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FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
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 ß-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 ≥2µg/ml), 2nd generation cephalosporins, e.g., cefuroxime, macrolides, tetracyclines and trimethoprim/sulfamethoxazole.
1.3 Community-Acquired Pneumonia: 5-day Treatment Regimen
LEVAQUIN® is indicated for the treatment of community-acquired pneumonia due to Streptococcus pneumoniae (excluding multi-drug-resistant strains [MDRSP]), Haemophilus influenzae, Haemophilus parainfluenzae, Mycoplasma pneumoniae, or Chlamydophila pneumoniae [see Dosage and Administration (2.1) and Clinical Studies (14.3)].
1.4 Acute Bacterial Sinusitis: 5-day and 10–14 day Treatment Regimens
LEVAQUIN® is indicated for the treatment of acute bacterial sinusitis due to Streptococcus pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis [see Clinical Studies (14.4)].
1.5 Acute Bacterial Exacerbation of Chronic Bronchitis
LEVAQUIN® is indicated for the treatment of acute bacterial exacerbation of chronic bronchitis due to methicillin-susceptible Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, Haemophilus parainfluenzae, or Moraxella catarrhalis.
1.6 Complicated Skin and Skin Structure Infections
LEVAQUIN® is indicated for the treatment of complicated skin and skin structure infections due to methicillin-susceptible Staphylococcus aureus, Enterococcus faecalis, Streptococcus pyogenes, or Proteus mirabilis [see Clinical Studies (14.5)].
1.7 Uncomplicated Skin and Skin Structure Infections
LEVAQUIN® is indicated for the treatment of uncomplicated skin and skin structure infections (mild to moderate) including abscesses, cellulitis, furuncles, impetigo, pyoderma, wound infections, due to methicillin-susceptible Staphylococcus aureus, or Streptococcus pyogenes.
1.8 Chronic Bacterial Prostatitis
LEVAQUIN® is indicated for the treatment of chronic bacterial prostatitis due to Escherichia coli, Enterococcus faecalis, or methicillin-susceptible Staphylococcus epidermidis [see Clinical Studies (14.6)].
1.9 Complicated Urinary Tract Infections: 5-day Treatment Regimen
LEVAQUIN® is indicated for the treatment of complicated urinary tract infections due to Escherichia coli, Klebsiella pneumoniae, or Proteus mirabilis [see Clinical Studies (14.7)].
1.10 Complicated Urinary Tract Infections: 10-day Treatment Regimen
LEVAQUIN® is indicated for the treatment of complicated urinary tract infections (mild to moderate) due to Enterococcus faecalis, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, or Pseudomonas aeruginosa [see Clinical Studies (14.8)].
1.11 Acute Pyelonephritis: 5 or 10-day Treatment Regimen
LEVAQUIN® is indicated for the treatment of acute pyelonephritis caused by Escherichia coli, including cases with concurrent bacteremia [see Clinical Studies (14.7, 14.8)].
1.12 Uncomplicated Urinary Tract Infections
LEVAQUIN® is indicated for the treatment of uncomplicated urinary tract infections (mild to moderate) due to Escherichia coli, Klebsiella pneumoniae, or Staphylococcus saprophyticus.
1.13 Inhalational Anthrax (Post-Exposure)
LEVAQUIN® is indicated for inhalational anthrax (post-exposure) to reduce the incidence or progression of disease following exposure to aerosolized Bacillus anthracis. The effectiveness of LEVAQUIN® is based on plasma concentrations achieved in humans, a surrogate marker considered likely to predict efficacy. 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 has not been studied. Prolonged LEVAQUIN® therapy in adults should only be used when the benefit outweighs the risk [see Dosage and Administration (2.1) and Clinical Studies (14.9)].
2 DOSAGE AND ADMINISTRATION
2.1 Dosage in 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 (2.2)].
| Type of Infection* | Dosed Every 24 hours | Duration (days)† |
|---|---|---|
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| Nosocomial Pneumonia | 750 mg | 7–14 |
| Community Acquired Pneumonia‡ | 500 mg | 7–14 |
| Community Acquired Pneumonia§ | 750 mg | 5 |
| Acute Bacterial Sinusitis | 750 mg | 5 |
| 500 mg | 10–14 | |
| Acute Bacterial Exacerbation of Chronic Bronchitis | 500 mg | 7 |
| Complicated Skin and Skin Structure Infections (SSSI) | 750 mg | 7–14 |
| Uncomplicated SSSI | 500 mg | 7–10 |
| Chronic Bacterial Prostatitis | 500 mg | 28 |
| Complicated Urinary Tract Infection (cUTI) or Acute Pyelonephritis (AP)¶ | 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), adultÞ,ß | 500 mg | 60ß |
2.2 Dosage Adjustment in Patients 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 2 shows how to adjust dose based on creatinine clearance.
| 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 |
2.3 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 (2.5)].
2.4 Administration Instructions
Food and LEVAQUIN® Tablets and Oral Solution
LEVAQUIN® Tablets can be administered without regard to food. It is recommended that LEVAQUIN® Oral Solution be taken 1 hour before or 2 hours after eating.
LEVAQUIN® Injection
Caution: Rapid or bolus intravenous infusion of LEVAQUIN® has been associated with hypotension and must be avoided. LEVAQUIN® Injection should be infused intravenously slowly over a period of not less than 60 or 90 minutes, depending on the dosage. LEVAQUIN® Injection should be administered only by intravenous infusion. It is not for intramuscular, intrathecal, intraperitoneal, or subcutaneous administration.
Hydration for Patients Receiving LEVAQUIN® Tablets, Oral Solution, and Injection
Adequate hydration of patients receiving oral or intravenous LEVAQUIN® should be maintained to prevent the formation of highly concentrated urine. Crystalluria and cylindruria have been reported with quinolones [see Adverse Reactions (6.1) and Patient Counseling Information (17.2)].
2.5 Preparation of Intravenous Product
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 3]. 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:
| 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 |
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, 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.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
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 4:
| 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 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. The premix flexible containers must be used within six days (250 mg) or seven days (500 mg, 750 mg) after removal from the foil overwrap. Once removed from the foil overwrap, the premix in flexible containers should be stored at room temperature (25°C; 77°F), avoiding excessive heat and protected from freezing and light. 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 contains equivalent of 500 mg of levofloxacin
- 30 mL vial contains equivalent of 750 mg of levofloxacin
INJECTION (5 mg/mL in 5% Dextrose) Premix in Single-Use Flexible Containers, for intravenous infusion
- 100 mL container, fill volume 50 mL (equivalent of 250 mg levofloxacin)
- 100 mL container, fill volume 100 mL (equivalent of 500 mg levofloxacin)
- 150 mL container, fill volume 150 mL (equivalent of 750 mg levofloxacin)
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 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, especially the elderly. 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 with quinolones, including LEVAQUIN®[see Adverse Reactions (6); Patient Counseling Information (17.3)].
5.4 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)].
5.5 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)].
5.6 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)].
5.7 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)].
5.8 Musculoskeletal Disorders in Pediatric Patients and Arthropathic Effects in Animals
LEVAQUIN® is not indicated for pediatric patients (less than 18 years of age). 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 Nonclinical Toxicology (13.2)].
5.9 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)].
5.10 Phototoxicity
Moderate to severe phototoxicity reactions have been observed in patients exposed to direct sunlight while receiving drugs in this class. Excessive exposure to sunlight should be avoided. However, in clinical trials with LEVAQUIN®, phototoxicity has been observed in less than 0.1% of patients. Therapy should be discontinued if phototoxicity (e.g., a skin eruption) occurs [see Adverse Reactions (6.3); Patient Counseling Information (17.3)].
5.11 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:
- Hypersensitivity Reactions [see Warnings and Precautions (5.1)]
- Other Serious and Sometimes Fatal Reactions [see Warnings and Precautions (5.2)]
- Tendon Effects [see Warnings and Precautions (5.3)]
- Central Nervous System Effects [see Warnings and Precautions (5.4)]
- Clostridium difficile-Associated Diarrhea [see Warnings and Precautions (5.5)]
- Peripheral Neuropathy [see Warnings and Precautions (5.6)]
- Prolongation of the QT Interval [see Warnings and Precautions (5.7)]
- Musculoskeletal Disorders in Pediatric Patients [see Warnings and Precautions (5.8)]
- Blood Glucose Disturbances [see Warnings and Precautions (5.9)]
- Phototoxicity [see Warnings and Precautions (5.10)]
- Development of Drug Resistant Bacteria [see Warnings and Precautions (5.11)]
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 (2.4)].
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 (2.4)].
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® in 7537 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 5 and Table 6, respectively. The most common adverse drug reactions (≥3%) are nausea, headache, diarrhea, insomnia, constipation, and dizziness.
| System/Organ Class | Adverse Reaction | % (N=7537) |
|---|---|---|
| Infections and Infestations | moniliasis | 1 |
| Psychiatric Disorders | insomnia* [see Warnings and Precautions (5.4)]
| 4 |
| Nervous System Disorders | headache dizziness [see Warnings and Precautions (5.4)] | 6 3 |
| Respiratory, Thoracic and Mediastinal Disorders | dyspnea [see Warnings and Precautions (5.1)] | 1 |
| Gastrointestinal Disorders | nausea diarrhea constipation abdominal pain vomiting dyspepsia | 7 5 3 2 2 2 |
| Skin and Subcutaneous Tissue Disorders | rash [see Warnings and Precautions (5.1)]
pruritus | 2 1 |
| Reproductive System and Breast Disorders | vaginitis | 1† |
| General Disorders and Administration Site Conditions | edema injection site reaction chest pain | 1 1 1 |
| System/Organ Class | Adverse Reaction |
|---|---|
|
|
| Infections and Infestations | genital moniliasis |
| Blood and Lymphatic System Disorders
| anemia thrombocytopenia granulocytopenia [see Warnings and Precautions (5.2)] |
| Immune System Disorders
| allergic reaction [See Warnings and Precautions (5.1, 5.2)] |
| Metabolism and Nutrition Disorders | hyperglycemia hypoglycemia [see Warnings and Precautions (5.9)] hyperkalemia |
| Psychiatric Disorders | anxiety agitation confusion depression hallucination nightmare* [see Warnings and Precautions (5.4)] sleep disorder* anorexia abnormal dreaming* |
| Nervous System Disorders | tremor convulsions [see Warnings and Precautions (5.4)] paresthesia [see Warnings and Precautions (5.6)] vertigo hypertonia hyperkinesias abnormal gait somnolence* syncope |
| Respiratory, Thoracic and Mediastinal Disorders | epistaxis |
| Cardiac Disorders | cardiac arrest palpitation ventricular tachycardia ventricular arrhythmia |
| Vascular Disorders | phlebitis |
| Gastrointestinal Disorders | gastritis stomatitis pancreatitis esophagitis gastroenteritis glossitis pseudomembraneous/ C. difficile colitis [see Warnings and Precautions (5.5)] |
| Hepatobiliary Disorders | abnormal hepatic function increased hepatic enzymes increased alkaline phosphatase |
| Skin and Subcutaneous Tissue Disorders | urticaria [see Warnings and Precautions (5.1)] |
| Musculoskeletal and Connective Tissue Disorders | arthralgia tendonitis [see Warnings and Precautions (5.3)] myalgia skeletal pain |
| Renal and Urinary Disorders | abnormal renal function acute renal failure [see Warnings and Precautions (5.2)] |
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 7 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.
| System/Organ Class | Adverse Reaction |
|---|---|
| Blood and Lymphatic System Disorders | pancytopenia aplastic anemia leukopenia hemolytic anemia [see Warnings and Precautions (5.2)] eosinophilia |
| Immune System Disorders | hypersensitivity reactions, sometimes fatal including: anaphylactic/anaphylactoid reactions anaphylactic shock angioneurotic edema serum sickness [see Warnings and Precautions (5.1, 5.2)] |
| Psychiatric Disorders | psychosis paranoia isolated reports of suicide attempt and suicidal ideation [see Warnings and Precautions (5.4)] |
| Nervous System Disorders
| anosmia ageusia parosmia dysgeusia peripheral neuropathy [see Warnings and Precautions (5.6)] isolated reports of encephalopathy abnormal electroencephalogram (EEG) dysphonia |
| Eye Disorders | vision disturbance, including diplopia visual acuity reduced vision blurred scotoma |
| Ear and Labyrinth Disorders | hypoacusis tinnitus |
| Cardiac Disorders | isolated reports of torsade de pointes electrocardiogram QT prolonged [see Warnings and Precautions (5.7) ] tachycardia |
| Vascular Disorders | vasodilatation |
| Respiratory, Thoracic and Mediastinal Disorders | isolated reports of allergic pneumonitis [see Warnings and Precautions (5.2)]
|
| Hepatobiliary Disorders | hepatic failure (including fatal cases) hepatitis jaundice [see Warnings and Precautions (5.2)] |
| Skin and Subcutaneous Tissue Disorders | bullous eruptions to include: Stevens-Johnson Syndrome toxic epidermal necrolysis erythema multiforme [see Warnings and Precautions (5.2)] photosensitivity reaction [see Warnings and Precautions (5.10)] leukocytoclastic vasculitis |
| Musculoskeletal and Connective Tissue Disorders | tendon rupture [see Warnings and Precautions (5.3)]
muscle injury, including rupture rhabdomyolysis |
| Renal and Urinary Disorders | interstitial nephritis [see Warnings and Precautions (5.2)]. |
| 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 (2.4)].
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 (5.9); 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 (5.4)].
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 (5.4)].
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.
8.4 Pediatric Use
LEVAQUIN® is not indicated for pediatric patients (less than 18 years of age) (See Warnings and Precautions [5.8]).
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 8.
| Follow-up Period | LEVAQUIN®
N = 1340 | Non-Fluoroquinolone*
N = 893 | p-value† |
|---|---|---|---|
|
|||
| 60 days | 28 (2.1%) | 8 (0.9%) | p = 0.038 |
| 1 year‡ | 46 (3.4%) | 16 (1.8%) | p = 0.025 |
Arthralgia was the most frequently occurring musculoskeletal disorder in both treatment groups. Most of the musculoskeletal disorders in both groups involved multiple weight-bearing joints. Disorders were moderate in 8/46 (17%) children and mild in 35/46 (76%) LEVAQUIN®-treated children and most were treated with analgesics. The median time to resolution was 7 days for LEVAQUIN®-treated children and 9 for non-fluoroquinolone-treated children (approximately 80% resolved within 2 months in both groups). No child had a severe or serious disorder and all musculoskeletal disorders resolved without sequelae.
Vomiting and diarrhea were the most frequently reported adverse events, occurring in similar frequency in the LEVAQUIN®-treated and non-fluoroquinolone-treated children.
In addition to the events reported in pediatric patients in clinical trials, events reported in adults during clinical trials or post-marketing experience may also be expected to occur in pediatric patients.
8.5 Geriatric Use
In phase 3 clinical trials, 1,190 LEVAQUIN®-treated patients (25%) were ≥ 65 years of age. Of these, 675 patients (14%) were between the ages of 65 and 74 and 515 patients (11%) 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.
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 (5.7)].
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 (5.3)].
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 (2.2)].
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 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 9.
| Regimen | Cmax | Tmax | AUC | CL/F1 | Vd/F2 | t1/2 | CLR |
|---|---|---|---|---|---|---|---|
| (µg/mL) | (h) | (µg·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 24 | |||||||