Levofloxacin: Package Insert and Label Information (Page 3 of 9)

5.8 Hepatotoxicity

Post-marketing reports of severe hepatotoxicity (including acute hepatitis and fatal events) have been received for patients treated with levofloxacin. No evidence of serious drug-associated hepatotoxicity was detected in clinical trials of over 7,000 patients. Severe hepatotoxicity generally occurred within 14 days of initiation of therapy and most cases occurred within 6 days. Most cases of severe hepatotoxicity were not associated with hypersensitivity [see Warnings and Precautions (5.6)]. The majority of fatal hepatotoxicity reports occurred in patients 65 years of age or older and most were not associated with hypersensitivity. Levofloxacin should be discontinued immediately if the patient develops signs and symptoms of hepatitis [see Adverse Reactions (6) and Patient Counseling Information (17)].

5.9 Risk of Aortic Aneurysm and Dissection

Fluoroquinolones, including levofloxacin, have been associated with aortic aneurysm and dissection. Findings from epidemiologic studies show a consistently increased risk of hospitalization for aortic aneurysm or dissection within two months following use of a fluoroquinolone antibacterial drug. The annual estimated background risk of aortic aneurysm is as high as approximately 300 aortic aneurysm events per 100,000 persons at the highest risk (e.g., age greater than 85 years). The evidence shows the potential for a 2-fold increased risk over the background risk following fluoroquinolone exposure and was based on a small number of cases, mostly in older patients. The cause for the risk of aortic aneurysm or dissection has not been identified, but the available data suggest that use of fluoroquinolones may contribute in the short term to aneurysm progression. In patients with a known aortic aneurysm or patients who are at greater risk for aortic aneurysms, reserve levofloxacin for use only when there are no alternative antibacterial treatments available.

5.10 Clostridium difficile -Associated Diarrhea

Clostridium difficile -associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including levofloxacin, 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) and Patient Counseling Information (17)].

5.11 Prolongation of the QT Interval

Some fluoroquinolones, including levofloxacin, 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 fluoroquinolones, including levofloxacin. Levofloxacin 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)].

5.12 Musculoskeletal Disorders in Pediatric Patients and Arthropathic Effects in Animals

Levofloxacin is indicated in pediatric patients (6 months of age and older) only for the prevention of inhalational anthrax (post-exposure) and for plague [see Indications and Usage (1.7, 1.8)]. An increased incidence of musculoskeletal disorders (arthralgia, arthritis, tendinopathy, and gait abnormality) compared to controls has been observed in pediatric patients receiving levofloxacin [see Use in Specific Populations (8.4)].
In immature rats and dogs, the oral and intravenous administration of levofloxacin resulted in increased osteochondrosis. Histopathological examination of the weight-bearing joints of immature dogs dosed with levofloxacin revealed persistent lesions of the cartilage. Other fluoroquinolones also produce similar erosions in the weight-bearing joints and other signs of arthropathy in immature animals of various species [see Animal Toxicology and/or Pharmacology (13.2)].

5.13 Blood Glucose Disturbances

Fluoroquinolones, including levofloxacin, have been associated with disturbances of blood glucose, including symptomatic hyperglycemia and hypoglycemia, 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. Severe cases of hypoglycemia resulting in coma or death have been reported. If a hypoglycemic reaction occurs in a patient being treated with levofloxacin, discontinue levofloxacin and initiate appropriate therapy immediately[see Adverse Reactions (6.2), Drug Interactions (7.3) and Patient Counseling Information (17)].

5.14 Photosensitivity/Phototoxicity

Moderate to severe photosensitivity/phototoxicity reactions, the latter of which may manifest as exaggerated sunburn reactions (e.g., burning, erythema, exudation, vesicles, blistering, edema) involving areas exposed to light (typically the face, “V” area of the neck, extensor surfaces of the forearms, dorsa of the hands), can be associated with the use of fluoroquinolones after sun or UV light exposure. Therefore, excessive exposure to these sources of light should be avoided. Drug therapy should be discontinued if photosensitivity/phototoxicity occurs [see Adverse Reactions (6.3) and Patient Counseling Information (17)].

5.15 Development of Drug Resistant Bacteria

Prescribing levofloxacin 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)].

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:
• Disabling and Potentially Irreversible Serious Adverse Reactions [see Warnings and Precautions (5.1)]
• Tendinitis and Tendon Rupture [see Warnings and Precautions (5.2)]
• Peripheral Neuropathy [see Warnings and Precautions (5.3)]
• Central Nervous System Effects [see Warnings and Precautions (5.4)]
• Exacerbation of Myasthenia Gravis [see Warnings and Precautions (5.5)]
• Other Serious and Sometimes Fatal Reactions [see Warnings and Precautions (5.6)]
• Hypersensitivity Reactions [see Warnings and Precautions (5.7)]
• Hepatotoxicity [see Warnings and Precautions (5.8)]
• Risk of Aortic Aneurysm and Dissection [see Warnings and Precautions (5.9)]
• Clostridium difficile-Associated Diarrhea [see Warnings and Precautions (5.10)]
• Prolongation of the QT Interval [see Warnings and Precautions (5.11)]
• Musculoskeletal Disorders in Pediatric Patients [see Warnings and Precautions (5.12)]
• Blood Glucose Disturbances [see Warnings and Precautions (5.13)]
• Photosensitivity/Phototoxicity [see Warnings and Precautions (5.14)]
• Development of Drug Resistant Bacteria [see Warnings and Precautions (5.15)]
Crystalluria and cylindruria have been reported with quinolones, including levofloxacin. Therefore, adequate hydration of patients receiving levofloxacin should be maintained to prevent the formation of a highly concentrated urine [see Dosage and Administration (2.5)].

6.2 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The data described below reflect exposure to levofloxacin 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 levofloxacin for a wide variety of infectious diseases [see Indications and Usage (1)]. Patients received levofloxacin doses of 750 mg once daily, 250 mg once daily, or 500 mg once or twice daily. Treatment duration was usually 3 to 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 levofloxacin doses of 750 mg once daily, 250 mg once daily, and 500 mg once or twice daily. Discontinuation of levofloxacin 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 levofloxacin-treated patients and less common adverse reactions, occurring in 0.1 to <1% of levofloxacin-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 Levofloxacin

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)]

63

Respiratory, Thoracic and Mediastinal Disorders

dyspnea [see Warnings and Precautions (5.7)]

1

Gastrointestinal Disorders

nausea diarrhea constipation abdominal pain vomiting dyspepsia

753222

Skin and Subcutaneous Tissue Disorders

rash [see Warnings and Precautions (5.7)] pruritus

21

Reproductive System and Breast Disorders

vaginitis

1

General Disorders and Administration Site Conditions

edema injection site reaction chest pain

111

* N = 7274
N=3758 (women)
# pool of studies included IV and oral administrationTable 5: Less Common (0.1 to 1%) Adverse Reactions Reported in Clinical Trials with Levofloxacin (N=7537)

System/Organ Class

Adverse Reaction

Infections and Infestations

genital moniliasis

Blood and Lymphatic System Disorders

anemiathrombocytopenia granulocytopenia[see Warnings and Precautions (5.6)]

Immune System Disorders

allergic reaction [see Warnings and Precautions (5.6, 5.7)]

Metabolism and Nutrition Disorders

hyperglycemia hypoglycemia [see Warnings and Precautions (5.13)] hyperkalemia

Psychiatric Disorders

anxiety agitationconfusiondepressionhallucinationnightmare* [see Warnings and Precautions (5.4)] sleep disorder* anorexiaabnormal dreaming*

Nervous System Disorders

tremorconvulsions [see Warnings and Precautions (5.4)] paresthesia [see Warnings and Precautions (5.3)] vertigohypertoniahyperkinesiasabnormal gaitsomnolence* syncope

Respiratory, Thoraic and Mediastinal Disorders

epistaxis

Cardiac Disorders

cardiac arrestpalpitationventricular tachycardiaventricular arrhythmia

Vascular Disorders

phlebitis

Gastrointestinal Disorders

gastritisstomatitispancreatitisesophagitisgastroenteritisglossitispseudomembranous/ C. difficile colitis [see Warnings and Precautions (5.10)]

Hepatobiliary Disorders

abnormal hepatic functionincreased hepatic enzymesincreased alkaline phosphatase

Skin and Subcutaneous Tissue Disorders

urticaria [see Warnings and Precautions (5.7)]

Musculoskeletal and Connective Tissue Disorders

arthralgiatendinitis[see Warnings and Precautions (5.2)] myalgiaskeletal pain

Renal and Urinary Disorders

abnormal renal functionacute renal failure [see Warnings and Precautions (5.6)]

* N = 7274
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 levofloxacin. The relationship of the drugs to these events is not presently established.

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