LEVOFLOXACIN

Pronounciation

• (lee-voh-FLOX-ah-sin)

Trade Name(s)

• Levaquin

• Antibacterial (fluoroquinolone)

• pH 3.8 to 5.8

Pretreatment:

Baseline studies indicated; see Monitor.

250 to 750 mg once every 24 hours. Dose and duration of treatment are based on degree of infection and specific diagnosis. CrCl equal to or greater than 50 mL/min is required. Dose and serum levels similar by oral or IV route. Transfer to oral dose as soon as practical.

No dose adjustment is required specifically for age, gender, race, or in impaired hepatic function.
■ Clearance is reduced and half-life is prolonged in patients with a CrCl less than 50 mL/min. See the following chart for dosing guidelines. See Important IV Therapy Facts on p. xix for formula to convert SCr to CrCl.
■ Supplemental doses are not required after hemodialysis or peritoneal dialysis.

Available in single-use vials and as prediluted, ready-to-use infusions.

Single-use vials:

Withdraw desired dose from single-use vial (10 mL for 250 mg, 20 mL for 500 mg, 30 mL for 750 mg). Each 10 mL (250 mg) must be further diluted with a minimum of 40 mL NS, D5W, D5NS, D5LR, or D5/₁/²NS. Desired concentration is 5 mg/mL. No preservatives; enter vial only once. When 500-mg (20-mL) vial is used to prepare two 250-mg doses, withdraw entire contents of vial at once using a single-entry procedure. Prepare and store second dose for subsequent use.

Premix flexible containers:

No further dilution necessary. Available as 250 mg in 50 mL, 500 mg in 100 mL, or 750 mg in 150 mL D5W. Instructions for access to and use of premix flexible containers are on its storage carton. Do not use flexible containers in series connections.

Filters:

Not required; however, contents of both vials and premixed solutions were filtered during manufacturing with polyvinyl mixed ester cellulose filters. Size not specified by manufacturer. No significant loss of potency expected.

Storage:

Store vials at CRT; protect from light. Store premix at or below 25° C (77° F); protect from freezing, light, and excessive heat. Premixed product may also be stored in the refrigerator. Brief exposure up to 40° C (104° F) does not adversely affect the product. Both are stable to expiration date. Solutions diluted from vials are stable at or below 25° C (77° F) for 3 days and for up to 14 days if refrigerated. May be frozen for up to 6 months. Do not force thaw (e.g., microwave or water bath) and do not refreeze. Discard any unused portion of premixed solutions and/or opened vials.

Manufacturer states, “Limited compatibility information available; other intravenous substances, additives, or other medications should not be added to levofloxacin or infused simultaneously through the same intravenous line.” Never administer in the same IV or through the same tubing with any solution containing multivalent cations (e.g., calcium, magnesium). Flush line with a compatible solution before and after administration of levofloxacin and/or any other drug through the same IV line.

Other sources suggest specific compatibilities dependent on concentration and manufacturer; consult a pharmacist.

Each 250- or 500-mg dose must be given over 60 minutes as an infusion. A 750-mg dose must be given over 90 minutes as an infusion. Too-rapid administration may cause hypotension. May be given through a Y-tube of infusion set. Temporarily discontinue other solutions infusing at the same site and flush tubing with compatible solutions before and after levofloxacin.

A synthetic, broad-spectrum, fluoroquinolone antibacterial agent. Bactericidal to aerobic gram-negative and gram-positive organisms through interference with enzymes (type II topoisomerases) needed for bacterial DNA replication, transcription, repair, and recombination. May be active against bacteria resistant to aminoglycosides, beta-lactam antibiotics, and macrolides. Onset of action is prompt, and serum levels are dose related. Mean terminal half-life is 6 to 8 hours. Steady state is achieved within 48 hours. Widely distributed into body tissues, including blister fluid and lung tissues. Moderately bound to serum protein (24% to 38%). Metabolism is minimal; primarily excreted as unchanged drug in urine. Very small amounts found in bile and feces. May cross placental barrier. May be secreted in breast milk.

Treatment of adults with mild, moderate, and severe infections caused by susceptible strains of designated microorganisms in conditions listed in this section.
■ Treatment of nosocomial pneumonia. For cases in which Pseudomonas aeruginosa is a documented or presumptive organism, combination therapy with an anti-pseudomonal beta-lactam is recommended.
■ Treatment of community-acquired pneumonia due to many organisms, including Streptococcus pneumoniae (including multidrug-resistant strains [MDRSPs]). MDRSP strains are resistant to two or more of the following antibiotics: penicillin, second-generation cephalosporins (e.g., cefuroxime), macrolides, tetracyclines, and sulfamethoxazole/trimethoprim.
■ Treatment of complicated skin and skin structure infections and mild to moderate uncomplicated skin and skin structure infections.
■ Treatment of complicated urinary tract infections and acute pyelonephritis (including cases with concurrent bacteremia).
■ Treatment of uncomplicated urinary tract infections. Because fluoroquinolones, including levofloxacin, have been associated with serious adverse reactions and because for some patients uncomplicated urinary tract infection is self-limiting, reserve levofloxacin for treatment of uncomplicated urinary tract infections in patients who have no alternative treatment options.
■ Treatment of acute bacterial exacerbation of chronic bronchitis (ABECB) and acute bacterial sinusitis (ABS). Because fluoroquinolones, including levofloxacin, have been associated with serious adverse reactions and because for some patients ABECB and ABS are self-limiting, reserve levofloxacin for treatment in patients who have no alternative treatment options.
■ To reduce the incidence or progression of inhalational anthrax following exposure to Bacillus anthracis in adults and pediatric patients. Begin administration as soon as possible after suspected or confirmed exposure. Transfer to oral therapy when practical.
■ Treatment of plague, including pneumonic and septicemic plague, due to Yersinia pestis, as well as prophylaxis for plague in adults and pediatric patients 6 months of age and older.
■ Treatment of chronic bacterial prostatitis (usually oral therapy).

History of hypersensitivity to levofloxacin, its components, or any other quinolone antimicrobial agents (e.g., ciprofloxacin, norfloxacin).

For IV use only.
■ To reduce the development of drug-resistant bacteria and maintain its effectiveness, levofloxacin should be used to treat or prevent only those infections proven or strongly suspected to be caused by bacteria.
■ Culture and sensitivity studies indicated to determine susceptibility of the causative organism to levofloxacin.
■ P. aeruginosa may develop resistance during treatment. Ongoing culture and sensitivity studies indicated.
■ The emergence of bacterial resistance to fluoroquinolones and the occurrence of crossresistance with other fluoroquinolones have been observed and are of concern. Proper use of fluoroquinolones and other classes of antibiotics is encouraged to avoid the emergence of resistant bacteria from overuse.
■ Cross-resistance may occur with other fluoroquinolones, but some microorganisms resistant to other fluoroquinolones may be susceptible to levofloxacin.
■ Prolonged use may cause superinfection because of overgrowth of nonsusceptible organisms.
■ Fluoroquinolones, including levofloxacin, have been associated with disabling and potentially irreversible serious adverse reactions that have occurred together in the same patient. Commonly seen adverse reactions include tendinitis and tendon rupture, arthralgia, myalgia, peripheral neuropathy, CNS effects (e.g., anxiety, confusion, depression, hallucinations, insomnia, severe headaches), and hypoglycemia or hyperglycemia. Due to the potential for side effects, the FDA suggests not using levofloxacin unless there are no other alternatives. These reactions can occur within hours to weeks after starting levofloxacin and have been seen in patients of any age and in patients without any pre-existing risk factors. Discontinue levofloxacin immediately and avoid the use of fluoroquinolones, including levofloxacin, in patients who experience any of these serious adverse reactions.
■ Fluoroquinolones, including levofloxacin, have been associated with an increased risk of seizures (convulsions), increased intracranial pressure (pseudotumor cerebri), tremors, and light-headedness. May trigger seizures or lower the seizure threshold. Use caution in patients with epilepsy or known or suspected CNS disorders that may predispose patients to seizures or lower the seizure threshold (e.g., severe cerebral arteriosclerosis, previous history of convulsions, reduced cerebral blood flow, altered brain structure, or stroke) or in the presence of other risk factors that may predispose patients to seizures (e.g., drugs that may lower the seizure threshold, renal dysfunction).
■ Fluoroquinolones, including levofloxacin, have been associated with an increased risk of psychiatric adverse reactions, including toxic psychosis; psychotic reactions progressing to suicidal ideations/thoughts, hallucinations, or paranoia; depression or self-injurious behavior such as attempted or completed suicide; anxiety, agitation, restlessness, or nervousness; confusion, delirium, disorientation, or disturbances in attention; insomnia or nightmares; and memory impairment. These reactions may occur after the first dose.
■ Use caution in patients with impaired renal function; see Dose Adjustments.
■ Severe, sometimes fatal hepatotoxicity has been reported. Symptoms appeared within 6 to 14 days of initiating therapy, and most cases were not associated with hypersensitivity. The majority of fatal hepatotoxicity reports occurred in patients 65 years of age or older; see Patient Education and Antidote.
■ Tendinitis and tendon rupture that required surgical repair or resulted in prolonged disability have been reported in patients of all ages receiving quinolones. Most frequently involves the Achilles tendon but has also been reported with the shoulder, hand, biceps, thumb, and other tendon sites.
■ Tendon rupture or tendinitis may occur during or up to months after fluoroquinolone therapy and may occur bilaterally. Risk may be increased in patients over 60 years of age; in patients taking corticosteroids; in patients with heart, kidney, or lung transplants; with strenuous physical activity; and in patients with renal failure or previous tendon disorders such as rheumatoid arthritis. Avoid levofloxacin in patients who have a history of tendon disorders or have experienced tendinitis or tendon rupture. Discontinue levofloxacin immediately if patient experiences pain, swelling, inflammation, or rupture of a tendon.
■ Prolongation of the QT interval on ECG and infrequent cases of arrhythmia (including torsades de pointes) have been reported. The risk of arrhythmia may be reduced by avoiding the use of levofloxacin in patients with known prolongation of the QT interval, uncorrected electrolyte imbalances (e.g., hypokalemia, hypomagnesemia), significant bradycardia, cardiomyopathy, or concurrent treatment with Class Ia antiarrhythmic agents (e.g., quinidine, procainamide) or Class III antiarrhythmic agents (e.g., amiodarone, sotalol) and any other drug that can prolong the QT interval; avoid coadministration; see Drug/Lab Interactions.
■ Fluoroquinolones have neuromuscular blocking activity and may exacerbate muscle weakness in persons with myasthenia gravis. Serious adverse events, including a requirement for ventilatory support and deaths, have been reported in these patients. Avoid use in patients with a known history of myasthenia gravis.
■ Fluoroquinolones, including levofloxacin, have been associated with an increased risk of peripheral neuropathy. Cases of sensory or sensorimotor axonal polyneuropathy resulting in paresthesias, hypoesthesias, dysesthesias (impairment of sensitivity or touch), or weakness have been reported. Symptoms may occur soon after initiation of therapy and may be irreversible. Avoid levofloxacin in patients who have previously experienced peripheral neuropathy.
■ Serious and occasionally fatal hypersensitivity and/or anaphylactic reactions have been reported. Often occur after the first dose.
■ Other serious events (sometimes fatal) due to hypersensitivity or uncertain etiology have been reported with fluoroquinolones, including levofloxacin; usually occur after multiple doses. Manifestations may include allergic pneumonitis, arthralgia, myalgia, renal or hepatic impairment/failure, hematologic toxicity, dermatologic toxicity, serum sickness, and vasculitis; see Side Effects, Post-Marketing. Immediately discontinue levofloxacin at the first appearance of a skin rash, jaundice, or other signs of hepatotoxicity or hypersensitivity.
■ Clostridium difficile–associated diarrhea (CDAD) has been reported. May range from mild diarrhea to fatal colitis. Consider in patients who present with diarrhea during or after treatment with levofloxacin.
■ Epidemiologic studies report an increased rate of aortic aneurysm and dissection within 2 months after use of fluoroquinolones, particularly in elderly patients. In patients with a known aortic aneurysm or in patients who are at greater risk for aortic aneurysms, levofloxacin use should be limited to cases in which no alternative antibacterial treatments are available.
■ Moderate to severe photosensitivity/phototoxicity reactions have been reported in patients receiving quinolones; see Patient Education.
■ Fluoroquinolones, including levofloxacin, have been associated with disturbances of blood glucose, including symptomatic hyperglycemia and hypoglycemia, usually in patients with diabetes who are receiving concomitant treatment with an oral hypoglycemic agent (e.g., glyburide) or with insulin. In these patients careful monitoring of blood glucose is recommended. Severe cases of hypoglycemia resulting in coma or death have been reported.
■ Not tested in humans for postexposure prevention of inhalation anthrax; however, plasma concentrations are considered to be in a range to produce effective results.
■ Safety for use in adults beyond 28 days or in pediatric patients beyond 14 days not studied; use only for prescribed indication; benefits must outweigh risks. An increased incidence of musculoskeletal adverse events has been observed in pediatric patients.

Monitor:

Obtain baseline CBC with differential, CrCl, and blood glucose. Periodic monitoring of organ systems, including hematopoietic, hepatic, and renal, is recommended.
■ Monitor for S/S of a hypersensitivity reaction (e.g., airway obstruction, angioedema, cardiovascular collapse, dyspnea, hypotension/shock, itching, loss of consciousness, seizure, tingling, urticaria, and other serious skin reactions). May cause anaphylaxis with the first or succeeding doses, even in patients without known hypersensitivity. Emergency equipment must always be available; see Precautions.
■ Monitor for S/S of peripheral neuropathy. Discontinue levofloxacin at the first symptoms of neuropathy (e.g., pain, burning, tingling, numbness and/or weakness) or if patient is found to have deficits in light touch, pain, temperature, position sense, vibratory sensation, and/or motor strength.
■ ECG monitoring for QT prolongation may be indicated in select patients.
■ Monitor for CNS adverse effects, including altered mental status, seizures, and changes in mood or behavior.
■ Monitor for S/S of tendinitis or tendon rupture.
■ Maintain adequate hydration to prevent concentrated urine throughout treatment. Crystalluria and cylindruria have been reported with quinolones.
■ Monitor infusion site for inflammation and/or extravasation.
■ Monitor blood glucose, especially in patients with diabetes.
■ See Precautions, Drug/Lab Interactions, and Antidote.

Patient Education:

A patient medication guide is available from the manufacturer.
■ Discontinue levofloxacin and promptly report the development of any severe adverse reaction.
■ Review all medicines and disease history with pharmacist or physician before initiating treatment.
■ Inform physician of any history of myasthenia gravis.
■ Patients with a history of myasthenia gravis should avoid the use of levofloxacin.
■ Drink fluids liberally.
■ Promptly report skin rash or any other hypersensitivity reaction.
■ Promptly report pain, burning, tingling, numbness and/or weakness in extremities. Nerve damage can be permanent.
■ Photosensitivity has been reported. Avoid excessive sunlight or artificial ultraviolet light. May cause severe sunburn; wear protective clothing, use sunscreen, and wear dark glasses outdoors. Report a sunburn-like reaction or skin eruption promptly.
■ Promptly report development of any CNS side effects (e.g., convulsions, dizziness, light-headedness, change in mood or behavior).
■ Inform physician of any history of seizures.
■ Request assistance with ambulation; may cause dizziness and light-headedness. Use caution in tasks that require alertness.
■ Effects of caffeine, theophylline preparations, and/or warfarin (Coumadin) may be increased; notify your physician if you take any of these agents. If diabetic and on medication, monitor your blood glucose carefully. If a hypoglycemia reaction occurs, discontinue levofloxacin and consult physician.
■ Promptly report S/S of liver injury (e.g., dark-colored urine, fever, itching, jaundice [yellowing of skin or whites of eyes], light-colored bowel movements, loss of appetite, nausea, right upper quadrant tenderness, tiredness, vomiting, weakness).
■ Promptly report tendon pain or inflammation, weakness, or the inability to use a joint; rest and refrain from exercise.
■ Before initiating therapy, parents should inform their child’s physician if their child has a history of joint-related problems, and they should notify their child’s physician of any tendon or joint-related problems that occur during or after therapy.
■ Promptly report diarrhea or bloody stools that occur during treatment or up to several months after an antibiotic has been discontinued; may indicate CDAD and require treatment.
■ Seek emergency medical care if sudden chest, stomach, or back pain is experienced.
■ See Precautions, Monitor, Drug/Lab Interactions, and Antidote.

Maternal/Child:

Safety for use in pregnancy not established; benefits must outweigh risks.
■ Discontinue breast-feeding.
■ Safety for use in pediatric patients under 18 years of age not established. Indicated in pediatric patients 6 months of age or older only for prevention of inhalation anthrax (postexposure) and prevention and treatment of plague. The risk-benefit assessment indicates that administration of levofloxacin to pediatric patients for these indications is appropriate. Safety for use in pediatric patients under 6 months of age not established.
■ An increased incidence of musculoskeletal disorders (arthralgia, arthritis, tendinopathy, and gait abnormality) compared with controls has been observed in pediatric patients receiving levofloxacin. May erode cartilage of weight-bearing joints or cause other signs of arthropathy in infants and children.

Elderly:

Half-life may be slightly extended due to age-related renal impairment. Dose reduction required only in the elderly with a CrCl of less than 50 mL/min.
■ Safety and effectiveness similar to that in younger adults; however, they may experience an increased risk of side effects (e.g., aortic aneurysm and dissection, CNS effects, hepatotoxicity, tendinitis, tendon rupture, risk of QT prolongation). Monitoring of renal function may be useful.
■ See Dose Adjustments and Precautions.

May cause ventricular arrhythmias or torsades de pointes with drugs that prolong the QT interval, such as Class Ia antiarrhythmic agents (e.g., quinidine, procainamide), Class III antiarrhythmic agents (e.g., amiodarone, sotalol), phenothiazines (e.g., chlorpromazine), tricyclic antidepressants (e.g., imipramine, amitriptyline). Avoid coadministration.
■ Risk of CNS stimulation and convulsive seizures may be increased with NSAIDs.
■ May cause hyperglycemia and hypoglycemia with concurrent administration of antidiabetic agents; monitoring of blood glucose recommended.
■ Interactions with theophylline that occur with other quinolones have not been noted, but monitoring of theophylline levels is recommended with concomitant use.
■ May enhance effects of warfarin; monitoring of PT or INR is recommended with concomitant use.
■ May cause false-positive when testing urine for opiates; more specific testing methods may be indicated.

The most common side effects are constipation, diarrhea, dizziness, headache, insomnia, and nausea. Abdominal pain, chest pain, crystalluria, cylindruria, dyspepsia, dyspnea, edema, injection site reaction, moniliasis, photosensitivity/phototoxicity (sun sensitivity), pruritus, rash, vaginitis, and vomiting have occurred. Abnormal dreaming, abnormal gait, abnormal hepatic function, abnormal renal function, acute renal failure, agitation, anemia, anorexia, anxiety, arthralgia, cardiac arrest, CDAD, confusion, convulsions, depression, epistaxis, esophagitis, gastritis, gastroenteritis, genital moniliasis, glossitis, granulocytopenia, hallucinations, hyperglycemia, hyperkalemia, hyperkinesia, hypersensitivity reactions, hypertonia, hypoglycemia, increased alkaline phosphatase, increased hepatic enzymes, myalgia, nightmares, palpitation, pancreatitis, paresthesia, phlebitis, pseudomembranous colitis, skeletal pain, sleep disorders, somnolence, stomatitis, syncope, tendinitis, thrombocytopenia, tremor, urticaria, ventricular arrhythmia, ventricular tachycardia, and vertigo have also been reported in fewer than 1% of patients.

Post-Marketing:

Abnormal EEG; hematologic abnormalities (agranulocytosis, anemia [hemolytic and aplastic], eosinophilia, leukopenia, pancytopenia, thrombocytopenia [including thrombotic thrombocytopenic purpura]); exacerbation of myasthenia gravis; eye disorders (e.g., blurred vision, diplopia, reduced visual acuity, scotoma, uveitis); hepatic failure, including fatal cases; fever; hepatitis; hypersensitivity reactions (sometimes fatal, including angioneurotic edema, anaphylaxis); interstitial nephritis; jaundice; leukocytoclastic vasculitis; multiorgan failure; muscle injury and increased muscle enzymes; paranoia; peripheral neuropathy; photosensitivity/phototoxicity reactions; prolonged INR; prolonged PT; prolonged QT interval; pseudotumor cerebri; psychosis; rhabdomyolysis; serum sickness; severe dermatologic reactions (e.g., acute generalized exanthematous pustulosis [AGEP], fixed drug eruptions, erythema multiforme, toxic epidermal necrolysis [Lyell’s syndrome], Stevens-Johnson syndrome); tachycardia; tendon rupture; tinnitus; vasodilation; and isolated reports of allergic pneumonitis, encephalopathy, suicidal ideation, suicide attempts, completed suicide, and torsades de pointes.

Keep physician informed of all side effects. Most minor side effects will be treated symptomatically; monitor closely. Discontinue levofloxacin at the first sign of any major side effect (CDAD, CNS symptoms, dermatologic reactions, hepatotoxicity, hypersensitivity, hypoglycemic reactions, phototoxicity, symptoms of peripheral neuropathy, or tendon rupture). Treat hypersensitivity reactions as indicated with epinephrine, airway management, oxygen, IV fluids, antihistamines (e.g., diphenhydramine), corticosteroids, and pressor amines (e.g., dopamine). Treat CNS symptoms as indicated. Mild cases of CDAD may respond to discontinuation of levofloxacin. Treat CDAD with fluids, electrolytes, protein supplements, and appropriate antibiotics (e.g., oral vancomycin) as indicated. In severe cases, surgical evaluation may be indicated. Complete rest is indicated for an affected tendon until treatment is available. Maintain hydration in overdose. No specific antidote; not removed by hemodialysis or peritoneal dialysis. Maintain patient until drug is excreted and symptoms subside.