Levaquin (levofloxacin 750 mg) Dailymed

• Anaphylactic reactions and allergic skin reactions, serious, occasionally fatal, may occur after first dose (4 , 5.7)
• Hematologic (including agranulocytosis, thrombocytopenia), and renal toxicities may occur after multiple doses (5.6)
• Hepatotoxicity: Severe, and sometimes fatal, hepatotoxicity has been reported. Discontinue immediately if signs and symptoms of hepatitis occur (5.8)
• Clostridium difficile-associated colitis: evaluate if diarrhea occurs (5.10)
• Prolongation of the QT interval and isolated cases of torsade de pointes have been reported. Avoid use in patients with known prolongation, those with hypokalemia, and with other drugs that prolong the QT interval (5.11, 8.5)

5.1 Disabling and Potentially Irreversible Serious Adverse Reactions Including Tendinitis and Tendon Rupture, Peripheral Neuropathy, and Central Nervous System Effects

Fluoroquinolones, including LEVAQUIN^®, have been associated with disabling and potentially irreversible serious adverse reactions from different body systems that can occur together in the same patient. 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 LEVAQUIN^®. Patients of any age or without pre-existing risk factors have experienced these adverse reactions [see Warnings and Precautions (5.2, 5.3, 5.4)].

Discontinue LEVAQUIN^® immediately at the first signs or symptoms of any serious adverse reaction. In addition, avoid the use of fluoroquinolones, including LEVAQUIN^®, in patients who have experienced any of these serious adverse reactions associated with fluoroquinolones.

5.2Tendinitis and Tendon Rupture

Fluoroquinolones, including LEVAQUIN^®, have been associated with an increased risk of tendinitis and tendon rupture in all ages [see Warnings and Precautions (5.1) and Adverse Reactions (6.2)]. This adverse reaction most frequently involves the Achilles tendon and has also been reported with the rotator cuff (the shoulder), the hand, the biceps, the thumb, and other tendon sites. Tendinitis or tendon rupture can occur within hours or days of starting LEVAQUIN^® or as long as several months after completion of fluoroquinolone therapy. Tendinitis and tendon rupture can occur bilaterally.

The risk of developing fluoroquinolone-associated tendinitis and tendon rupture is increased in patients over 60 years of age, in those taking corticosteroid drugs, and in patients with kidney, heart or lung transplants. Other factors that may independently increase the risk of tendon rupture include strenuous physical activity, renal failure, and previous tendon disorders such as rheumatoid arthritis. Tendinitis and tendon rupture have been reported in patients taking fluoroquinolones who do not have the above risk factors. Discontinue LEVAQUIN^® immediately if the patient experiences pain, swelling, inflammation or rupture of a tendon. Patients should be advised to rest at the first sign of tendinitis or tendon rupture, and to contact their healthcare provider regarding changing to a non-quinolone antimicrobial drug. Avoid LEVAQUIN^® in patients who have a history of tendon disorders or tendon rupture [see Adverse Reactions (6.3) and Patient Counseling Information (17)].

5.3Peripheral Neuropathy

Fluoroquinolones, including LEVAQUIN^®, have been associated with an increased risk of peripheral neuropathy. 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 fluoroquinolones, including LEVAQUIN^®. Symptoms may occur soon after initiation of LEVAQUIN^® and may be irreversible in some patients [see Warnings and Precautions (5.1) and Adverse Reactions (6.1, 6.2)].

Discontinue LEVAQUIN^® immediately 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. Avoid fluoroquinolones, including LEVAQUIN^®, in patients who have previously experienced peripheral neuropathy [see Adverse Reactions (6) and Patient Counseling Information (17)].

5.4 Central Nervous System Effects

Psychiatric Adverse Reactions

Fluoroquinolones, including LEVAQUIN^®, have been associated with an increased risk of psychiatric adverse reactions, including: toxic psychoses, hallucinations, or paranoia; depression, or suicidal thoughts; anxiety, agitation, restlessness, or nervousness; confusion, delirium, disorientation, or disturbances in attention; insomnia or nightmares; memory impairment. Attempted or completed suicide have been reported, especially in patients with a medical history of depression, or an underlying risk factor for depression. These reactions may occur following the first dose. If these reactions occur in patients receiving LEVAQUIN^®, discontinue LEVAQUIN^® and institute appropriate measures.

Central Nervous System Adverse Reactions

Fluoroquinolones, including LEVAQUIN^®, have been associated with an increased risk of seizures (convulsions), increased intracranial pressure (including pseudotumor cerebri), tremors, and lightheadedness. As with other fluoroquinolones, 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). If these reactions occur in patients receiving LEVAQUIN^®, discontinue LEVAQUIN^® and institute appropriate measures [see Adverse Reactions (6), Drug Interactions (7.4 , 7.5), and Patient Counseling Information (17)].

5.5Exacerbation of Myasthenia Gravis

Fluoroquinolones, including LEVAQUIN^®, have neuromuscular blocking activity and may exacerbate muscle weakness in patients with myasthenia gravis. Postmarketing serious adverse reactions including deaths and requirement for ventilatory support, have been associated with fluoroquinolone use in patients with myasthenia gravis. Avoid LEVAQUIN^® in patients with a known history of myasthenia gravis [see Adverse Reactions (6.3) and Patient Counseling Information (17)].

5.6Other Serious and Sometimes Fatal Adverse Reactions

Other serious and sometimes fatal adverse reactions, some due to hypersensitivity, and some due to uncertain etiology, have been reported rarely in patients receiving therapy with fluoroquinolones, 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.

Discontinue LEVAQUIN^® immediately at the first appearance of skin rash, jaundice, or any other sign of hypersensitivity and institute supportive measures [see Adverse Reactions (6) and Patient Counseling Information (17)].

5.7Hypersensitivity Reactions

Serious and occasionally fatal hypersensitivity and/or anaphylactic reactions have been reported in patients receiving therapy with fluoroquinolones, 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) and Patient Counseling Information (17)].

5.8Hepatotoxicity

Post-marketing reports of severe hepatotoxicity (including acute hepatitis and fatal events) have been received for patients treated with LEVAQUIN^®. 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. LEVAQUIN^® should be discontinued immediately if the patient develops signs and symptoms of hepatitis [see Adverse Reactions (6) and Patient Counseling Information (17)].

5.9Risk of Aortic Aneurysm and Dissection

Epidemiologic studies report an increased rate of aortic aneurysm and dissection within two months following use of fluoroquinolones, particularly in elderly patients. The cause for the increased risk has not been identified. In patients with a known aortic aneurysm or patients who are at greater risk for aortic aneurysms, reserve LEVAQUIN^® for use only when there are no alternative antibacterial treatments available.

5.10-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) and Patient Counseling Information (17)].

5.11 Prolongation of the QT Interval

Some fluoroquinolones, 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 fluoroquinolones, 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)].

5.12Musculoskeletal Disorders in Pediatric Patients and Arthropathic Effects in Animals

LEVAQUIN^® 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 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 Animal Toxicology and/or Pharmacology (13.2)].

5.13 Blood Glucose Disturbances

Fluoroquinolones, including LEVAQUIN^®, 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 LEVAQUIN^®, discontinue LEVAQUIN^® 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, bulering, 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 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)].

6 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 LEVAQUIN^®. Therefore, adequate hydration of patients receiving LEVAQUIN^® should be maintained to prevent the formation of a highly concentrated urine [see Dosage and Administration (2.5)].


The most common reactions (≥3%) were nausea, headache, diarrhea, insomnia, constipation and dizziness (6.2).

To report SUSPECTED ADVERSE REACTIONS, contact Janssen Pharmaceuticals, Inc. at 1-800-526-7736 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 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 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^® pool of studies included IV and oral administration

System/Organ Class	Adverse Reaction	%(N=7537)
Infections and Infestations	moniliasis	1
Psychiatric Disorders	insomniaN = 7274 [see Warnings and Precautions (5.4)]	4
Nervous System Disorders
	headache	6
	dizziness [see Warnings and Precautions (5.4)]	3
Respiratory, Thoracic and Mediastinal Disorders	dyspnea [see Warnings and Precautions (5.7)]	1
Gastrointestinal Disorders	nausea	7
	diarrhea	5
	constipation	3
	abdominal pain	2
	vomiting	2
	dyspepsia	2
Skin and Subcutaneous Tissue Disorders	rash [see Warnings and Precautions (5.7)]	2
	pruritus	1
Reproductive System and Breast Disorders	Vaginitis	1N = 3758 (women)
General Disorders and Administration Site Conditions	edema	1
	injection site reaction	1
	chest pain	1

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

System/Organ Class	Adverse Reaction
Infections and Infestations	genital moniliasis
Blood and Lymphatic System Disorders	anemiathrombocytopeniagranulocytopenia [see Warnings and Precautions (5.6)]
Immune System Disorders	allergic reaction [see Warnings and Precautions (5.6, 5.7)]
Metabolism and Nutrition Disorders	hyperglycemiahypoglycemia [see Warnings and Precautions (5.13)] hyperkalemia
Psychiatric Disorders	anxietyagitationconfusiondepressionhallucinationnightmare [see Warnings and Precautions (5.4)] sleep disorderN = 7274 anorexiaabnormal dreaming
Nervous System Disorders	tremorconvulsions [see Warnings and Precautions (5.4)] paresthesia [see Warnings and Precautions (5.3)] vertigohypertoniahyperkinesiasabnormal gaitsomnolence syncope
Respiratory, Thoracic 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)]

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.

6.2 Postmarketing Experience

Table 6 uls 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

System/Organ Class	Adverse Reaction
Blood and Lymphatic System Disorders	pancytopeniaaplastic anemialeukopeniahemolytic anemia [see Warnings and Precautions (5.6) ] eosinophilia
Immune System Disorders	hypersensitivity reactions, sometimes fatal including:  anaphylactic/anaphylactoid reactions  anaphylactic shock  angioneurotic edema  serum sickness [see Warnings and Precautions (5.6, 5.7)]
Psychiatric Disorders	psychosisparanoiaisolated reports of suicidal ideation, suicide attempt and completed suicide [see Warnings and Precautions (5.4)]
Nervous System Disorders	exacerbation of myasthenia gravis [see Warnings and Precautions (5.5)] anosmiaageusiaparosmiadysgeusiaperipheral neuropathy (may be irreversible) [see Warnings and Precautions (5.3)] isolated reports of encephalopathyabnormal electroencephalogram (EEG)dysphoniapseudotumor cerebri [see Warnings and Precautions (5.4)]
Eye Disorders	uveitisvision disturbance, including diplopiavisual acuity reducedvision blurredscotoma
Ear and Labyrinth Disorders	hypoacusistinnitus
Cardiac Disorders	isolated reports of torsade de pointeselectrocardiogram QT prolonged [see Warnings and Precautions (5.11)] tachycardia
Vascular Disorders	vasodilatation
Respiratory, Thoracic and Mediastinal Disorders	isolated reports of allergic pneumonitis [see Warnings and Precautions (5.6)]
Hepatobiliary Disorders	hepatic failure (including fatal cases)hepatitisjaundice [see Warnings and Precautions (5.6), (5.8)]
Skin and Subcutaneous Tissue Disorders	bullous eruptions to include:  Stevens-Johnson Syndrome  toxic epidermal necrolysis  Acute Generalized Exanthematous Pustulosis (AGEP)  fixed drug eruptions  erythema multiforme [see Warnings and Precautions (5.6)] photosensitivity/phototoxicity reaction [see Warnings and Precautions (5.14)] leukocytoclastic vasculitis
Musculoskeletal and Connective Tissue Disorders	tendon rupture [see Warnings and Precautions (5.2)] muscle injury, including rupturerhabdomyolysis
Renal and Urinary Disorders	interstitial nephritis [see Warnings and Precautions (5.6)]
General Disorders and Administration Site Conditions	multi-organ failurepyrexia
Investigations	prothrombin time prolongedinternational normalized ratio prolongedmuscle enzymes increased

Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablets are taken within 2 hours of these products. (2.4 , 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR and watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.13 , 7.3)

7.1Chelation 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.

7.2Warfarin

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) and Patient Counseling Information (17)].

7.3Antidiabetic 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 [see Warnings and Precautions (5.13), Adverse Reactions (6.2) , and Patient Counseling Information (17)].

7.4Non-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 [see Warnings and Precautions (5.4)].

7.5Theophylline

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 [see Warnings and Precautions (5.4)].

7.6Cyclosporine

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 fluoroquinolones. Levofloxacin C_max and k_e were slightly lower while T_max and t_½ 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.

7.7Digoxin

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.

7.8Probenecid and Cimetidine

No significant effect of probenecid or cimetidine on the C_max of levofloxacin was observed in a clinical study involving healthy volunteers. The AUC and t_½ 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.

7.9Interactions 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.

8 Use In Specific Populations

• Geriatrics: Severe hepatotoxicity has been reported. The majority of reports describe patients 65 years of age or older (5.8, 8.5, 17). May have increased risk of tendinopathy (including rupture), especially with concomitant corticosteroid use (5.2, 8.5, 17). May be more susceptible to prolongation of the QT interval. (5.11, 8.5, 17).
• Pediatrics: Musculoskeletal disorders (arthralgia, arthritis, tendinopathy, and gait abnormality) seen in more LEVAQUIN^®-treated patients than in comparator. Shown to cause arthropathy and osteochondrosis in juvenile animals (5.12, 8.4, 13.2). Safety in pediatric patients treated for more than 14 days has not been studied. Risk-benefit appropriate only for the treatment of inhalational anthrax (post-exposure) (1.7 , 2.2 , 8.4 , 14.9) and plague (1.8, 2.2, 8.4, 14.10)
• Lactation: Breastfeeding is not recommended during treatment, but a lactating woman may pump and discard breastmilk during treatment and an additional 2 days after the last dose. In patients treated for inhalational anthrax (post exposure), consider the risks and benefits of continuing breastfeeding.

8.1 Pregnancy

Risk Summary

Published information from case reports, case control studies and observational studies on levofloxacin administered during pregnancy have not identified any drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes.

In animal reproduction studies, oral administration of levofloxacin 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 was seen in the rat study, but was absent at doses up to 1.2 times the maximum recommended human dose (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.

Data

Animal Data

Levofloxacin was not teratogenic in an embryofetal development study in rats treated during organogenesis with oral doses as high as 810 mg/kg/day which corresponds to 9.4 times the MRHD (based upon doses normalized for total body surface area). The oral dose of 810 mg/kg/day (high dose) to rats caused decreased fetal body weight and increased fetal mortality that was not seen at the next lower dose (mid-dose, 90 mg/kg/day, equivalent to 1.2 times the MRHD (based upon doses normalized for total body surface area). Maternal toxicity was limited to lower weight gain in the mid and high dose groups. No teratogenicity was observed in an embryofetal development study in rabbits dosed orally during organogenesis with doses as high as 50 mg/kg/day, which corresponds to 1.1 times the MRHD (based upon doses normalized for total body surface area). Maternal toxicity at that dose consisted of lower weight gain and decreased food consumption relative to controls and abortion in four of sixteen dams.

8.2 Lactation

Risk Summary

Published literature reports that levofloxacin is present in human milk following intravenous and oral administration (see Data ). There is no information regarding effects of LEVAQUIN on milk production or the breastfed infant. Because of the potential risks of serious adverse reactions, in breastfed infants, for most indications, a lactating woman may consider pumping and discarding breast milk during treatment with LEVAQUIN and an additional two days (five half-lives) after the last dose. Alternatively, advise a lactating woman that breastfeeding is not recommended during treatment with LEVAQUIN and for an additional two days (five half-lives) after the last dose [see Use in Specific Populations (8.4) and Clinical Pharmacology (12.3)] .

However, for inhalation anthrax (post exposure), during an incident resulting in exposure to anthrax, the risk-benefit assessment of continuing breastfeeding while the mother (and potentially the infant) is (are) on LEVAQUIN may be acceptable [see Dosage and Administration (2.2), Pediatric Use (8.4), and Clinical Studies (14.2)]. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for LEVAQUIN and any potential adverse effects on the breastfed child from LEVAQUIN or from the underlying maternal condition.

Data

A published literature reports that peak levofloxacin human milk concentration was 8.2 mg/L at 5 hours after dosing in a woman who received 500 mg of intravenous, followed by oral, levofloxacin daily. For an infant fed exclusively with human milk (approximately 900 ml/day), an estimated maximum daily dose of levofloxacin through breastfeeding is 5 mg (i.e., approximately 1% of maternal daily dose). The above data come from a single case and may not be generalizable to the general population of lactating women.

8.4 Pediatric Use

Quinolones, including levofloxacin, cause arthropathy and osteochondrosis in juvenile animals of several species. [see Warnings and Precautions (5.12) and Animal Toxicology and/or Pharmacology (13.2)].

Inhalational Anthrax (Post-Exposure)

Levofloxacin is indicated in pediatric patients 6 months of age and older, for inhalational anthrax (post-exposure). The risk-benefit assessment indicates that administration of levofloxacin to pediatric patients is appropriate. The safety of levofloxacin in pediatric patients treated for more than 14 days has not been studied [see Indications and Usage (1.7) , Dosage and Administration (2.2) and Clinical Studies (14.9)].

Plague

Levofloxacin is indicated in pediatric patients, 6 months of age and older, for treatment of plague, including pneumonic and septicemic plague due to Yersinia pestis (Y. pestis) and prophylaxis for plague. Efficacy studies of LEVAQUIN^® could not be conducted in humans with pneumonic plague for ethical and feasibility reasons. Therefore, approval of this indication was based on an efficacy study conducted in animals. The risk-benefit assessment indicates that administration of levofloxacin to pediatric patients is appropriate [see Indications and Usage (1.8) , Dosage and Administration (2.2) and Clinical Studies (14.10)].

Safety and effectiveness of LEVAQUIN^® in pediatric patients below the age of six months have not been established.

Pharmacokinetics following intravenous administration

The pharmacokinetics of levofloxacin following a single intravenous dose were investigated in pediatric patients ranging in age from six months to 16 years. Pediatric patients cleared levofloxacin faster than adult patients resulting in lower plasma exposures than adults for a given mg/kg dose [see Clinical Pharmacology (12.3) and Clinical Studies (14.9)].

Dosage in Pediatric Patients with Inhalational Anthrax or Plague

For the recommended LEVAQUIN^® tablet dosage in pediatric patients with inhalational anthrax or plague, see Dosage and Administration (2.2). LEVAQUIN^® Tablets cannot be administered to pediatric patients who weigh less than 30 kg because of the limitations of the available strengths. Alternative formulations of levofloxacin may be considered for pediatric patients who weigh less than 30 kg.

Adverse Reactions

In clinical trials, 1534 pediatric patients (6 months to 16 years of age) were treated with oral and intravenous LEVAQUIN^®. Pediatric patients 6 months to 5 years of age received LEVAQUIN^® 10 mg/kg twice a day and pediatric patients greater than 5 years of age received 10 mg/kg once a day (maximum 500 mg per day) for approximately 10 days. LEVAQUIN^® Tablets can only be administered to pediatric patients with inhalational anthrax (post-exposure) or plague who are 30 kg or greater due to the limitations of the available strengths [see Dosage and Administration (2.2)].

A subset of pediatric patients 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, tendinopathy, gait abnormality) during 60 days and 1 year following the first dose of the study drug. Pediatric patients treated with LEVAQUIN^® had a significantly higher incidence of musculoskeletal disorders when compared to the non-fluoroquinolone-treated children as illustrated in Table 7. LEVAQUIN^® Tablets can only be administered to pediatric patients with inhalational anthrax (post-exposure) or plague who are 30 kg or greater due to the limitations of the available strengths [see Dosage and Administration (2.2)].

Table 7: Incidence of Musculoskeletal Disorders in Pediatric Clinical Trial

Follow-up Period	LEVAQUIN® N = 1340	Non-FluoroquinoloneNon-Fluoroquinolone: ceftriaxone, amoxicillin/clavulanate, clarithromycin N = 893	p-value2-sided Fisher's Exact Test
60 days	28 (2.1%)	8 (0.9%)	p = 0.038
1 yearThere were 1199 LEVAQUIN®-treated and 804 non-fluoroquinolone-treated pediatric patients who had a one-year evaluation visit. However, the incidence of musculoskeletal disorders was calculated using all reported events during the specified period for all pediatric patients enrolled regardless of whether they completed the 1-year evaluation visit.	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 pediatric patients and most were treated with analgesics. The median time to resolution was 7 days for LEVAQUIN^®-treated pediatric patients and 9 for non-fluoroquinolone-treated children (approximately 80% resolved within 2 months in both groups). No pediatric patient had a severe or serious disorder and all musculoskeletal disorders resolved without sequelae.

Vomiting and diarrhea were the most frequently reported adverse reactions, occurring in similar frequency in the LEVAQUIN^®-treated and non-fluoroquinolone-treated pediatric patients.

In addition to the adverse reactions reported in pediatric patients in clinical trials, adverse reactions reported in adults during clinical trials or post-marketing experience [see Adverse Reactions (6)] may also be expected to occur in pediatric patients.

8.5 Geriatric Use

Geriatric patients 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 in patients receiving concomitant corticosteroid therapy. Tendinitis or tendon rupture can involve the Achilles, hand, shoulder, or other tendon sites and can occur during or after completion of therapy; cases occurring up to several months after fluoroquinolone treatment have been reported. 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 LEVAQUIN^® and contact their healthcare provider if any symptoms of tendinitis or tendon rupture occur [see Boxed Warning ; Warnings and Precautions (5.2) ; and Adverse Reactions (6.3)].

In Phase 3 clinical trials, 1,945 LEVAQUIN^®-treated patients (26%) were ≥ 65 years of age. Of these, 1,081 patients (14%) were between the ages of 65 and 74 and 864 patients (12%) 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.

Severe, and sometimes fatal, cases of hepatotoxicity have been reported post-marketing in association with LEVAQUIN^®. The majority of fatal hepatotoxicity reports occurred in patients 65 years of age or older and most were not associated with hypersensitivity. LEVAQUIN^® should be discontinued immediately if the patient develops signs and symptoms of hepatitis [see Warnings and Precautions (5.8)].

Epidemiologic studies report an increased rate of aortic aneurysm and dissection within two months following use of fluoroquinolones, particularly in elderly patients [see Warnings and Precautions (5.9) ].

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 (5.11)].

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)].

8.6Renal Impairment

Clearance of levofloxacin is substantially reduced and plasma elimination half-life is substantially prolonged in patients with renal impairment (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 (2.3)].

8.7Hepatic Impairment

Pharmacokinetic studies in patients with hepatic impairment 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.