levofloxacin (Rx)

1-10%

Nausea (7%)

Headache (6%)

Diarrhea (5%)

Insomnia (4%)

Constipation (3%)

Dizziness (3%)

Dyspepsia (2%)

Rash (2%)

Vomiting (2%)

Chest pain (1%)

Dyspnea (1%)

Edema (1%)

Fatigue (1%)

Injection-site reaction (1%)

Moniliasis (1%)

Pain (1%)

Pruritus (1%)

Vaginitis (1%)

<1%

Cardiac: Cardiac arrest, palpitation, ventricular tachycardia, arrhythmia

Nervous system: Tremor, convulsions, paresthesia, vertigo, hypertonia, hyperkinesias, abnormal gait, somnolence, syncope

Metabolic: Hypoglycemia, hyperglycemia, hyperkalemia

Blood/lymphatic system: Anemia, thrombocytopenia, granulocytopenia

Musculoskeletal/connective tissue: Arthralgia, tendonitis, myalgia, skeletal pain

Gastrointestinal (GI): Gastritis, stomatitis, pancreatitis, esophagitis, gastroenteritis, glossitis, pseudomembranous/C difficile colitis

Hepatobiliary: Abnormal hepatic function, increased hepatic enzymes, increased alkaline phosphatase

Psychiatric: Anxiety, agitation, confusion, depression, hallucinations, nightmares, sleep disorder, anorexia, abnormal dreaming

Other: Immune hypersensitivity reaction, acute renal failure, urticaria, phlebitis, epistaxis

Postmarketing Reports

Cardiac: Prolonged QT interval, torsades de pointes, tachycardia

Vascular disorders: Aortic aneurysm and dissection

Musculoskeletal/connective tissue: Tendon rupture, muscle injury, rhabdomyolysis

Skin/subcutaneous tissue: Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, photosensitivity/phototoxicity, leukocytoclastic vasculitis

Renal and urinary disorders: Interstitial nephritis

Vascular disorders: Vasodilation; increased risk of aortic aneurysm and dissection

Blood/lymphatic system: Pancytopenia, aplastic anemia, leukopenia, hemolytic anemia, eosinophilia

Hepatobiliary: Hepatic failure, hepatitis, jaundice

Psychiatric: Psychosis, paranoia, suicidal ideation, isolated reports of suicide attempts

Nervous system: Exacerbation of myasthenia gravis, anosmia, ageusia, parosmia, dysgeusia, peripheral neuropathy, abnormal electroencephalogram (EEG), dysphonia, isolated reports of encephalopathy, pseudotumor cerebri

Central nervous system effects (hallucinations, anxiety, depression, insomnia, severe headaches, and confusion)

Respiratory, thoracic and mediastinal disorders: Isolated reports of allergic pneumonitis

Immune system disorders: Hypersensitivity reactions, sometimes fatal including: anaphylactic/anaphylactoid reactions, anaphylactic shock, angioneurotic edema, serum sickness

Eye disorders: Uveitis, vision disturbance (including diplopia), visual acuity reduced, vision blurred, scotoma

Otologic: Hypoacusis, tinnitus

General disorders and administration site conditions: Multiorgan failure, pyrexia

Contraindications

Documented hypersensitivity

Cautions

Anaphylactic reactions and allergic skin reactions, serious, occasionally fatal, may occur after first dose

Use caution in hematologic and renal toxicities

Hepatotoxicity reported with therapy

Peripheral neuropathy: Sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias, and weakness reported; peripheral neuropathy may occur rapidly after initiating and may potentially become permanent

Commonly seen adverse reactions include tendinitis, tendon rupture, arthralgia, myalgia, peripheral neuropathy, and central nervous system effects (hallucinations, anxiety, depression, insomnia, severe headaches, and confusion); these reactions can occur within hours to weeks after starting therapy, including in patients of any age or without pre-existing risk factors; discontinue therapy immediately at first signs or symptoms of any serious adverse reaction; in addition, avoid use of fluoroquinolones, in patients who have experienced any serious adverse reactions associated with fluoroquinolones

Risk of developing fluoroquinolone-associated tendinitis and tendon rupture is increased in patients over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants; other factors that may independently increase risk of tendon rupture include strenuous physical activity, renal failure, and previous tendon disorders such as rheumatoid arthritis (see Black Box Warnings)

Excessive sunlight may result in moderate-to-severe phototoxicity

Fatal hypoglycemia reported in elderly patients with or without diabetes; prompt treatment when symptoms are present is essential

May cause C difficile-associated colitis

Prolonged use may result in fungal or bacterial superinfection

Prolongation of QT interval and isolated cases of torsades de pointes; avoid use in patients with known QT prolongation, those with hypokalemia, and those taking other QT-prolonging drugs

May produce false-positive urine opiate screens

In prolonged therapy, perform periodic evaluations of organ system function (eg, renal, hepatic, hematopoietic); adjust dosage in renal impairment; superinfections may occur with prolonged or repeated antibiotic therapy

Pediatric patients may experience increased incidence of musculoskeletal disorders (eg, arthralgia, arthritis, tendinopathy, gait abnormality)

Acute onset of retinal detachment increased 4.5-fold with oral fluoroquinolones in a single case-controlled study - JAMA 2012;307(13):1414-1419; another study disputes these findings (relative risk, 1.29) - JAMA 2013;310(20):2184-2190

Clostridium difficile-associated diarrhea (CDAD) has been reported; if CDAD 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

Prescribing antibiotics in absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to patient and increases risk of development of drug-resistant bacteria

CNS effects

• Fluoroquinolones have been associated with an increased risk of CNS effects, including: convulsions, increased intracranial pressure (including pseudotumor cerebri), and toxic psychosis
• May also cause CNS events including: nervousness, agitation, insomnia, anxiety, nightmares, paranoia, dizziness, confusion, tremors, hallucinations, depression, and psychotic reactions have progressed to suicidal ideations/thoughts and self-injurious behavior such as attempted or completed suicide; reactions may occur following the first dose; advise patients to inform their healthcare provider immediately if these reactions occur, discontinue treatment, and institute appropriate care
• Fluoroquinolone are also known to trigger seizures or lower the seizure threshold; use with caution in epileptic patients and patients with known or suspected CNS disorders that may predispose to seizures or lower the seizure threshold (eg, severe cerebral arteriosclerosis, previous history of convulsion, reduced cerebral blood flow, altered brain structure, or stroke), or in the presence of other risk factors that may predispose to seizures or lower the seizure threshold (eg, certain drug therapy, renal dysfunction)

FDA MedWatch Safety Alert

• Issued 12-20-2018
• Increase in rate of aortic aneurysm and dissection reported within two months following use of fluoroquinolones, particularly in elderly patients
• May occur with fluoroquinolones for systemic use (IV or PO)
• Patients who have an aortic aneurysm or are at risk for an aortic aneurysm (eg, patients with peripheral atherosclerotic vascular diseases, hypertension, certain genetic conditions [eg, Marfan syndrome, Ehlers-Danlos syndrome], elderly patients)
• Prescribe fluoroquinolones to these patients only when no other treatment options are available
• Advise patients to seek immediate medical treatment for any symptoms associated with aortic aneurysm
• Stop treatment immediately if a patient reports side effects suggestive of aortic aneurysm or dissection

FDA MedWatch Safety Alert

• Issued July 10, 2018
• The FDA is strengthening the current warnings in the prescribing information for fluoroquinolone antibiotics to inform clinicians of significant decreases in blood glucose and certain mental health adverse effects
• Hypoglycemia, sometimes resulting in coma, occurred more frequently in elderly patients or in diabetic patients taking oral hypoglycemic medicine or insulin
• Alert patients regarding hypoglycemic symptoms and carefully monitor blood glucose levels; instruct patients how to treat themselves if symptoms of hypoglycemia occur
• This safety alert affects only systemic formulations; early signs and symptoms of low blood glucose include confusion, dizziness, feeling shaky, unusual hunger, headaches, irritability, pounding heart or very fast pulse, pale skin, sweating, trembling, weakness, and/or unusual anxiety
• Mental health side effects are to be added to or updated across all the fluoroquinolones are disturbances in attention, disorientation, agitation, nervousness, memory impairment, and delirium
• Inform patients of the potential risk of psychiatric adverse reactions that can occur after just 1 dose
• Immediately discontinue treatment if CNS adverse effects occur, including psychiatric adverse reactions, or blood glucose disturbances occur and switch to a nonfluoroquinolone antibiotic if possible

Pregnancy

Levofloxacin has not been shown to increase risk of major birth defects, miscarriage or adverse maternal or fetal outcomes

Animal data

• Oral administration to pregnant rats and rabbits during organogenesis at doses up to 9.4 times and 1.1 times the maximum recommended human dose (MRHD), respectively, did not result in teratogenicity; fetal toxicity reported in the rat study, but absent at doses up to 1.2 times maximum recommended human dose

Lactation

Drug is present in human milk following intravenous and oral administration; there is no information regarding effects on milk production or breastfed infant; because of potential risks of serious adverse reactions, in breastfed infants, a lactating woman may consider pumping and discarding breast milk during treatment and an additional two days (five half-lives) after last dose

Alternatively, advise a lactating woman that breastfeeding is not recommended during treatment and for an additional two days (five half-lives) after last dose

For inhalation anthrax (post-exposure), during an incident resulting in exposure to anthrax, risk-benefit assessment of continuing breastfeeding while the mother (and potentially the infant) is (are) on this drug may be acceptable

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

L-stereoisomer of parent compound ofloxacin; D-isomer form is inactive

Inhibits DNA gyrase activity, which in turn promotes breakage of DNA strands

Good monotherapy with extended coverage against Pseudomonas spp, as well as excellent activity against pneumococcus

Absorption

Well absorbed

Bioavailability: 99%

Peak serum time: 1-2 hr

Distribution

Cerebrospinal fluid (CSF) concentrations ~15% of serum levels; high concentrations achieved in prostate, gynecologic tissues, sinus, breast milk, saliva

Vd: 74-112 L

Metabolism

Limited metabolism in humans

Elimination

Half-life: 6-8 hr

Excretion: Urine (primarily as unchanged drug); after oral administration, 87% is recovered as unchanged drug in urine within 48 hr, and <4% is recovered in feces in 72 hr

Oral Administration

Administer without regard to food

Oral solution should be taken 1 hour before or 2 hours after eating

IV Incompatibilities

Y-site: Acyclovir, alprostadil, furosemide, heparin, indomethacin, insulin (at 100 U/mL + 5 mg/mL levofloxacin), nitroglycerin, propofol, sodium nitroprusside

IV Compatibilities

Additive: Linezolid

Y-site: Amikacin, aminophylline, ampicillin, bivalirudin, caffeine, cefotaxime, cimetidine, clindamycin, dexamethasone, dexmedetomidine, dobutamine, dopamine, epinephrine, fenoldopam, fentanyl, gentamicin, lactated hetastarch, insulin (at 1 U/mL + 5 mg/mL levofloxacin), isoproterenol, lidocaine, linezolid, lorazepam, metoclopramide, oxacillin, pancuronium, penicillin G sodium, phenobarbital, phenylephrine, sodium bicarbonate, vancomycin

IV Preparation

Premixed: No further preparation needed

Single-use vials: Dilute in 50-100 mL D5W or NS or D5/NS solution for injection to 5 mg/mL; alternative solutions include sodium lactate, Plasma-Lyte, D5/lactated Ringer, D5/NS and potassium chloride

Reconstituted solution should be clear, slightly yellow, and free of particulate matter

Reconstituted drug is stable for 72 hours at room temperature, 14 days when refrigerated in plastic containers, and 6 months when frozen

Thaw at room temperature or in refrigerator only

IV Administration

Give by IV infusion only, not bolus; rapid or bolus administration has been associated with hypotension and must be avoided

Infuse 250-500 mg over 60 minutes or 750 mg over 90 minutes

Avoid using IV line with solution containing multivalent cations (ie, magnesium, calcium)

Compatible with potassium additives