Levaquin has been related to the side effect of Abdominal distress. If you are taking Levaquin and have experienced Abdominal distress this information may be of use to you.
IMPORTANT NOTE: The following information is intended to supplement, not substitute for, the expertise and judgment of your physician, pharmacist or other healthcare professional. It should not be construed to indicate that use of the drug is safe, appropriate, or effective for you. Consult your healthcare professional before using this drug.
LEVAQUIN
-
levofloxacin tablet, film coated LEVAQUIN
-
levofloxacin solution LEVAQUIN
-
levofloxacin injection, solution, concentrate PriCara Unit of Ortho-McNeil Pharmaceutical, Inc.
----------
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use LEVAQUIN
safely and effectively. See full prescribing information for LEVAQUIN.
LEVAQUIN
(levofloxacin)
tablet, film coated for
oral
use LEVAQUIN
(levofloxacin)
solution for
oral
use LEVAQUIN
(levofloxacin)
injection, solution, concentrate for
intravenous
use Initial U.S. Approval:
1996
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 bacteria.
RECENT MAJOR CHANGES
Indications and Usage
Inhalational Anthrax (post-exposure) (1.13)
in pediatrics
5/2008
Dosage and Administration
Dosage in Adult Patients with Normal Renal Function (2.1)
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)
DOSAGE AND ADMINISTRATION
Dosage in patients with normal renal function (2.1)
Inhalational Anthrax (Post-Exposure) (1.13) Adults
and Pediatric Patients > 50 kg and ≥ 6 months of age Pediatric
Patients < 50 kg and ≥ 6 months of age
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)
DOSAGE FORMS AND STRENGTHS
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
CONTRAINDICATIONS
Known hypersensitivity to LEVAQUIN® or
other quinolones (4, 5.1)
WARNINGS AND PRECAUTIONS
Anaphylactic reactions and allergic skin reactions, serious, occasionally
fatal, may occur after first dose (4, 5.1)
Hematologic (including agranulocytosis, thrombocytopenia), and renal
toxicities may occur after multiple doses (5.2)
Hepatotoxicity: Severe, and sometimes fatal, hepatoxicity has been reported.
Discontinue immediately if signs and symptoms of hepatitis occur (5.3)
Achilles or other tendon rupture, risk is increased with concomitant
corticosteroids and in patients over 65 years of age. Discontinue if pain
or inflammation in a tendon occurs (5.4, 8.5)
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)
ADVERSE REACTIONS
The most common reactions (≥3%) were nausea,
headache, diarrhea, insomnia, constipation and dizziness (6.2).
To report SUSPECTED ADVERSE REACTIONS, contact PriCara Unit of Ortho-McNeil Pharmaceutical, Inc. at
1-800-526-7736
or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
DRUG INTERACTIONS
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)
Geriatrics: Severe hepatotoxicity
has been reported. The majority of reports describe patients 65 years of age
or older (5.3, 8.5, 17). May have increased risk of tendon disorders (including
rupture), especially with concomitant corticosteroid use (5.4, 8.5, 17). May be
more susceptible to prolongation of the QT interval. (5.8, 8.5, 17).
Pediatrics: Musculoskeletal
disorders (arthralgia, arthritis, tendonopathy, and gait abnormality) seen
in more LEVAQUIN®-treated patients than in comparator. Shown
to cause arthropathy and osteochondrosis in juvenile animals (5.9, 8.4, 13.2). Safety
in pediatric patients treated for more than 14 days has not been studied.
Risk-benefit appropriate only for the treatment of inhalational anthrax (post-exposure)
(1.13, 2.2, 8.4, 14.9).
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling
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).
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 ≥2 mcg/mL), 2nd generation cephalosporins, e.g., cefuroxime,
macrolides, tetracyclines and trimethoprim/sulfamethoxazole.
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)].
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)].
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 incidenceor progression of disease following exposure to
aerosolized Bacillus
anthracis. The effectiveness of LEVAQUIN® 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
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 should only
be used when the benefit outweighs the risk [see
Dosage and Administration (2.1, 2.2) and
Clinical Studies (14.9)].
2 DOSAGE AND ADMINISTRATION
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 ≥ 50 mL/min)
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.
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.
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
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
in adults should only be used when the benefit outweighs the risk.
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)¶
750 mg
5
Complicated Urinary Tract Infection (cUTI) or Acute
Pyelonephritis (AP)#
250 mg
10
Uncomplicated Urinary Tract Infection
250 mg
3
Inhalational Anthrax
(Post-Exposure), adult and pediatric patients > 50 kg and ≥ 6 months
of age Þ,ß Pediatric patients < 50 kg and ≥ 6 months of
age Þ,ß
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 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.
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 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) andPatient 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:
Tear outer wrap at the notch and remove solution container.
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.
Do not use if the solution is cloudy or a precipitate is present.
Use sterile equipment.
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:
Close flow control clamp of administration set.
Remove cover from port at bottom of container.
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.
Suspend container from hanger.
Squeeze and release drip chamber to establish proper fluid level in
chamber during infusion of LEVAQUIN® Injection Premix in Flexible
Containers.
Open flow control clamp to expel air from set. Close clamp.
Regulate rate of administration with flow control clamp.
3 DOSAGE FORMS AND STRENGTHS
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 to 250 mg levofloxacin)
100 mL container, fill volume 100 mL (equivalent to 500 mg levofloxacin)
150 mL container, fill volume 150 mL (equivalent to 750 mg levofloxacin)
4 CONTRAINDICATIONS
LEVAQUIN® is contraindicated in persons
with known hypersensitivity to levofloxacin, or other quinolone antibacterials [see Warnings and Precautions (5.1)].
5 WARNINGS AND PRECAUTIONS
5.1 Hypersensitivity Reactions
Serious and occasionally fatal hypersensitivity
and/or anaphylactic reactions have been reported in patients receiving therapy
with quinolones, 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)].
5.2 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 quinolones, 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)].
5.3 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 (5.2)].
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)].
5.4 Tendon Effects
Ruptures of the shoulder, hand, Achilles tendon, or other
tendons that required surgical repair or resulted in prolonged disability
have been reported in patients receiving quinolones, including LEVAQUIN®.
Postmarketing surveillance reports indicate that this risk is increased in
patients receiving concomitant corticosteroids and in patients over 65 years
of age. LEVAQUIN® should be discontinued if the patient experiences
pain, inflammation, or rupture of a tendon. Patients should rest and refrain
from exercise until the diagnosis of tendonitis or tendon rupture has been
confidently excluded. Tendon rupture can occur during or after therapy withquinolones, including LEVAQUIN®[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 quinolones, including LEVAQUIN®. Quinolones 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
quinolones, 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 quinolones,
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 quinolones, 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 quinolones, 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 fluoroquinolones 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 quinolones, 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 quinolones 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)].
6 ADVERSE REACTIONS
6.1 Serious and Otherwise Important Adverse Reactions
The following serious and otherwise important adverse
drug reactions are discussed in greater detail in other sections of labeling:
Hypotension has been associated with rapid or bolus
intravenous infusion of LEVAQUIN®. LEVAQUIN® should
be infused slowly over 60 to 90 minutes, depending on dosage [see
Dosage and Administration (2.5)].
Crystalluria and cylindruria have been
reported with quinolones, including LEVAQUIN®. Therefore,
adequate hydration of patients receiving LEVAQUIN® should
be maintained to prevent the formation of a highly concentrated urine [see Dosage and Administration
(2.5)].
6.2 Clinical Trial Experience
Because clinical trials are conducted under widely
varying conditions, adverse reaction rates observed in the clinical trials
of a drug cannot be directly compared to rates in the clinical trials of another
drug and may not reflect the rates observed in practice.
The data described below reflect exposure to LEVAQUIN® in7537 patients in 29 pooled Phase 3 clinical trials. The population studied
had a mean age of 50 years (approximately 74% of the population was < 65
years of age), 50% were male, 71% were Caucasian, 19% were Black. Patients
were treated with LEVAQUIN® for a wide variety of infectious
diseases [see Indications
and Usage (1)]. Patients received LEVAQUIN® doses
of 750 mg once daily, 250 mg once daily, or 500 mg once or twice daily. Treatment
duration was usually 3–14 days, and the mean number of days on therapy
was 10 days.
The overall incidence, type and
distribution of adverse reactions was similar in patients receiving LEVAQUIN® doses
of 750 mg once daily, 250 mg once daily, and 500 mg once or twice daily. Discontinuation
of LEVAQUIN® due to adverse drug reactions occurred in 4.3%
of patients overall, 3.8% of patients treated with the 250 mg and 500 mg doses
and 5.4% of patients treated with the 750 mg dose. The most common adverse
drug reactions leading to discontinuation with the 250 and 500 mg doses were
gastrointestinal (1.4%), primarily nausea (0.6%); vomiting (0.4%); dizziness
(0.3%); and headache (0.2%). The most common adverse drug reactions leading
to discontinuation with the 750 mg dose were gastrointestinal (1.2%), primarily
nausea (0.6%), vomiting (0.5%); dizziness (0.3%); and headache (0.3%).
Adverse reactions occurring in ≥1% of LEVAQUIN®-treated
patients and less common adverse reactions, occurring in 0.1 to <1% of
LEVAQUIN®-treated patients, are shown in Table 6 and Table
7, respectively. The most common adverse drug reactions (≥3%) are nausea,
headache, diarrhea, insomnia, constipation, and dizziness.
Table 6: Common (≥1%) Adverse Reactions
Reported in Clinical Trials with LEVAQUIN®
In clinical trials using multiple-dose therapy,
ophthalmologic abnormalities, including cataracts and multiple punctate lenticular
opacities, have been noted in patients undergoing treatment with quinolones,
including LEVAQUIN®. The relationship of the drugs to these
events is not presently established.
6.3 Postmarketing Experience
Table 8 lists adverse reactions that have been identified
during post-approval use of LEVAQUIN®. Because these reactions
are reported voluntarily from a population of uncertain size, reliably estimating
their frequency or establishing a causal relationship to drug exposure is
not always possible.
Table
8: Postmarketing Reports Of Adverse Drug Reactions
General
Disorders and Administration Site Conditions
multi-organ failure pyrexia
Investigations
prothrombin time prolonged international normalized
ratio prolonged muscle enzymes increased
7 DRUG INTERACTIONS
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 quinolones, 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 quinolones with oral
antacids, sucralfate, multivitamins, didanosine, or metal cations. However,
no quinolone 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
quinolones 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 quinolone, 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 quinolones 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 quinolones. 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 quinolones, 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.
8 USE IN SPECIFIC POPULATIONS
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.
8.3 Nursing Mothers
Based on data on other quinolones 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.
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
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.
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.
8.5 Geriatric Use
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 (5.3)].
Patients
over 65 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 with concomitant steroid therapy. Tendon rupture
usually involves the Achilles, hand or shoulder tendons and can occur during
therapy or up to a few months post completion of therapy. 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 therapy and inform their physicians if any
tendon symptoms occur [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)].
8.6 Renal Impairment
Clearance of levofloxacin is substantially reduced
and plasma elimination half-life is substantially prolonged in patients with
impaired renal function (creatinine clearance < 50 mL/min), requiring dosage
adjustment in such patients to avoid accumulation. Neither hemodialysis nor
continuous ambulatory peritoneal dialysis (CAPD) is effective in removal of
levofloxacin from the body, indicating that supplemental doses of LEVAQUIN® are
not required following hemodialysis or CAPD [see
Dosage and Administration (2.3)].
8.7 Hepatic Impairment
Pharmacokinetic studies in hepatically impaired
patients have not been conducted. Due to the limited extent of levofloxacin
metabolism, the pharmacokinetics of levofloxacin are not expected to be affected
by hepatic impairment.
10 OVERDOSAGE
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.
11 DESCRIPTION
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 clear 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.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Levofloxacin is a member of the fluoroquinolone
class of antibacterial agents [see Clinical Pharmacology (12.4)].
12.3 Pharmacokinetics
The mean ±SD pharmacokinetic parameters of
levofloxacin determined under single and steady-state conditions following
oral tablet, oral solution, or intravenous (IV) doses of LEVAQUIN® are
summarized in Table 10.
Table
10: Mean ±SD Levofloxacin PK Parameters
Regimen
Cmax
Tmax
AUC
CL/F1
Vd/F2
t1/2
CLR
(mcg/mL)
(h)
(mcg∙h/mL)
(mL/min)
(L)
(h)
(mL/min)
1 clearance/bioavailability
2 volume of distribution/bioavailability
3 healthy males 18–53 years of age
4 60 min infusion for 250 mg and 500 mg doses, 90 min infusion
for 750 mg dose
5 healthy male and female subjects 18–54 years of age
6 500 mg every 48h for patients with moderate renal impairment
(CLCR 20–50 mL/min) and infections of the respiratory tract or skin
7 dose-normalized values (to 500 mg dose), estimated by population
pharmacokinetic modeling
8 healthy males 22–75 years of age
9 healthy females 18–80 years of age
10 young healthy male and female subjects 18–36 years
of age
11 healthy elderly male and female subjects 66–80 years
of age
12 healthy males and females 19–55 years of age.
*Absolute bioavailability; F=0.99 ± 0.08 from a 500 mg
tablet and F=0.99 ± 0.06 from a 750 mg tablet;
ND=not determined.
Single
dose
250 mg oral tablet3
2.8 ± 0.4
1.6 ± 1.0
27.2 ± 3.9
156 ± 20
ND
7.3 ± 0.9
142 ± 21
500 mg oral tablet3*
5.1 ± 0.8
1.3 ± 0.6
47.9 ± 6.8
178 ± 28
ND
6.3 ± 0.6
103 ± 30
500 mg oral solution12
5.8 ± 1.8
0.8 ± 0.7
47.8 ± 10.8
183 ± 40
112 ± 37.2
7.0 ± 1.4
ND
500 mg IV3
6.2 ± 1.0
1.0 ± 0.1
48.3 ± 5.4
175 ± 20
90 ± 11
6.4 ± 0.7
112 ± 25
750 mg oral tablet5*
9.3 ± 1.6
1.6 ± 0.8
101 ± 20
129 ± 24
83 ± 17
7.5 ± 0.9
ND
750 mg IV5
11.5 ±4.04
ND
110 ±40
126 ±39
75 ± 13
7.5 ± 1.6
ND
Multiple
dose
500 mg every 24h oral tablet3
5.7 ± 1.4
1.1 ± 0.4
47.5 ± 6.7
175 ± 25
102 ± 22
7.6 ± 1.6
116 ± 31
500 mg every 24h IV3
6.4 ± 0.8
ND
54.6 ± 11.1
158 ± 29
91 ± 12
7.0 ± 0.8
99 ± 28
500 mg or 250 mg every 24h IV, patients with bacterial
infection6
8.7± 4.07
ND
72.5 ± 51.27
154 ± 72
111 ± 58
ND
ND
750 mg every 24h oral tablet5
8.6 ± 1.9
1.4 ± 0.5
90.7 ± 17.6
143 ± 29
100 ± 16
8.8 ± 1.5
116 ± 28
750 mg every 24h IV5
12.1 ± 4.14
ND
108 ± 34
126 ± 37
80 ± 27
7.9 ± 1.9
ND
500
mg oral tablet single dose, effects of gender and age:
Male8
5.5 ± 1.1
1.2 ± 0.4
54.4 ± 18.9
166 ± 44
89 ± 13
7.5 ± 2.1
126 ± 38
Female9
7.0 ± 1.6
1.7 ± 0.5
67.7 ± 24.2
136 ± 44
62 ± 16
6.1 ± 0.8
106 ± 40
Young10
5.5 ± 1.0
1.5 ± 0.6
47.5 ± 9.8
182 ± 35
83 ± 18
6.0 ± 0.9
140 ± 33
Elderly11
7.0 ± 1.6
1.4 ± 0.5
74.7 ± 23.3
121 ± 33
67 ± 19
7.6 ± 2.0
91 ± 29
500
mg oral single dose tablet, patients with renal insufficiency:
CLCR 50–80 mL/min
7.5 ± 1.8
1.5 ± 0.5
95.6 ± 11.8
88 ± 10
ND
9.1 ± 0.9
57 ± 8
CLCR 20–49 mL/min
7.1 ± 3.1
2.1 ± 1.3
182.1 ± 62.6
51 ± 19
ND
27 ± 10
26 ± 13
CLCR <20 mL/min
8.2 ± 2.6
1.1 ± 1.0
263.5 ± 72.5
33 ± 8
ND
35 ± 5
13 ± 3
Hemodialysis
5.7 ± 1.0
2.8 ± 2.2
ND
ND
ND
76 ± 42
ND
CAPD
6.9 ± 2.3
1.4 ± 1.1
ND
ND
ND
51 ± 24
ND
Absorption
Levofloxacin is rapidly and essentially
completely absorbed after oral administration. Peak plasma concentrations
are usually attained one to two hours after oral dosing. The absolute bioavailability
of levofloxacin from a 500 mg tablet and a 750 mg tablet of LEVAQUIN® are
both approximately 99%, demonstrating complete oral absorption of levofloxacin.
Following a single intravenous dose of LEVAQUIN® to healthy
volunteers, the mean ±SD peak plasma concentration attained was 6.2 ±1.0
mcg/mL after a 500 mg dose infused over 60 minutes and 11.5 ±4.0 mcg/mL
after a 750 mg dose infused over 90 minutes. LEVAQUIN® Oral
Solution and Tablet formulations are bioequivalent.
Levofloxacin
pharmacokinetics are linear and predictable after single and multiple oral
or IV dosing regimens. Steady-state conditions are reached within 48 hours
following a 500 mg or 750 mg once-daily dosage regimen. The mean ±SD
peak and trough plasma concentrations attained following multiple once-daily
oral dosage regimens were approximately 5.7 ±1.4 and 0.5 ±0.2 mcg/mL
after the 500 mg doses, and 8.6 ±1.9 and 1.1 ±0.4 mcg/mL after the
750 mg doses, respectively. The mean ±SD peak and trough plasma concentrations
attained following multiple once-daily IV regimens were approximately 6.4±0.8 and 0.6 ±0.2 mcg/mL after the 500 mg doses,
and 12.1 ±4.1
and 1.3 ±0.71 mcg/mL after the 750 mg doses, respectively. Oral administration
of a 500 mg dose of LEVAQUIN® with food prolongs the time
to peak concentration by approximately 1 hour and decreases the peak concentration
by approximately 14% following tablet and approximately 25% following oral
solution administration. Therefore, 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.
The plasma concentration profile of levofloxacin after IV
administration is similar and comparable in extent of exposure (AUC) to that
observed for LEVAQUIN® Tablets when equal doses (mg/mg) are
administered. Therefore, the oral and IV routes of administration can be considered
interchangeable (see Figure
2 and Figure 3).
Figure
2: Mean Levofloxacin Plasma Concentration vs. Time Profile: 750 mg
Figure 3: Mean Levofloxacin
Plasma Concentration vs. Time Profile: 500 mg
Distribution
The mean volume of distribution
of levofloxacin generally ranges from 74 to 112 L after single and multiple
500 mg or 750 mg doses, indicating widespread distribution into body tissues.
Levofloxacin reaches its peak levels in skin tissues and in blister fluid
of healthy subjects at approximately 3 hours after dosing. The skin tissue
biopsy to plasma AUC ratio is approximately 2 and the blister fluid to plasma
AUC ratio is approximately 1 following multiple once-daily oral administration
of 750 mg and 500 mg doses of LEVAQUIN®, respectively, to
healthy subjects. Levofloxacin also penetrates well into lung tissues. Lung
tissue concentrations were generally 2- to 5- fold higher than plasma concentrations
and ranged from approximately 2.4 to 11.3 mcg/g over a 24-hour period after
a single 500 mg oral dose.
In
vitro, over a clinically relevant range (1 to 10 mcg/mL) of serum/plasma
levofloxacin concentrations, levofloxacin is approximately 24 to 38% bound
to serum proteins across all species studied, as determined by the equilibrium
dialysis method. Levofloxacin is mainly bound to serum albumin in humans.
Levofloxacin binding to serum proteins is independent of the drug concentration.
Metabolism
Levofloxacin is stereochemically
stable in plasma and urine and does not invert metabolically to its enantiomer,
D-ofloxacin. Levofloxacin undergoes limited metabolism in humans and is primarily
excreted as unchanged drug in the urine. Following oral administration, approximately
87% of an administered dose was recovered as unchanged drug in urine within
48 hours, whereas less than 4% of the dose was recovered in feces in 72 hours.
Less than 5% of an administered dose was recovered in the urine as the desmethyl
and N-oxide metabolites, the only metabolites identified in humans. These
metabolites have little relevant pharmacological activity.
Excretion
Levofloxacin is excreted
largely as unchanged drug in the urine. The mean terminal plasma elimination
half-life of levofloxacin ranges from approximately 6 to 8 hours following
single or multiple doses of levofloxacin given orally or intravenously. The
mean apparent total body clearance and renal clearance range from approximately
144 to 226 mL/min and 96 to 142 mL/min, respectively. Renal clearance in excess
of the glomerular filtration rate suggests that tubular secretion of levofloxacin
occurs in addition to its glomerular filtration. Concomitant administration
of either cimetidine or probenecid results in approximately 24% and 35% reduction
in the levofloxacin renal clearance, respectively, indicating that secretion
of levofloxacin occurs in the renal proximal tubule. No levofloxacin crystals
were found in any of the urine samples freshly collected from subjects receiving
LEVAQUIN®.
Geriatric
There are no significant
differences in levofloxacin pharmacokinetics between young and elderly subjects
when the subjects' differences in creatinine clearance are taken into
consideration. Following a 500 mg oral dose of LEVAQUIN® to
healthy elderly subjects (66 – 80 years of age), the mean terminal
plasma elimination half-life of levofloxacin was about 7.6 hours, as compared
to approximately 6 hours in younger adults. The difference was attributable
to the variation in renal function status of the subjects and was not believed
to be clinically significant. Drug absorption appears to be unaffected by
age. LEVAQUIN® dose adjustment based on age alone is not necessary [See Use in Specific Populations
(8.5)].
Pediatrics
The
pharmacokinetics of levofloxacin following a single 7 mg/kg intravenous dose
were investigated in pediatric patients ranging in age from 6 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. Subsequent
pharmacokinetic analyses predicted that a dosage regimen of 8 mg/kg every
12 hours (not to exceed 250 mg per dose) for pediatric patients 6 months to
17 years of age would achieve comparable steady state plasma exposures (AUC0-24 and
Cmax) to those observed in adult patients administered 500 mg of
levofloxacin once every 24 hours.
Gender
There are no significant differences in levofloxacin pharmacokinetics
between male and female subjects when subjects' differences in creatinine
clearance are taken into consideration. Following a 500 mg oral dose of LEVAQUIN® to
healthy male subjects, the mean terminal plasma elimination half-life of levofloxacin
was about 7.5 hours, as compared to approximately 6.1 hours in female subjects.
This difference was attributable to the variation in renal function status
of the male and female subjects and was not believed to be clinically significant.
Drug absorption appears to be unaffected by the gender of the subjects. Dose
adjustment based on gender alone is not necessary.
Race
The effect of race on levofloxacin
pharmacokinetics was examined through a covariate analysis performed on data
from 72 subjects: 48 white and 24 non-white. The apparent total body clearance
and apparent volume of distribution were not affected by the race of the subjects.
Renal Impairment
Clearance of levofloxacin
is substantially reduced and plasma elimination half-life is substantially
prolonged in patients with impaired renal function (creatinine clearance <
50 mL/min), requiring dosage adjustment in such patients to avoid accumulation.
Neither hemodialysis nor continuous ambulatory peritoneal dialysis (CAPD)
is effective in removal of levofloxacin from the body, indicating that supplemental
doses of LEVAQUIN® are not required following hemodialysis
or CAPD [see Dosage and
Administration (2.3), Use in Specific Populations
(8.6)].
Hepatic
Impairment
Pharmacokinetic
studies in hepatically impaired patients have not been conducted. Due to the
limited extent of levofloxacin metabolism, the pharmacokinetics of levofloxacin
are not expected to be affected by hepatic impairment [See
Use in Specific Populations (8.7)].
Bacterial
Infection
The pharmacokinetics
of levofloxacin in patients with serious community-acquired bacterial infections
are comparable to those observed in healthy subjects.
Drug-Drug
Interactions
The potential
for pharmacokinetic drug interactions between LEVAQUIN® and
antacids warfarin, theophylline, cyclosporine, digoxin, probenecid, and cimetidine
has been evaluated [see Drug
Interactions (7)].
12.4 Microbiology
Mechanism
of Action
Levofloxacin
is the L-isomer of the racemate, ofloxacin, a quinolone antimicrobial agent.
The antibacterial activity of ofloxacin resides primarily in the L-isomer.
The mechanism of action of levofloxacin and other fluoroquinolone antimicrobials
involves inhibition of bacterial topoisomerase IV and DNA gyrase (both of
which are type II topoisomerases), enzymes required for DNA replication, transcription,
repair and recombination.
Drug Resistance
Fluoroquinolone resistance
can arise through mutations in defined regions of DNA gyrase or topoisomerase
IV, termed the Quinolone-Resistance Determining Regions (QRDRs), or through
altered efflux.
Fluoroquinolones, including
levofloxacin, differ in chemical structure and mode of action from aminoglycosides,
macrolides and β-lactam antibiotics, including penicillins. Fluoroquinolones
may, therefore, be active against bacteria resistant to these antimicrobials.
Resistance to levofloxacin due to spontaneous mutation in vitro is a rare occurrence (range: 10-9 to
10-10). Although cross-resistance has been observed between levofloxacin
and some other fluoroquinolones, some microorganisms resistant to other fluoroquinolones
may be susceptible to levofloxacin.
Activity
in vitro and in
vivo
Levofloxacin
has in vitro activity against a wide
range of Gram-negative and Gram-positive microorganisms.
Levofloxacin is often bactericidal at concentrations equal
to or slightly greater than inhibitory concentrations.
Levofloxacin has been shown to be active against most strains
of the following microorganisms both in vitro
and in clinical infections as described in Indications and Usage (1):
Aerobic
Gram-Positive Microorganisms
Enterococcus faecalis (many strains are only
moderately susceptible)
MDRSP (Multi-drug resistant Streptococcus
pneumoniae) isolates are strains resistant to two or more of the
following antibiotics: penicillin (MIC ≥2 mcg/mL), 2nd generation cephalosporins,
e.g., cefuroxime; macrolides, tetracyclines and trimethoprim/sulfamethoxazole.
As with other drugs in
this class, some strains of Pseudomonas aeruginosa
may develop resistance fairly rapidly during treatment with LEVAQUIN®.
Other
Microorganisms
Chlamydophila pneumoniae
Mycoplasma pneumoniae
Levofloxacin has been shown to be active against Bacillus anthracis both in
vitro and by use of plasma levels as a surrogate marker in a rhesus
monkey model for anthrax (post-exposure) [see
Indications and Usage (1.13), Clinical Studies (14.9)].
The following in vitro
data are available, but their clinical
significance is unknown: Levofloxacin
exhibits in vitro minimum inhibitory
concentrations (MIC values) of 2 mcg/mL or less against most (≥90%)
strains of the following microorganisms; however, the safety and effectiveness
of LEVAQUIN® in treating clinical infections due to these
microorganisms have not been established in adequate and well-controlled trials.
Aerobic
Gram-Positive Microorganisms
Staphylococcus haemolyticus
β-hemolytic Streptococcus (Group C/F)
β-hemolytic Streptococcus (Group G)
Streptococcus agalactiae
Streptococcus milleri
Viridans group streptococci
Aerobic
Gram-Negative Microorganisms
Acinetobacter baumannii
Acinetobacter lwoffii
Bordetella pertussis
Citrobacter koseri
Citrobacter freundii
Enterobacter aerogenes
Enterobacter sakazakii
Klebsiella oxytoca
Morganella morganii
Pantoea agglomerans
Proteus vulgaris
Providencia rettgeri
Providencia stuartii
Pseudomonas fluorescens
Anaerobic
Gram-Positive Microorganisms
Clostridium perfringens
Susceptibility
Tests
Susceptibility
testing for levofloxacin should be performed, as it is the optimal predictor
of activity.
Dilution techniques: Quantitative methods are used to determine antimicrobial minimal
inhibitory concentrations (MIC values). These MIC values provide estimates
of the susceptibility of bacteria to antimicrobial compounds. The MIC values
should be determined using a standardized procedure. Standardized procedures
are based on a dilution method1 (broth or agar) or equivalent with
standardized inoculum concentrations and standardized concentrations of levofloxacin
powder. The MIC values should be interpreted according to the criteria outlined
in Table 11.
Diffusion techniques: Quantitative methods that require measurement of zone diameters
also provide reproducible estimates of the susceptibility of bacteria to antimicrobial
compounds. One such standardized procedure2 requires the use of
standardized inoculum concentrations. This procedure uses paper disks impregnated
with 5 mcg levofloxacin to test the susceptibility of microorganisms to levofloxacin.
Reports
from the laboratory providing results of the standard single-disk susceptibility
test with a 5 mcg levofloxacin disk should be interpreted according the criteria
outlined in Table 11. Interpretation involves correlation of the diameter
obtained in the disk test with the MIC for levofloxacin.
Table 11: Susceptibility Interpretive Criteria for LEVAQUIN®
These interpretive standards
are applicable only to broth microdilution susceptibility testing with Haemophilus influenzae and Haemophilus
parainfluenzae using Haemophilus Test Medium.1
The current absence of data on
resistant strains precludes defining any categories other than "Susceptible."
Strains yielding MIC /zone diameter results suggestive of a "nonsusceptible"
category should be submitted to a reference laboratory for further testing.
These interpretive standards
are applicable only to disk diffusion susceptibility testing with Haemophilus influenzae and Haemophilus
parainfluenzae using Haemophilus Test Medium.2
These interpretive standards
are applicable only to broth microdilution susceptibility tests using cation-adjusted
Mueller-Hinton broth with 2–5% lysed horse blood.
These zone diameter standards
for Streptococcus spp. including S. pneumoniae apply only to tests performed
using Mueller-Hinton agar supplemented with 5% sheep blood and incubated in
5% CO2.
A report of Susceptible indicates
that the pathogen is likely to be inhibited if the antimicrobial compound
in the blood reaches the concentrations usually achievable. A report of Intermediate indicates that the result should
be considered equivocal, and, if the microorganism is not fully susceptible
to alternative, clinically feasible drugs, the test should be repeated. This
category implies possible clinical applicability in body sites where the drug
is physiologically concentrated or in situations where a high dosage of drug
can be used. This category also provides a buffer zone which prevents small
uncontrolled technical factors from causing major discrepancies in interpretation.
A report of Resistant indicates that
the pathogen is not likely to be inhibited if the antimicrobial compound in
the blood reaches the concentrations usually achievable; other therapy should
be selected.
Quality Control: Standardized susceptibility test procedures require the use
of laboratory control microorganisms to control the technical aspects of the
laboratory procedures. For dilution technique, standard levofloxacin powder
should give the MIC values provided in Table 12. For diffusion technique,
the 5 mcg levofloxacin disk should provide zone diameters provided in Table
12.
Table 12: Quality Control for
Susceptibility Testing
This quality control range
is applicable to only H. influenzae ATCC
49247 tested by a broth microdilution procedure using Haemophilus Test Medium
(HTM).1
This quality control range is
applicable to only S. pneumoniae ATCC
49619 tested by a broth microdilution procedure using cation-adjusted Mueller-Hinton
broth with 2–5% lysed horse blood.
This quality control range is
applicable to only S. pneumoniae ATCC
49619 tested by a disk diffusion procedure using Mueller-Hinton agar supplemented
with 5% sheep blood and incubated in 5% CO2.
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
In a lifetime bioassay in rats, levofloxacin exhibited
no carcinogenic potential following daily dietary administration for 2 years;
the highest dose (100 mg/kg/day) was
1.4 times the highest recommended human dose (750 mg) based upon relative
body surface area. Levofloxacin did not shorten the time to tumor development
of UV-induced skin tumors in hairless albino (Skh-1) mice at any levofloxacin
dose level and was therefore not photo-carcinogenic under conditions of this
study. Dermal levofloxacin concentrations in the hairless mice ranged from
25 to 42 mcg/g at the highest levofloxacin dose level (300 mg/kg/day) used
in the photo-carcinogenicity study. By comparison, dermal levofloxacin concentrations
in human subjects receiving 750 mg of LEVAQUIN® averaged approximately
11.8 mcg/g at Cmax.
Levofloxacin
was not mutagenic in the following assays: Ames bacterial mutation assay (S. typhimurium and E.
coli), CHO/HGPRT forward mutation assay, mouse micronucleus test,
mouse dominant lethal test, rat unscheduled DNA synthesis assay, and the mouse
sister chromatid exchange assay. It was positive in the in vitro chromosomal
aberration (CHL cell line) and sister chromatid exchange (CHL/IU cell line)
assays.
Levofloxacin caused no impairment of
fertility or reproductive performance in rats at oral doses as high as 360
mg/kg/day, corresponding to 4.2 times the highest recommended human dose based
upon relative body surface area and intravenous doses as high as 100 mg/kg/day,
corresponding to 1.2 times the highest recommended human dose based upon relative
body surface area.
13.2 Animal Toxicology and/or Pharmacology
Levofloxacin and other quinolones have been shown
to cause arthropathy in immature animals of most species tested [see
Warnings and Precautions (5.9)]. 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. Three-month old beagle dogs dosed orally with levofloxacin
at 40 mg/kg/day exhibited clinically severe arthrotoxicity resulting in the
termination of dosing at Day 8 of a 14-day dosing routine. Slight musculoskeletal
clinical effects, in the absence of gross pathological or histopathological
effects, resulted from the lowest dose level of 2.5 mg/kg/day (approximately
0.2-fold the pediatric dose based upon AUC comparisons). Synovitis and articular
cartilage lesions were observed at the 10 and 40 mg/kg dose levels (approximately
0.7-fold and 2.4-fold the pediatric dose, respectively, based on AUC comparisons).
Articular cartilage gross pathology and histopathology persisted to the end
of the 18-week recovery period for those dogs from the 10 and 40 mg/kg/day
dose levels.
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 nor inhibitor in the human therapeutic plasma concentration
range; therefore, no drug metabolizing enzyme-related interactions with other
drugs or agents are anticipated.
14 CLINICAL STUDIES
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.
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)
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=the number of microbiologically evaluable
patients who were clinical successes; N=number of microbiologically evaluable
patients in the designated resistance group.
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)
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.
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 bacterialsinusitis 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)
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
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.
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).
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
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.
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).
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
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-Cure*
The mITT population
included patients who had a pathogen isolated at baseline. Patients with missing
response were counted as failures in this analysis.
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 X 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.
15 REFERENCES
Clinical and Laboratory Standards Institute. Methods
for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically
Approved Standard – Seventh Edition. Clinical and Laboratory
Standards Institute document M7-A7, Vol. 26, No. 2, CLSI, Wayne, PA, January
2006.
Clinical and Laboratory Standards Institute. Performance
Standards for Antimicrobial Disk Susceptibility Tests. Approved
Standard – Ninth Edition. Clinical and Laboratory Standards Institute
document M2-A9, Vol. 26, No. 1, CLSI, Wayne, PA, January 2006.
16 HOW SUPPLIED/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 0045-1520-50)
–
unit-dose/100 tablets (NDC 0045-1520-10)
500 mg tablets are peach and are imprinted: "LEVAQUIN" on one side and
"500" on the other side
–
bottles of 50 (NDC 0045-1525-50)
–
unit-dose/100 tablets (NDC 0045-1525-10)
750 mg tablets are white and are imprinted "LEVAQUIN" on one side and
"750" on the other side
–
bottles of 20 (NDC 0045-1530-20)
–
unit-dose/100 tablets (NDC 0045-1530-10)
–
LĒVA-pak 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.
16.2 LEVAQUIN® Oral Solution
LEVAQUIN® Oral Solution is supplied
in a 16 oz. multi-use bottle (NDC 0045-1515-01). 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 OMP DIVISION, ORTHO-McNEIL PHARMACEUTICAL, INC.
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 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 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 0045-0067-01)
5 mg/mL (500 mg), 100 mL flexible container, 100 mL fill (NDC 0045-0068-01)
5 mg/mL (750 mg), 150 mL flexible container, 150 mL fill (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 Hospira,
Inc., Lake Forest, IL 60045.
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 quinolone use:
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.
Tendon Disorders: Patients
should discontinue LEVAQUIN® treatment and inform their physician
if they experience pain, inflammation, or rupture of a tendon, and to rest
and refrain from exercise until the diagnosis of tendonitis or tendon rupture
has been excluded. The risk of serious tendon disorders is higher in those
over 65 years of age, especially those on corticosteroids.
Convulsions: Convulsions
have been reported in patients taking quinolones, 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 quinolone antibiotics. Patients should
minimize or avoid exposure to natural or artificial sunlight (tanning beds
or UVA/B treatment) while taking quinolones. If patients need to be outdoors
when taking quinolones, 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.
17.5 FDA-Approved Patient Labeling
Patient Information
About: LEVAQUIN® (levofloxacin) Tablets 250 mg Tablets, 500 mg Tablets, and 750 mg Tablets
And LEVAQUIN® (levofloxacin) Oral Solution, 25 mg/mL
This leaflet contains important information about LEVAQUIN®,
and should be read completely before you begin treatment. This leaflet does
not take the place of discussions with your doctor or healthcare professional
about your medical condition or your treatment. This leaflet does not list
all benefits and risks of LEVAQUIN®. The medicine described
here can be prescribed only by a licensed health care professional. If you
have any questions about LEVAQUIN® talk to your health care
professional. Only your healthcare professional can determine if LEVAQUIN® is
right for you.
What
is LEVAQUIN®?
LEVAQUIN® is
a quinolone antibiotic used to treat lung, sinus, skin, and urinary tract
infections caused by certain germs called bacteria. LEVAQUIN® kills
many of the types of bacteria that can infect the lungs, sinuses, skin, and
urinary tract and has been shown in a large number of clinical trials to be
safe and effective for the treatment of bacterial infections.
Sometimes viruses rather than bacteria may infect the lungs
and sinuses (for example, the common cold). LEVAQUIN®, like
other antibiotics, does not kill viruses.
You
should contact your healthcare professional if you think that your condition
is not improving while taking LEVAQUIN®. LEVAQUIN® Tablets
are terra cotta pink for the 250 mg tablet, peach colored for the 500 mg tablet,
or white for the 750 mg tablet. The appearance of LEVAQUIN® Oral
Solution may range from clear yellow to clear greenish-yellow.
How and when should
I take LEVAQUIN®?
LEVAQUIN® should
be taken once a day for 3, 5, 7, 10, 14 or 28 days depending on your prescription.
LEVAQUIN® Tablets should be swallowed and may be taken with
or without food. LEVAQUIN® Oral Solution should be taken 1
hour before or 2 hours after eating. Try to take the tablet and oral solution
at the same time each day and drink fluids liberally.
You
may begin to feel better quickly; however, in order to make sure that all
bacteria are killed, you should complete the full course of medication. Do
not take more than the prescribed dose of LEVAQUIN® even if
you missed a dose by mistake. You should not take a double dose.
Who should not take
LEVAQUIN®?
You
should not take LEVAQUIN® if you have ever had a severe allergic
reaction to any of the group of antibiotics known as "quinolones" such as
ciprofloxacin. Serious and occasionally fatal allergic reactions have been
reported in patients receiving therapy with quinolones, including LEVAQUIN®.
If you are pregnant or are planning to become pregnant while
taking LEVAQUIN®, talk to your healthcare professional before
taking this medication. LEVAQUIN® is not recommended for use
during pregnancy or nursing, as the effects on the unborn child or nursing
infant are unknown.
Due to possible side effects,
LEVAQUIN® is not recommended for pediatric patients except
in the prevention of anthrax after inhalational exposure.
What are possible side
effects of LEVAQUIN®?
LEVAQUIN® is generally well tolerated. The
most common adverse drug reactions (≥3%) are nausea, headache, diarrhea,
insomnia, constipation, and dizziness.
You
should be careful about driving or operating machinery until you are sure
LEVAQUIN® is not causing dizziness.
Allergic
reactions have been reported in patients receiving quinolones including LEVAQUIN®,
even after just one dose. If you develop hives, skin rash or other symptoms
of an allergic reaction, you should stop taking this medication and call your
healthcare professional.
Hepatotoxicity (liver
damage) has been reported in patients receiving LEVAQUIN®.
Call your doctor right away if you have unexplained symptoms such as: nausea
or vomiting, stomach pain, fever, weakness, abdominal pain or tenderness,
itching, unusual or unexplained tiredness, loss of appetite, light colored
bowel movements, dark colored urine or yellowing of your skin or the whites
of your eyes.
Pain, swelling,
and tears of Achilles, shoulder, or hand tendons have been reported in patients
receiving fluoroquinolones, including LEVAQUIN®. The risk
for tendon effects is higher if you are over 65 years old, and especially
if you are taking corticosteroids. If you develop pain, swelling, or rupture
of a tendon, you should stop taking LEVAQUIN®, avoid exercise
and strenuous use of the affected area, and contact your healthcare professional.
Sun sensitivity (photosensitivity), which can appear as
skin eruption or severe sunburn, can occur in some patients taking quinolone
antibiotics after exposure to sunlight or artificial ultraviolet (UV) light
(e.g., tanning beds). LEVAQUIN® has been infrequently associated
with photosensitivity. Avoid excessive exposure to sunlight or artificial
UV light while taking LEVAQUIN®. Use a sunscreen and wear
protective clothing if out in the sun. If photosensitivity develops, contact
your physician.
If you have diabetes and you
develop a hypoglycemic reaction while on LEVAQUIN®, you should
stop taking LEVAQUIN® and call your healthcare professional.
Convulsions have been reported in patients receiving quinolone
antibiotics including LEVAQUIN®. If you have experienced convulsions
in the past, be sure to let your physician know that you have a history of
convulsions.
Quinolones, including LEVAQUIN®,
may also cause central nervous system stimulation which may lead to tremors,
restlessness, anxiety, lightheadedness, confusion, hallucinations, paranoia,
depression, nightmares, insomnia, and rarely, suicidal thoughts or acts.
Diarrhea that usually ends after treatment is a common problem
caused by antibiotics. A more serious form of diarrhea can occur during or
up to 2 months after the use of antibiotics. This has been reported with all
antibiotics including with LEVAQUIN®. If you develop a watery
and bloody stool with or without stomach cramps and fever, contact your physician
as soon as possible.
In a few people, LEVAQUIN®,
like some other antibiotics, may produce a small effect on the heart that
is seen on an electrocardiogram test. The rare heart problem is called QT
prolongation and can cause an abnormal heartbeat and can be very dangerous.
The chances of this event are increased in those with a family history of
prolonged QT interval, low potassium (hypokalemia), and who are taking drugs
to control heart rhythm, called class IA (quinidine, procainamide) or class
III (amiodarone, sotalol) antiarrhythmic agents. You should call your healthcare
professional right away if you have any prolonged heart palpitations (a change
in the way your heart beats) or a loss of consciousness (fainting spells).
If you notice any side effects not mentioned in this leaflet
or you have concerns about the side effects you are experiencing, please inform
your healthcare professional.
For more complete
information regarding LEVAQUIN®, please refer to the full
prescribing information, which may be obtained from your healthcare professional,
pharmacist, or the Physicians Desk Reference (PDR).
What about other medicines I am taking?
Taking warfarin and LEVAQUIN® together
can further predispose you to the development of bleeding problems. If you
take warfarin, be sure to tell your healthcare professional.
Many antacids and multivitamins may interfere with the absorption
of LEVAQUIN® and may prevent it from working properly. You
should take LEVAQUIN® either 2 hours before or 2 hours after
taking these products.
It is important to let
your healthcare professional know all of the medicines you are using.
What if I have been prescribed
LEVAQUIN® for possible anthrax exposure?
LEVAQUIN® has been approved to reduce
the chance of developing anthrax infection following exposure to the anthrax
bacteria. With the exception of using LEVAQUIN® to prevent
anthrax after possible exposure, LEVAQUIN® is not recommended
for children. If you are pregnant, or plan to become pregnant while taking
LEVAQUIN®, you and your doctor should discuss if the benefits
of taking LEVAQUIN® for anthrax outweigh the risks.
LEVAQUIN® is
generally well tolerated. Side effects that may occur during treatment to
prevent anthrax might be acceptable due to the seriousness of the disease.
You and your doctor should discuss the risks of not taking your medicine against
the risks of experiencing side effects.
Other information
Take
your dose of LEVAQUIN® once a day.
Complete
the course of medication even if you are feeling better.
Keep this medication out of the reach of children.
Some quinolones, 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.
This information
does not take the place of discussions with your doctor or healthcare professional
about your medical condition or your treatment.
OMP
DIVISION ORTHO-McNEIL PHARMACEUTICAL, INC. Raritan, New Jersey,
USA 08869
U.S. Patent No. 5,053,407.
May 2008
LEVAQUIN
levofloxacin
tablet, film coated
Product Information
Product Type
HUMAN PRESCRIPTION DRUG
NDC Product Code (Source)
0045-1520
Route of Administration
ORAL
DEA Schedule
INGREDIENTS
Name (Active Moiety)
Type
Strength
levofloxacin (levofloxacin)
Active
250 MILLIGRAM In 1 TABLET
hypromellose
Inactive
crospovidone
Inactive
magnesium stearate
Inactive
microcrystalline cellulose
Inactive
polyethylene glycol
Inactive
polysorbate 80
Inactive
synthetic red iron oxide
Inactive
titanium dioxide
Inactive
Product Characteristics
Color
pink (terra cotta pink)
Score
no score
Shape
OVAL (capsule shaped)
Size
15mm
Flavor
Imprint Code
LEVAQUIN;250
Contains
Coating
true
Symbol
false
Packaging
#
NDC
Package Description
Multilevel Packaging
1
0045-1520-50
50 TABLET
In 1
BOTTLE
None
2
0045-1520-10
10 BLISTER PACK
In 1
CARTON
contains a BLISTER PACK
2
10 TABLET
In 1
BLISTER PACK
This package is contained within the CARTON (0045-1520-10)
LEVAQUIN
levofloxacin
tablet, film coated
Product Information
Product Type
HUMAN PRESCRIPTION DRUG
NDC Product Code (Source)
0045-1525
Route of Administration
ORAL
DEA Schedule
INGREDIENTS
Name (Active Moiety)
Type
Strength
levofloxacin (levofloxacin)
Active
500 MILLIGRAM In 1 TABLET
hypromellose
Inactive
crospovidone
Inactive
magnesium stearate
Inactive
microcrystalline cellulose
Inactive
polyethylene glycol
Inactive
polysorbate 80
Inactive
synthetic red iron oxide
Inactive
titanium dioxide
Inactive
synthetic yellow iron oxide
Inactive
Product Characteristics
Color
orange (peach)
Score
no score
Shape
OVAL (capsule shaped)
Size
18mm
Flavor
Imprint Code
LEVAQUIN;500
Contains
Coating
true
Symbol
false
Packaging
#
NDC
Package Description
Multilevel Packaging
1
0045-1525-50
50 TABLET
In 1
BOTTLE
None
2
0045-1525-10
10 BLISTER PACK
In 1
CARTON
contains a BLISTER PACK
2
10 TABLET
In 1
BLISTER PACK
This package is contained within the CARTON (0045-1525-10)
LEVAQUIN
levofloxacin
tablet, film coated
Product Information
Product Type
HUMAN PRESCRIPTION DRUG
NDC Product Code (Source)
0045-1530
Route of Administration
ORAL
DEA Schedule
INGREDIENTS
Name (Active Moiety)
Type
Strength
levofloxacin (levofloxacin)
Active
750 MILLIGRAM In 1 TABLET
hypromellose
Inactive
crospovidone
Inactive
magnesium stearate
Inactive
microcrystalline cellulose
Inactive
polyethylene glycol
Inactive
polysorbate 80
Inactive
titanium dioxide
Inactive
Product Characteristics
Color
white (white)
Score
no score
Shape
OVAL (capsule shaped)
Size
20mm
Flavor
Imprint Code
LEVAQUIN;750
Contains
Coating
true
Symbol
false
Packaging
#
NDC
Package Description
Multilevel Packaging
1
0045-1530-20
20 TABLET
In 1
BOTTLE
None
2
0045-1530-10
10 BLISTER PACK
In 1
CARTON
contains a BLISTER PACK
2
10 TABLET
In 1
BLISTER PACK
This package is contained within the CARTON (0045-1530-10)
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Abdominal distress - Levaquin Remedies
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