Levaquin (levofloxacin) Side Effects, Warnings, and Drug Interactions

Levaquin (levofloxacin) is an antibiotic used to treat infections of the sinuses, skin, lungs, ears, airways, bones, and joints caused by susceptible bacteria; urinary infections (UTIs) and prostatitis (infection of the prostate); infectious diarrhea caused by E. coli, Campylobacter jejuni, and Shigella bacteria; various obstetric infections, including mastitis (infection of the breast); and inhalational anthrax exposure. Levaquin is used to prevent and treat plague caused by Yersinia pestis.

Common side effects of Levaquin include nausea, vomiting, diarrhea, headache, constipation, difficulty sleeping, dizziness, abdominal pain, rash, gas, and itching.

Serious side effects of Levaquin include tendinitis and even rupture of tendons (particularly the Achilles tendon), worsened muscle weakness in individuals with myasthenia gravis, peripheral neuropathy, central nervous system effects, low or high blood sugar (hypoglycemia or hyperglycemia), Clostridium difficile-associated diarrhea, abnormal heart beats, liver dysfunction, seizures (rare), pseudomembranous colitis, sensitivity of the skin to sunlight (photosensitivity), and worsening low blood glucose levels when combined with sulfonylureas.

Drug interactions of Levaquin include products that contain iron, calcium, zinc, or magnesium; sucralfate, didanosine, nonsteroidal anti-inflammatory drugs (NSAIDs), and warfarin. Levaquin is not recommended for use in pregnant women since Levaquin causes joint and bone deformities in juvenile animals of several species. Levaquin is excreted in breast milk. Mothers should decide whether to stop breastfeeding or discontinue Levaquin.

Serious side effects and warnings include:

• Levofloxacin as well as other antibiotics in the fluoroquinolone class of antibiotics have been associated with tendinitis and even rupture of tendons, particularly the Achilles tendon.
• Fluoroquinolones have neuromuscular blocking activity and can worsen muscle weakness in individuals with myasthenia gravis.

The most frequently reported side effects are:

• Nausea or vomiting
• Diarrhea
• Headache
• Constipation

Less common side effects include:

• Difficulty sleeping
• Dizziness
• Abdominal pain
• Rash
• Abdominal gas
• Itching

Rare allergic reactions have been described are:

• Hives
• Anaphylaxis (shock)

What are the serious side effects (adverse effects) of levofloxacin?

Possible serious side effects of levofloxacin include:

• Peripheral neuropathy
• Central nervous system effects
• Hypoglycemia
• Hyperglycemia
• Clostridium difficile-associated diarrhea
• Abnormal heart beats
• Liver dysfunction
• Sun sensitivity

Other serious side effects and adverse events of levofloxacin include:

• Levofloxacin should be used with caution in patients with central nervous system diseases such as seizures, because rare seizures have been reported in patients receiving Levaquin.
• Levofloxacin should be avoided in children and adolescents less than 18 years of age, as safe use in these patients has not been established.
• Many antibiotics, including levofloxacin, can alter the normal bacteria in the colon and encourage overgrowth of a bacterium responsible for the development of inflammation of the colon, (C. difficile or pseudomembranous colitis). Patients who develop signs of pseudomembranous colitis after starting Levaquin (diarrhea, fever, abdominal pain, and possibly shock) should contact their doctor immediately.
• Patients taking Levofloxacin can develop sensitivity of the skin to direct sunlight (photosensitivity) and should avoid exposure to sunlight or use sunblock.
• Fluoroquinolones worsen low blood glucose levels when combined with sulfonylureas (for example, glyburide [Micronase, Diabeta, Glynase, Prestab]).
• Because of serious side effects associate with fluoroquinolones, they should not be used for treating uncomplicated urinary tract infections, acute bacterial exacerbation of chronic bronchitis or acute bacterial sinusitis unless there are no other alternatives.

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:

• Disabling and Potentially Irreversible Serious Adverse Reactions
• Tendinitis and Tendon Rupture
• Peripheral Neuropathy
• Central Nervous System Effects
• Exacerbation of Myasthenia Gravis
• Other Serious and Sometimes Fatal Reactions
• Hypersensitivity Reactions
• Hepatotoxicity
• Clostridium difficile-Associated Diarrhea
• Prolongation of the QT Interval
• Musculoskeletal Disorders in Pediatric Patients
• Blood Glucose Disturbances
• Photosensitivity/Phototoxicity
• Development of Drug Resistant Bacteria

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.

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. 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 4 and Table 5, respectively. The most common adverse drug reactions (≥3%) are nausea, headache, diarrhea, insomnia, constipation, and dizziness.

Table 4: Common (≥1%) Adverse Reactions Reported in Clinical Trials with Levaquin^®*

Table 5: Less Common (0.1 to 1%) Adverse Reactions Reported in Clinical Trials with Levaquin^® (N = 7537)

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.

Postmarketing Experience

Table 6 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, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Table 6: Postmarketing Reports Of Adverse Drug Reactions

Chelation Agents

Antacids, Sucralfate, Metal Cations, Multivitamins

While the chelation by divalent cations is less marked than with other fluoroquinolones, concurrent administration of Levaquin^® Tablets 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 multivitamin 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.

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.

Antidiabetic Agents

Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with fluoroquinolones and an antidiabetic agent. Therefore, careful monitoring of blood glucose is recommended when these agents are co-administered.

Non-Steroidal Anti-Inflammatory Drugs

The concomitant administration of a non-steroidal anti-inflammatory drug with a fluoroquinolone, including Levaquin^® , may increase the risk of CNS stimulation and convulsive seizures.

Theophylline

No significant effect of Levaquin^® on the plasma concentrations, AUC, and other disposition parameters for theophylline was detected in a clinical study involving healthy volunteers. Similarly, no apparent effect of theophylline on levofloxacin absorption and disposition was observed.

However, concomitant administration of other fluoroquinolones with theophylline has resulted in prolonged elimination half-life, elevated serum theophylline levels, and a subsequent increase in the risk of theophylline-related adverse reactions in the patient population. Therefore, theophylline levels should be closely monitored and appropriate dosage adjustments made when Levaquin^® is co-administered. Adverse reactions, including seizures, may occur with or without an elevation in serum theophylline levels.

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 coadministered with some other fluoroquinolones.

Levofloxacin Cmax and k_e were slightly lower while Tmax and t_1/2 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.

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.

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 t_1/2 of levofloxacin were higher while CL/F and CL_R 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.

Interactions With Laboratory Or Diagnostic Testing

Some fluoroquinolones, including Levaquin^® , may produce false-positive urine screening results for opiates using commercially available immunoassay kits. Confirmation of positive opiate screens by more specific methods may be necessary.