®-treated patients (26%) were ≥ 65 years of age.
Of these, 1,081 patients (14%) were between the ages of 65 and 74 and 864 patients (12%) were 75 years or older.
No overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.
Severe, and sometimes fatal, cases of hepatotoxicity have been reported post-marketing in association with LEVAQUIN®.
The majority of fatal hepatotoxicity reports occurred in patients 65 years of age or older and most were not associated with hypersensitivity.
LEVAQUIN® should be discontinued immediately if the patient develops signs and symptoms of hepatitis [see Warnings and Precautions (5.4)].
Elderly patients may be more susceptible to drug-associated effects on the QT interval.
Therefore, precaution should be taken when using LEVAQUIN® with concomitant drugs that can result in prolongation of the QT interval (e.g., Class IA or Class III antiarrhythmics) or in patients with risk factors for torsade de pointes (e.g., known QT prolongation, uncorrected hypokalemia) [see Warnings and Precautions (5.8)].
The pharmacokinetic properties of levofloxacin in younger adults and elderly adults do not differ significantly when creatinine clearance is taken into consideration.
However, since the drug is known to be substantially excreted by the kidney, the risk of toxic reactions to this drug may be greater in patients with impaired renal function.
Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [see Clinical Pharmacology (12.3)].
DOSAGE FORMS AND STRENGTHS
3 TABLETS, Film-coated, capsule-shaped •250 mg terra cotta pink tablets, imprinted with “250” on one side and “LEVAQUIN” on the other •500 mg peach tablets, imprinted with “500” on one side and “LEVAQUIN” on the other •750 mg white tablets, imprinted with “750” on one side and “LEVAQUIN” on the other ORAL SOLUTION, 25mg/mL, clear yellow to clear greenish-yellow color INJECTION, Single-Use Vials of concentrated solution for dilution for intravenous infusion, clear yellow to clear greenish-yellow in appearance •20 mL vial of 25 mg/mL levofloxacin solution, equivalent to 500 mg of levofloxacin •30 mL vial of 25 mg/mL levofloxacin solution, equivalent to 750 mg of levofloxacin INJECTION (5 mg/mL in 5% Dextrose) Premix in Single-Use Flexible Containers, for intravenous infusion •100 mL container, fill volume 50 mL (equivalent of 250 mg levofloxacin) •100 mL container, fill volume 100 mL (equivalent of 500 mg levofloxacin) •150 mL container, fill volume 150 mL (equivalent of 750 mg levofloxacin) Formulation (3) Strength Tablets 250 mg, 500 mg, and 750 mg Oral Solution 25 mg/mL Injection: single-use vials for dilution 500 mg in 20 mL 750 mg in 30 mL Injection: premix single-use flexible containers 250 mg in 50 mL 500 mg in 100 mL 750 mg in 150 mL
MECHANISM OF ACTION
12.1 Mechanism of Action Levofloxacin is a member of the fluoroquinolone class of antibacterial agents [see Clinical Pharmacology (12.4)].
INDICATIONS AND USAGE
1 To reduce the development of drug-resistant bacteria and maintain the effectiveness of LEVAQUIN® and other antibacterial drugs, LEVAQUIN® 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.
LEVAQUIN® Tablets/Injection and Oral Solution are indicated for the treatment of adults (≥18 years of age) with mild, moderate, and severe infections caused by susceptible strains of the designated microorganisms in the conditions listed in this section.
LEVAQUIN® Injection is indicated when intravenous administration offers a route of administration advantageous to the patient (e.g., patient cannot tolerate an oral dosage form).
LEVAQUIN® is a fluoroquinolone antibacterial indicated in adults (≥18 years of age) with infections caused by designated, susceptible bacteria (1, 12.4).
•Pneumonia: nosocomial (1.1) and community acquired (1.2, 1.3) •Acute bacterial sinusitis (1.4) •Acute bacterial exacerbation of chronic bronchitis (1.5) •Skin and skin structure infections: complicated (1.6) and uncomplicated (1.7) •Chronic bacterial prostatitis (1.8) •Urinary tract infections: complicated (1.9, 1.10) and uncomplicated (1.12) •Acute pyelonephritis (1.11) •Inhalational anthrax, post-exposure (1.13).
Not tested in humans for post-exposure prevention of inhalational anthrax; plasma concentrations are likely to predict efficacy (14.9) Culture and susceptibility testing Appropriate culture and susceptibility tests should be performed before treatment in order to isolate and identify organisms causing the infection and to determine their susceptibility to levofloxacin [see Clinical Pharmacology (12.4)].
Therapy with LEVAQUIN® may be initiated before results of these tests are known; once results become available, appropriate therapy should be selected.
As with other drugs in this class, some strains of Pseudomonas aeruginosa may develop resistance fairly rapidly during treatment with LEVAQUIN®.
Culture and susceptibility testing performed periodically during therapy will provide information about the continued susceptibility of the pathogens to the antimicrobial agent and also the possible emergence of bacterial resistance.
1.1 Nosocomial Pneumonia LEVAQUIN® is indicated for the treatment of nosocomial pneumonia due to methicillin-susceptible Staphylococcus aureus, Pseudomonas aeruginosa, Serratia marcescens, Escherichia coli, Klebsiella pneumoniae, Haemophilus influenzae, or Streptococcus pneumoniae.
Adjunctive therapy should be used as clinically indicated.
Where Pseudomonas aeruginosa is a documented or presumptive pathogen, combination therapy with an anti-pseudomonal β-lactam is recommended [see Clinical Studies (14.1)].
1.2 Community-Acquired Pneumonia: 7–14 day Treatment Regimen LEVAQUIN® is indicated for the treatment of community-acquired pneumonia due to methicillin-susceptible Staphylococcus aureus, Streptococcus pneumoniae (including multi-drug-resistant Streptococcus pneumoniae [MDRSP]), Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Moraxella catarrhalis, Chlamydophila pneumoniae, Legionella pneumophila, or Mycoplasma pneumoniae [see Dosage and Administration (2.1) and Clinical Studies (14.2)].
MDRSP isolates are strains resistant to two or more of the following antibacterials: penicillin (MIC ≥2mcg/mL), 2nd generation cephalosporins, e.g., cefuroxime, macrolides, tetracyclines and trimethoprim/sulfamethoxazole.
1.3 Community-Acquired Pneumonia: 5-day Treatment Regimen LEVAQUIN® is indicated for the treatment of community-acquired pneumonia due to Streptococcus pneumoniae (excluding multi-drug-resistant strains [MDRSP]), Haemophilus influenzae, Haemophilus parainfluenzae, Mycoplasma pneumoniae, or Chlamydophila pneumoniae [see Dosage and Administration (2.1) and Clinical Studies (14.3)].
1.4 Acute Bacterial Sinusitis: 5-day and 10–14 day Treatment Regimens LEVAQUIN® is indicated for the treatment of acute bacterial sinusitis due to Streptococcus pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis [see Clinical Studies (14.4)].
1.5 Acute Bacterial Exacerbation of Chronic Bronchitis LEVAQUIN® is indicated for the treatment of acute bacterial exacerbation of chronic bronchitis due to methicillin-susceptible Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, Haemophilus parainfluenzae, or Moraxella catarrhalis.
1.6 Complicated Skin and Skin Structure Infections LEVAQUIN® is indicated for the treatment of complicated skin and skin structure infections due to methicillin-susceptible Staphylococcus aureus, Enterococcus faecalis, Streptococcus pyogenes, or Proteus mirabilis [see Clinical Studies (14.5)].
1.7 Uncomplicated Skin and Skin Structure Infections LEVAQUIN® is indicated for the treatment of uncomplicated skin and skin structure infections (mild to moderate) including abscesses, cellulitis, furuncles, impetigo, pyoderma, wound infections, due to methicillin-susceptible Staphylococcus aureus, or Streptococcus pyogenes.
1.8 Chronic Bacterial Prostatitis LEVAQUIN® is indicated for the treatment of chronic bacterial prostatitis due to Escherichia coli, Enterococcus faecalis, or methicillin-susceptible Staphylococcus epidermidis [see Clinical Studies (14.6)].
1.9 Complicated Urinary Tract Infections: 5-day Treatment Regimen LEVAQUIN® is indicated for the treatment of complicated urinary tract infections due to Escherichia coli, Klebsiella pneumoniae, or Proteus mirabilis [see Clinical Studies (14.7)].
1.10 Complicated Urinary Tract Infections: 10-day Treatment Regimen LEVAQUIN® is indicated for the treatment of complicated urinary tract infections (mild to moderate) due to Enterococcus faecalis, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, or Pseudomonas aeruginosa [see Clinical Studies (14.8)].
1.11 Acute Pyelonephritis: 5 or 10-day Treatment Regimen LEVAQUIN® is indicated for the treatment of acute pyelonephritis caused by Escherichia coli, including cases with concurrent bacteremia [see Clinical Studies (14.7, 14.8)].
1.12 Uncomplicated Urinary Tract Infections LEVAQUIN® is indicated for the treatment of uncomplicated urinary tract infections (mild to moderate) due to Escherichia coli, Klebsiella pneumoniae, or Staphylococcus saprophyticus.
1.13 Inhalational Anthrax (Post-Exposure) LEVAQUIN® is indicated for inhalational anthrax (post-exposure) to reduce the incidence or progression of disease following exposure to aerosolized Bacillus anthracis.
The effectiveness of LEVAQUIN® is based on plasma concentrations achieved in humans, a surrogate marker considered likely to predict clinical benefit.
LEVAQUIN® has not been tested in humans for the post-exposure prevention of inhalation anthrax.
The safety of LEVAQUIN® in adults for durations of therapy beyond 28 days or in pediatric patients for durations of therapy beyond 14 days has not been studied.
Prolonged LEVAQUIN® therapy in adults should only be used when the benefit outweighs the risk [see Dosage and Administration (2.1), (2.2) and Clinical Studies (14.9)].
PEDIATRIC USE
8.4 Pediatric Use Quinolones, including levofloxacin, cause arthropathy and osteochondrosis in juvenile animals of several species.
[see Warnings and Precautions (5.9) and Animal Toxicology and/or Pharmacology (13.2)].
Inhalational Anthrax (Post-Exposure) Levofloxacin is indicated in pediatric patients for inhalational anthrax (post-exposure).
The risk-benefit assessment indicates that administration of levofloxacin to pediatric patients is appropriate.
The safety of levofloxacin in pediatric patients treated for more than 14 days has not been studied.
The pharmacokinetics of levofloxacin following a single intravenous dose were investigated in pediatric patients ranging in age from six months to 16 years.
Pediatric patients cleared levofloxacin faster than adult patients resulting in lower plasma exposures than adults for a given mg/kg dose [see Indications and Usage (1.13), Dosage and Administration (2.2), Clinical Pharmacology (12.3) and Clinical Studies (14.9)].
Adverse Events In clinical trials, 1534 children (6 months to 16 years of age) were treated with oral and intravenous LEVAQUIN®.
Children 6 months to 5 years of age received LEVAQUIN® 10 mg/kg twice a day and children greater than 5 years of age received 10 mg/kg once a day (maximum 500 mg per day) for approximately 10 days.
A subset of children in the clinical trials (1340 LEVAQUIN®-treated and 893 non-fluoroquinolone-treated) enrolled in a prospective, long-term surveillance study to assess the incidence of protocol-defined musculoskeletal disorders (arthralgia, arthritis, tendonopathy, gait abnormality) during 60 days and 1 year following the first dose of study drug.
Children treated with LEVAQUIN® had a significantly higher incidence of musculoskeletal disorders when compared to the non-fluoroquinolone-treated children as illustrated in Table 9.
Table 9: Incidence of Musculoskeletal Disorders in Pediatric Clinical Trial Follow-up Period LEVAQUIN® N = 1340 Non-Fluoroquinolone Non-Fluoroquinolone: ceftriaxone, amoxicillin/ clavulanate, clarithromycin N = 893 p-value 2-sided Fisher’s Exact Test 60 days 28 (2.1%) 8 (0.9%) p = 0.038 1 year There were 1199 LEVAQUIN ® -treated and 804 non-fluoroquinolone-treated children who had a one-year evaluation visit.
However, the incidence of musculoskeletal disorders were calculated using all reported events during the specified period for all children enrolled regardless of whether they completed the 1-year evaluation visit.
46 (3.4%) 16 (1.8%) p = 0.025 Arthralgia was the most frequently occurring musculoskeletal disorder in both treatment groups.
Most of the musculoskeletal disorders in both groups involved multiple weight-bearing joints.
Disorders were moderate in 8/46 (17%) children and mild in 35/46 (76%) LEVAQUIN®-treated children and most were treated with analgesics.
The median time to resolution was 7 days for LEVAQUIN®-treated children and 9 for non-fluoroquinolone-treated children (approximately 80% resolved within 2 months in both groups).
No child had a severe or serious disorder and all musculoskeletal disorders resolved without sequelae.
Vomiting and diarrhea were the most frequently reported adverse events, occurring in similar frequency in the LEVAQUIN®-treated and non-fluoroquinolone-treated children.
In addition to the events reported in pediatric patients in clinical trials, events reported in adults during clinical trials or post-marketing experience [see Adverse Reactions (6) ] may also be expected to occur in pediatric patients.
PREGNANCY
8.1 Pregnancy Pregnancy Category C.
Levofloxacin was not teratogenic in rats at oral doses as high as 810 mg/kg/day which corresponds to 9.4 times the highest recommended human dose based upon relative body surface area, or at intravenous doses as high as 160 mg/kg/day corresponding to 1.9 times the highest recommended human dose based upon relative body surface area.
The oral dose of 810 mg/kg/day to rats caused decreased fetal body weight and increased fetal mortality.
No teratogenicity was observed when rabbits were dosed orally as high as 50 mg/kg/day which corresponds to 1.1 times the highest recommended human dose based upon relative body surface area, or when dosed intravenously as high as 25 mg/kg/day, corresponding to 0.5 times the highest recommended human dose based upon relative body surface area.
There are, however, no adequate and well-controlled studies in pregnant women.
LEVAQUIN® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
NUSRING MOTHERS
8.3 Nursing Mothers Based on data on other fluoroquinolones and very limited data on LEVAQUIN®, it can be presumed that levofloxacin will be excreted in human milk.
Because of the potential for serious adverse reactions from LEVAQUIN® in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
BOXED WARNING
Fluoroquinolones, including LEVAQUIN®, are associated with an increased risk of tendinitis and tendon rupture in all ages.
This risk is further increased in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants [See Warnings and Precautions (5.1) ].
Warning: Fluoroquinolones, including LEVAQUIN®, are associated with an increased risk of tendinitis and tendon rupture in all ages.
This risk is further increased in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants [See Warnings and Precautions (5.1) ].
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS •Risk of tendinitis and tendon rupture is increased.
This risk is further increased in older patients usually over 60 years of age, in patients taking corticosteroids, and in patients with kidney, heart or lung transplants.
Discontinue if pain or inflammation in a tendon occurs (5.1, 8.5) •Anaphylactic reactions and allergic skin reactions, serious, occasionally fatal, may occur after first dose (4, 5.2) •Hematologic (including agranulocytosis, thrombocytopenia), and renal toxicities may occur after multiple doses (5.3) •Hepatotoxicity: Severe, and sometimes fatal, hepatoxicity has been reported.
Discontinue immediately if signs and symptoms of hepatitis occur (5.4) •Central nervous system effects, including convulsions, anxiety, confusion, depression, and insomnia may occur after the first dose.
Use with caution in patients with known or suspected disorders that may predispose them to seizures or lower the seizure threshold (5.5) • Clostridium difficile-associated colitis: evaluate if diarrhea occurs (5.6) •Peripheral neuropathy: discontinue if symptoms occur in order to prevent irreversibility (5.7) •Prolongation of the QT interval and isolated cases of torsade de pointes have been reported.
Avoid use in patients with known prolongation, those with hypokalemia, and with other drugs that prolong the QT interval (5.8, 8.5) 5.1 Tendinopathy and Tendon Rupture Fluoroquinolones, including LEVAQUIN®, are associated with an increased risk of tendinitis and tendon rupture in all ages.
This adverse reaction most frequently involves the Achilles tendon, and rupture of the Achilles tendon may require surgical repair.
Tendinitis and tendon rupture in the rotator cuff (the shoulder), the hand, the biceps, the thumb, and other tendon sites have also been reported.
The risk of developing fluoroquinolone-associated tendinitis and tendon rupture is further increased in older patients usually over 60 years of age, in those taking corticosteroid drugs, and in patients with kidney, heart or lung transplants.
Factors, in addition to age and corticosteroid use, that may independently increase the risk of tendon rupture include strenuous physical activity, renal failure, and previous tendon disorders such as rheumatoid arthritis.
Tendinitis and tendon rupture have been reported in patients taking fluoroquinolones who do not have the above risk factors.
Tendon rupture can occur during or after completion of therapy; cases occurring up to several months after completion of therapy have been reported.
LEVAQUIN® should be discontinued if the patient experiences pain, swelling, inflammation or rupture of a tendon.
Patients should be advised to rest at the first sign of tendinitis or tendon rupture, and to contact their healthcare provider regarding changing to a non-quinolone antimicrobial drug.
[see Adverse Reactions (6.3) ; Patient Counseling Information (17.3) ] .
5.2 Hypersensitivity Reactions Serious and occasionally fatal hypersensitivity and/or anaphylactic reactions have been reported in patients receiving therapy with fluoroquinolones, including LEVAQUIN®.
These reactions often occur following the first dose.
Some reactions have been accompanied by cardiovascular collapse, hypotension/shock, seizure, loss of consciousness, tingling, angioedema (including tongue, laryngeal, throat, or facial edema/swelling), airway obstruction (including bronchospasm, shortness of breath, and acute respiratory distress), dyspnea, urticaria, itching, and other serious skin reactions.
LEVAQUIN® should be discontinued immediately at the first appearance of a skin rash or any other sign of hypersensitivity.
Serious acute hypersensitivity reactions may require treatment with epinephrine and other resuscitative measures, including oxygen, intravenous fluids, antihistamines, corticosteroids, pressor amines, and airway management, as clinically indicated [see Adverse Reactions (6); Patient Counseling Information (17.3)].
5.3 Other Serious and Sometimes Fatal Reactions Other serious and sometimes fatal events, some due to hypersensitivity, and some due to uncertain etiology, have been reported rarely in patients receiving therapy with fluoroquinolones, including LEVAQUIN®.
These events may be severe and generally occur following the administration of multiple doses.
Clinical manifestations may include one or more of the following: •fever, rash, or severe dermatologic reactions (e.g., toxic epidermal necrolysis, Stevens-Johnson Syndrome); •vasculitis; arthralgia; myalgia; serum sickness; •allergic pneumonitis; •interstitial nephritis; acute renal insufficiency or failure; •hepatitis; jaundice; acute hepatic necrosis or failure; •anemia, including hemolytic and aplastic; thrombocytopenia, including thrombotic thrombocytopenic purpura; leukopenia; agranulocytosis; pancytopenia; and/or other hematologic abnormalities.
The drug should be discontinued immediately at the first appearance of skin rash, jaundice, or any other sign of hypersensitivity and supportive measures instituted [see Adverse Reactions (6); Patient Counseling Information (17.3)].
5.4 Hepatotoxicity Post-marketing reports of severe hepatotoxicity (including acute hepatitis and fatal events) have been received for patients treated with LEVAQUIN®.
No evidence of serious drug-associated hepatotoxicity was detected in clinical trials of over 7,000 patients.
Severe hepatotoxicity generally occurred within 14 days of initiation of therapy and most cases occurred within 6 days.
Most cases of severe hepatotoxicity were not associated with hypersensitivity [see Warnings and Precautions (5.3)].
The majority of fatal hepatotoxicity reports occurred in patients 65 years of age or older and most were not associated with hypersensitivity.
LEVAQUIN® should be discontinued immediately if the patient develops signs and symptoms of hepatitis [see Adverse Reactions (6); Patient Counseling Information (17.3).]] 5.5 Central Nervous System Effects Convulsions and toxic psychoses have been reported in patients receiving fluoroquinolones, including LEVAQUIN®.
Fluoroquinolones may also cause increased intracranial pressure and central nervous system stimulation which may lead to tremors, restlessness, anxiety, lightheadedness, confusion, hallucinations, paranoia, depression, nightmares, insomnia, and, rarely, suicidal thoughts or acts.
These reactions may occur following the first dose.
If these reactions occur in patients receiving LEVAQUIN®, the drug should be discontinued and appropriate measures instituted.
As with other fluoroquinolones, LEVAQUIN® should be used with caution in patients with a known or suspected central nervous system (CNS) disorder that may predispose them to seizures or lower the seizure threshold (e.g., severe cerebral arteriosclerosis, epilepsy) or in the presence of other risk factors that may predispose them to seizures or lower the seizure threshold (e.g., certain drug therapy, renal dysfunction.) [see Adverse Reactions (6) ; Drug Interactions (7.4, 7.5) ; Patient Counseling Information (17.3)].
5.6 Clostridium difficile-Associated Diarrhea Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including LEVAQUIN®, 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 [see Adverse Reactions (6.2), Patient Counseling Information (17.3)].
5.7 Peripheral Neuropathy Rare cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and weakness have been reported in patients receiving fluoroquinolones, including LEVAQUIN®.
LEVAQUIN® should be discontinued if the patient experiences symptoms of neuropathy including pain, burning, tingling, numbness, and/or weakness or other alterations of sensation including light touch, pain, temperature, position sense, and vibratory sensation in order to prevent the development of an irreversible condition [see Adverse Reactions (6), Patient Counseling Information (17.3)] 5.8 Prolongation of the QT Interval Some fluoroquinolones, including LEVAQUIN®, have been associated with prolongation of the QT interval on the electrocardiogram and infrequent cases of arrhythmia.
Rare cases of torsade de pointes have been spontaneously reported during postmarketing surveillance in patients receiving fluoroquinolones, including LEVAQUIN®.
LEVAQUIN® should be avoided in patients with known prolongation of the QT interval, patients with uncorrected hypokalemia, and patients receiving Class IA (quinidine, procainamide), or Class III (amiodarone, sotalol) antiarrhythmic agents.
Elderly patients may be more susceptible to drug-associated effects on the QT interval [see Adverse Reactions (6.3), Use in Specific Populations (8.5), and Patient Counseling Information (17.3)].
5.9 Musculoskeletal Disorders in Pediatric Patients and Arthropathic Effects in Animals LEVAQUIN® is indicated in pediatric patients (≥6 months of age) only for the prevention of inhalational anthrax (post-exposure) [see Indications and Usage (1.13)].
An increased incidence of musculoskeletal disorders (arthralgia, arthritis, tendonopathy, and gait abnormality) compared to controls has been observed in pediatric patients receiving LEVAQUIN® [see Use in Specific Populations (8.4)].
In immature rats and dogs, the oral and intravenous administration of levofloxacin resulted in increased osteochondrosis.
Histopathological examination of the weight-bearing joints of immature dogs dosed with levofloxacin revealed persistent lesions of the cartilage.
Other quinolones also produce similar erosions in the weight-bearing joints and other signs of arthropathy in immature animals of various species [see Animal Toxicology and/or Pharmacology (13.2)].
5.10 Blood Glucose Disturbances As with other fluoroquinolones, disturbances of blood glucose, including symptomatic hyper- and hypoglycemia, have been reported with LEVAQUIN®, usually in diabetic patients receiving concomitant treatment with an oral hypoglycemic agent (e.g., glyburide) or with insulin.
In these patients, careful monitoring of blood glucose is recommended.
If a hypoglycemic reaction occurs in a patient being treated with LEVAQUIN®, LEVAQUIN® should be discontinued and appropriate therapy should be initiated immediately [see Adverse Reactions (6.2); Drug Interactions (7.3); Patient Counseling Information (17.4)].
5.11 Photosensitivity/Phototoxicity Moderate to severe photosensitivity/phototoxicity reactions, the latter of which may manifest as exaggerated sunburn reactions (e.g., burning, erythema, exudation, vesicles, blistering, edema) involving areas exposed to light (typically the face, “V” area of the neck, extensor surfaces of the forearms, dorsa of the hands), can be associated with the use of fluoroquinolones after sun or UV light exposure.
Therefore, excessive exposure to these sources of light should be avoided.
Drug therapy should be discontinued if photosensitivity/phototoxicity occurs [see Adverse Reactions (6.3); Patient Counseling Information (17.3)].
5.12 Development of Drug Resistant Bacteria Prescribing LEVAQUIN® 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 [see Patient Counseling Information (17.1)].
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION See FDA-Approved Medication Guide (17.5) 17.1 Antibacterial Resistance Antibacterial drugs including LEVAQUIN® should only be used to treat bacterial infections.
They do not treat viral infections (e.g., the common cold).
When LEVAQUIN® 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 LEVAQUIN® or other antibacterial drugs in the future.
17.2 Administration with Food, Fluids, and Concomitant Medications Patients should be informed that LEVAQUIN® Tablets may be taken with or without food.
LEVAQUIN® Oral Solution should be taken 1 hour before or 2 hours after eating.
The tablet and oral solution should be taken at the same time each day.
Patients should drink fluids liberally while taking LEVAQUIN® to avoid formation of a highly concentrated urine and crystal formation in the urine.
Antacids containing magnesium, or aluminum, as well as sucralfate, metal cations such as iron, and multivitamin preparations with zinc or didanosine should be taken at least two hours before or two hours after oral LEVAQUIN® administration.
17.3 Serious and Potentially Serious Adverse Reactions Patients should be informed of the following serious adverse reactions that have been associated with LEVAQUIN® or other fluoroquinolone use: • Tendon Disorders: Patients should contact their healthcare provider if they experience pain, swelling, or inflammation of a tendon, or weakness or inability to use one of their joints; rest and refrain from exercise; and discontinue LEVAQUIN® treatment.
The risk of severe tendon disorders with fluoroquinolones is higher in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants.
• Hypersensitivity Reactions: Patients should be informed that LEVAQUIN® can cause hypersensitivity reactions, even following the first dose.
Patients should discontinue the drug at the first sign of a skin rash, hives or other skin reactions, a rapid heartbeat, difficulty in swallowing or breathing, any swelling suggesting angioedema (e.g., swelling of the lips, tongue, face, tightness of the throat, hoarseness), or other symptoms of an allergic reaction.
• Hepatotoxicity: Severe hepatotoxicity (including acute hepatitis and fatal events) has been reported in patients taking LEVAQUIN®.
Patients should inform their physician and be instructed to discontinue LEVAQUIN® treatment immediately if they experience any signs or symptoms of liver injury including: loss of appetite, nausea, vomiting, fever, weakness, tiredness, right upper quadrant tenderness, itching, yellowing of the skin and eyes, light colored bowel movements or dark colored urine.
• Convulsions: Convulsions have been reported in patients taking fluoroquinolones, including LEVAQUIN®.
Patients should notify their physician before taking this drug if they have a history of convulsions.
• Neurologic Adverse Effects (e.g., dizziness, lightheadedness): Patients should know how they react to LEVAQUIN® before they operate an automobile or machinery or engage in other activities requiring mental alertness and coordination.
• Diarrhea: Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued.
Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic.
If this occurs, patients should contact their physician as soon as possible.
• Peripheral Neuropathies: If symptoms of peripheral neuropathy including pain, burning, tingling, numbness, and/or weakness develop, patients should discontinue treatment and contact their physician.
• Prolongation of the QT Interval: Patients should inform their physician of any personal or family history of QT prolongation or proarrhythmic conditions such as hypokalemia, bradycardia, or recent myocardial ischemia; if they are taking any Class IA (quinidine, procainamide), or Class III (amiodarone, sotalol) antiarrhythmic agents.
Patients should notify their physicians if they have any symptoms of prolongation of the QT interval, including prolonged heart palpitations or a loss of consciousness.
• Musculoskeletal Disorders in Pediatric Patients: Parents should inform their child’s physician if their child has a history of joint-related problems before taking this drug.
Parents of pediatric patients should also notify their child’s physician of any tendon or joint-related problems that occur during or following LEVAQUIN® therapy [see Warnings and Precautions (5.9) and Use in Specific Populations (8.4)].
• Photosensitivity/Phototoxicity: Patients should be advised that photosensitivity/phototoxicity has been reported in patients receiving fluoroquinolone antibiotics.
Patients should minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while taking fluoroquinolones.
If patients need to be outdoors when taking fluoroquinolones, they should wear loose-fitting clothes that protect skin from sun exposure and discuss other sun protection measures with their physician.
If a sunburn like reaction or skin eruption occurs, patients should contact their physician.
17.4 Drug Interactions with Insulin, Oral Hypoglycemic Agents, and Warfarin Patients should be informed that if they are diabetic and are being treated with insulin or an oral hypoglycemic agent and a hypoglycemic reaction occurs, they should discontinue LEVAQUIN® and consult a physician.
Patients should be informed that concurrent administration of warfarin and LEVAQUIN® has been associated with increases of the International Normalized Ratio (INR) or prothrombin time and clinical episodes of bleeding.
Patients should notify their physician if they are taking warfarin, be monitored for evidence of bleeding, and also have their anticoagulation tests closely monitored while taking warfarin concomitantly.
Manufactured by: •Janssen Ortho LLC, Gurabo, Puerto Rico 00778 (for the Tablets).
•Janssen Pharmaceutica N.V., Beerse, Belgium (for the Oral Solution and Injection, Single-Use Vials).
•Hospira, Inc., Lake Forest, IL 60045 (for the Injection Pre-Mixed Solution Single-Use in Flexible Container).
Manufactured for: •PriCara, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc.
Raritan, NJ 08869 (for the Tablets and Oral Solution) •Ortho-McNeil, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc.
Raritan, NJ 08869 (for the Injection, Single-Use Vials and Injection Pre-Mixed Solution Single-Use in Flexible Container) ©Ortho-McNeil-Janssen Pharmaceuticals, Inc U.S.
Patent No.
5,053,407.
Issued July 2009 17.5 FDA-Approved Medication Guide
DOSAGE AND ADMINISTRATION
2 •Dosage in patients with normal renal function (2.1) Type of Infection Dose Every 24 hours Duration (days) Nosocomial Pneumonia (1.1) 750 mg 7–14 Community Acquired Pneumonia (1.2) 500 mg 7–14 Community Acquired Pneumonia (1.3) 750 mg 5 Acute Bacterial Sinusitis (1.4) 750 mg 5 500 mg 10–14 Acute Bacterial Exacerbation of Chronic Bronchitis (1.5) 500 mg 7 Complicated Skin and Skin Structure Infections (SSSI) (1.6) 750 mg 7–14 Uncomplicated SSSI (1.7) 500 mg 7–10 Chronic Bacterial Prostatitis (1.8) 500 mg 28 Complicated Urinary Tract Infection (1.9) or Acute Pyelonephritis (1.11) 750 mg 5 Complicated Urinary Tract Infection (1.10) or Acute Pyelonephritis (1.11) 250 mg 10 Uncomplicated Urinary Tract Infection (1.12) 250 mg 3 Inhalational Anthrax (Post-Exposure) (1.13) Adults and Pediatric Patients > 50 kg and ≥ 6 months of age 500 mg 60 Pediatric Patients < 50 kg and ≥ 6 months of age 8 mg/kg BID (not to exceed 250 mg/dose) 60 •Adjust dose for creatinine clearance < 50 mL/min (2.3, 8.6, 12.3) •IV Injection, Single-Use or Premix: Slow IV infusion only, over 60 or 90 minutes depending on dose.
Avoid rapid or bolus IV (2.5) •Dilute single-use vials to 5 mg/mL prior to IV infusion (2.6) •Do not mix with other medications in vial or IV line (2.6) 2.1 Dosage in Adult Patients with Normal Renal Function The usual dose of LEVAQUIN® Tablets or Oral Solution is 250 mg, 500 mg, or 750 mg administered orally every 24 hours, as indicated by infection and described in Table 1.
The usual dose of LEVAQUIN® Injection is 250 mg or 500 mg administered by slow infusion over 60 minutes every 24 hours or 750 mg administered by slow infusion over 90 minutes every 24 hours, as indicated by infection and described in Table 1.
These recommendations apply to patients with creatinine clearance ≥ 50 mL/min.
For patients with creatinine clearance <50 mL/min, adjustments to the dosing regimen are required [see Dosage and Administration (2.3)].
Table 1: Dosage in Adult Patients with Normal Renal Function (creatinine clearance ≥ 50mL/min) Type of Infection Due to the designated pathogens [see Indications and Usage (1)] .
Dosed Every 24 hours Duration (days) Sequential therapy (intravenous to oral) may be instituted at the discretion of the physician.
Nosocomial Pneumonia 750 mg 7–14 Community Acquired PneumoniaDue to methicillin-susceptible Staphylococcus aureus, Streptococcus pneumoniae (including multi-drug-resistant strains [MDRSP]), Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Moraxella catarrhalis, Chlamydophila pneumoniae, Legionella pneumophila, or Mycoplasma pneumoniae [see Indications and Usage (1.2)].
500 mg 7–14 Community Acquired PneumoniaDue to Streptococcus pneumoniae (excluding multi-drug-resistant strains [MDRSP]), Haemophilus influenzae, Haemophilus parainfluenzae, Mycoplasma pneumoniae, or Chlamydophila pneumoniae [see Indications and Usage (1.3)].
750 mg 5 Acute Bacterial Sinusitis 750 mg 5 500 mg 10–14 Acute Bacterial Exacerbation of Chronic Bronchitis 500 mg 7 Complicated Skin and Skin Structure Infections (SSSI) 750 mg 7–14 Uncomplicated SSSI 500 mg 7–10 Chronic Bacterial Prostatitis 500 mg 28 Complicated Urinary Tract Infection (cUTI) or Acute Pyelonephritis (AP) This regimen is indicated for cUTI due to Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis and AP due to E.
coli, including cases with concurrent bacteremia.
750 mg 5 Complicated Urinary Tract Infection (cUTI) or Acute Pyelonephritis (AP)This regimen is indicated for cUTI due to Enterococcus faecalis, Enterococcus cloacae, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa; and for AP due to E.
coli.
250 mg 10 Uncomplicated Urinary Tract Infection 250 mg 3 Inhalational Anthrax (Post-Exposure), adult and pediatric patients > 50 kg and ≥ 6 months of ageDrug administration should begin as soon as possible after suspected or confirmed exposure to aerosolized B.
anthracis.
This indication is based on a surrogate endpoint.
Levofloxacin plasma concentrations achieved in humans are reasonably likely to predict clinical benefit [see Clinical Studies (14.9)].
, The safety of LEVAQUIN® in adults for durations of therapy beyond 28 days or in pediatric patients for durations beyond 14 days has not been studied.
An increased incidence of musculoskeletal adverse events compared to controls has been observed in pediatric patients [see Warnings and Precautions (5.9), Use in Specific Populations (8.4) , and Clinical Studies (14.9)].
Prolonged LEVAQUIN® therapy should only be used when the benefit outweighs the risk.
Pediatric patients < 50 kg and ≥ 6 months of age , 500 mg see Table 2 below (2.2) 60 60 2.2 Dosage in Pediatric Patients The dosage in pediatric patients ≥ 6 months of age is described below in Table 2.
Table 2: Dosage in Pediatric Patients ≥ 6 months of age Type of Infection Due to Bacillus anthracis [see Indications and Usage (1.13)] Dose Freq.
Once every Duration Sequential therapy (intravenous to oral) may be instituted at the discretion of the physician.
Inhalational Anthrax (post-exposure)Drug administration should begin as soon as possible after suspected or confirmed exposure to aerosolized B.
anthracis.
This indication is based on a surrogate endpoint.
Levofloxacin plasma concentrations achieved in humans are reasonably likely to predict clinical benefit [see Clinical Studies (14.9) ] , The safety of LEVAQUIN® in pediatric patients for durations of therapy beyond 14 days has not been studied.
An increased incidence of musculoskeletal adverse events compared to controls has been observed in pediatric patients [see Warnings and Precautions (5.9), Use in Specific Populations (8.4) , and Clinical Studies (14.9)].
Prolonged LEVAQUIN® therapy should only be used when the benefit outweighs the risk.
Pediatric patients > 50 kg and ≥ 6 months of age 500 mg 24 hr 60 days Pediatric patients < 50 kg and ≥ 6 months of age 8 mg/kg (not to exceed 250 mg per dose) 12 hr 60 days 2.3 Dosage Adjustment in Adults with Renal Impairment Administer LEVAQUIN® with caution in the presence of renal insufficiency.
Careful clinical observation and appropriate laboratory studies should be performed prior to and during therapy since elimination of levofloxacin may be reduced.
No adjustment is necessary for patients with a creatinine clearance ≥ 50 mL/min.
In patients with impaired renal function (creatinine clearance <50 mL/min), adjustment of the dosage regimen is necessary to avoid the accumulation of levofloxacin due to decreased clearance [see Use in Specific Populations (8.6)].
Table 3 shows how to adjust dose based on creatinine clearance.
Table 3: Dosage Adjustment in Adult Patients with Renal Impairment (creatinine clearance <50 mL/min) Dosage in Normal Renal Function Every 24 hours Creatinine Clearance 20 to 49 mL/min Creatinine Clearance 10 to 19 mL/min Hemodialysis or Chronic Ambulatory Peritoneal Dialysis (CAPD) 750 mg 750 mg every 48 hours 750 mg initial dose, then 500 mg every 48 hours 750 mg initial dose, then 500 mg every 48 hours 500 mg 500 mg initial dose, then 250 mg every 24 hours 500 mg initial dose, then 250 mg every 48 hours 500 mg initial dose, then 250 mg every 48 hours 250 mg No dosage adjustment required 250 mg every 48 hours.
If treating uncomplicated UTI, then no dosage adjustment is required No information on dosing adjustment is available 2.4 Drug Interaction With Chelation Agents: Antacids, Sucralfate, Metal Cations, Multivitamins LEVAQUIN® Tablets and Oral Solution LEVAQUIN® Tablets and Oral Solution should be administered at least two hours before or two hours after antacids containing magnesium, aluminum, as well as sucralfate, metal cations such as iron, and multivitamin preparations with zinc or didanosine chewable/buffered tablets or the pediatric powder for oral solution [see Drug Interactions (7.1) and Patient Counseling Information (17.2)].
LEVAQUIN® Injection LEVAQUIN® Injection should not be co-administered with any solution containing multivalent cations, e.g., magnesium, through the same intravenous line [see Dosage and Administration (2.6)].
2.5 Administration Instructions Food and LEVAQUIN® Tablets and Oral Solution LEVAQUIN® Tablets can be administered without regard to food.
It is recommended that LEVAQUIN® Oral Solution be taken 1 hour before or 2 hours after eating.
LEVAQUIN® Injection Caution: Rapid or bolus intravenous infusion of LEVAQUIN® has been associated with hypotension and must be avoided.
LEVAQUIN® Injection should be infused intravenously slowly over a period of not less than 60 or 90 minutes, depending on the dosage.
LEVAQUIN® Injection should be administered only by intravenous infusion.
It is not for intramuscular, intrathecal, intraperitoneal, or subcutaneous administration.
Hydration for Patients Receiving LEVAQUIN® Tablets, Oral Solution, and Injection Adequate hydration of patients receiving oral or intravenous LEVAQUIN® should be maintained to prevent the formation of highly concentrated urine.
Crystalluria and cylindruria have been reported with quinolones [see Adverse Reactions (6.1) and Patient Counseling Information (17.2)].
2.6 Preparation of Intravenous Product Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Because only limited data are available on the compatibility of LEVAQUIN® Injection with other intravenous substances, additives or other medications should not be added to LEVAQUIN® Injection Premix in Single-Use Flexible Containers and 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 compatible with LEVAQUIN® Injection and with any other drug(s) administered via this common line LEVAQUIN® Injection in Single-Use Vials Single-use vials require dilution prior to administration.
LEVAQUIN® Injection is supplied in single-use vials containing a concentrated levofloxacin solution with the equivalent of 500 mg (20 mL vial) and 750 mg (30 mL vial) of levofloxacin in Water for Injection, USP.
The 20 mL and 30 mL vials each contain 25 mg of levofloxacin/mL.
These LEVAQUIN® Injection single-use vials must be further diluted with an appropriate solution prior to intravenous administration [see Table 4].
The concentration of the resulting diluted solution should be 5 mg/mL prior to administration.
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: Table 4: Compatible Intravenous Solutions Intravenous Fluids Final pH of LEVAQUIN® Solution 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, and 0.15% Potassium Chloride Injection 4.61 Sodium Lactate Injection (M/6) 5.54 Since no preservative or bacteriostatic agent is present in this product, aseptic technique must be used in preparation of the final intravenous solution.
Since the vials are for single-use only, any unused portion remaining in the vial should be discarded.
When used to prepare two 250 mg doses from the 20 mL vial containing 500 mg of levofloxacin, the full content of the vial should be withdrawn at once using a single-entry procedure, and a second dose should be prepared and stored for subsequent use [see Stability of LEVAQUIN® Injection Following Dilution].
Prepare the desired dosage of levofloxacin according to Table 5: Table 5: Preparation of LEVAQUIN® Intravenous Solution Desired Dosage Strength From Appropriate Vial, Withdraw Volume Volume of Diluent Infusion 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.
This intravenous drug product should be inspected visually for particulate matter prior to administration.
Samples containing visible particles should be discarded.
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 compatible intravenous solution and frozen in glass bottles or plastic intravenous 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.
LEVAQUIN® Injection Premix in Single-Use Flexible Containers (5 mg/mL) LEVAQUIN® Injection is also supplied in flexible containers within a foil overwrap.
These contain a premixed, ready to use levofloxacin solution in 5% dextrose (D5W) for single-use.
The 100 mL premixed flexible containers contain either 250 mg/50 mL or 500 mg/100 mL of levofloxacin solution.
The 150 mL flexible container contains 750 mg/150 mL of levofloxacin solution.
The concentration of each container is 5 mg/mL.
No further dilution of these preparations is necessary.
Because the premix flexible containers are for single-use only, any unused portion should be discarded.
Instructions for the Use of LEVAQUIN® Injection Premix in Flexible Containers: 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 Premix in Flexible Containers.
6.Open flow control clamp to expel air from set.
Close clamp.
7.Regulate rate of administration with flow control clamp.