LEVOFLOXACIN- levofloxacin tablet, film coated

United States - English - NLM (National Library of Medicine)

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Active ingredient:
LEVOFLOXACIN (UNII: 6GNT3Y5LMF) (LEVOFLOXACIN ANHYDROUS - UNII:RIX4E89Y14)
Available from:
Bryant Ranch Prepack
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Levofloxacin tablets are indicated in adult patients for the treatment of nosocomial pneumonia due to methicillin-susceptible Staphylococcus aureus, Pseudomonas aeruginosa, Serratia marcescens, Escherichia coli, Klebsiella pneumoniae, Haemophilus influenzae, or Streptococcus pneumoniae . Adjunctive therapy should be used as clinically indicated. Where Pseudomonas aeruginosa is a documented or presumptive pathogen, combination therapy with an anti-pseudomonal β-lactam is recommended [see ClinicalStudies (14.1 ) ]. Levofloxacin tablets are indicated in adult patients for the treatment of community-acquired pneumonia due to methicillin-susceptible Staphylococcus aureus, Streptococcus pneumoniae (including multi-drug-resistant Streptococcus pneumoniae [MDRSP]), Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Moraxella catarrhalis, Chlamydophila pneumoniae, Legionella pneumophila, or Mycoplasma pneumoniae [see Dosageand Administration (2.1) and Clinical Studies (14.2) ]. MDRSP isolate
Product summary:
Product: 71335-1277 NDC: 71335-1277-1 30 TABLET, FILM COATED in a BOTTLE NDC: 71335-1277-2 10 TABLET, FILM COATED in a BOTTLE NDC: 71335-1277-3 7 TABLET, FILM COATED in a BOTTLE NDC: 71335-1277-4 14 TABLET, FILM COATED in a BOTTLE NDC: 71335-1277-5 5 TABLET, FILM COATED in a BOTTLE NDC: 71335-1277-6 20 TABLET, FILM COATED in a BOTTLE NDC: 71335-1277-7 60 TABLET, FILM COATED in a BOTTLE NDC: 71335-1277-8 3 TABLET, FILM COATED in a BOTTLE NDC: 71335-1277-9 50 TABLET, FILM COATED in a BOTTLE
Authorization status:
Abbreviated New Drug Application
Authorization number:
71335-1277-1, 71335-1277-2, 71335-1277-3, 71335-1277-4, 71335-1277-5, 71335-1277-6, 71335-1277-7, 71335-1277-8, 71335-1277-9

LEVOFLOXACIN- levofloxacin tablet, film coated

Bryant Ranch Prepack

----------

MEDICATION GUIDE

Levofloxacin Tablets USP, 250 mg, 500 mg and 750 mg

(lee'' voe flox' a sin)

What is the most important information I should know about levofloxacin tablets?

Levofloxacin tablets, a fluoroquinolone antibiotic, can cause serious side effects. Some of these serious side

effects can happen at the same time and could result in death.

If you have any of the following serious side effects while you take levofloxacin tablets, you should stop

taking levofloxacin tablets immediately and get medical help right away.

1. Tendon rupture or swelling of the tendon (tendinitis).

Tendon problems can happen in people of all ages who takelevofloxacin tablets. Tendons are tough

cords of tissue that connect muscles to bones. Some tendon problems include:

pain

swelling

tears and swelling of tendons including the back of the ankle (Achilles), shoulder, hand, or

other tendon sites.

The risk of getting tendon problems while you take levofloxacin if you:

are over 60 years of age

are taking steroids (corticosteroids)

have had a kidney, heart or lung transplant.

Tendon problems can happen in people who do not have the above risk factors when they take

levofloxacin tablets.

Other reasons that can increase your risk of tendon problems can include:

physical activity or exercise

kidney failure

tendon problems in the past, such as in people with rheumatoid arthritis (RA).

Stop taking levofloxacin tablets immediately and get medical help right away at the first sign of

tendon pain, swelling or inflammation. Avoid exercise and using the affected area.

The most common area of pain and swelling is the Achilles tendon at the back of your ankle. This can

also happen with other tendons. You may need a different antibiotic that is not a fluoroquinolone to

treat your infection.

Tendon rupture can happen while you are taking or after you have finished taking levofloxacin

tablets. Tendon ruptures can happen within hours or days of taking levofloxacin tablets and have

happened up to several months after people have finished taking their fluoroquinolone.

Stop taking levofloxacin tablets immediately and get medical help right away if you get any of the

following signs or symptoms of a tendon rupture:

hear or feel a snap or pop in a tendon area

bruising right after an injury in a tendon area

unable to move the affected area or bear weight

The tendon problems may be permanent.

2. Changes in sensation and possible nerve damage (Peripheral Neuropathy). Damage to the nerves in arms,

hands, legs, or feet can happen in people who take fluoroquinolones, including levofloxacin tablets. Stop

taking levofloxacin tablets immediately and talk to your healthcare provider right away if you get any of the

following symptoms of peripheral neuropathy in your arms, hands, legs, or feet:

pain

burning

numbness

weakness

tingling

The nerve damage may be permanent.

3. Central Nervous System (CNS) effects. Mental health problems and seizures have been reported in people

who take fluoroquinolone antibacterial medicines, including levofloxacin tablets. Tell your healthcare

provider if you have a history of mental health problems, including depression, or have a history of seizures

before you start taking levofloxacin tablets. CNS side effects may happen as soon as after taking the first

dose of levofloxacin tablets. Stop taking levofloxacin tablets immediately and talk to your healthcare

provider right away if you get any of these side effects, or other changes in mood or behavior:

seizures

hear voices, see things, or sense things that are not there (hallucinations)

feel restless or agitated

tremors

feel anxious or nervous

confusion

depression

reduced awareness of surroundings

trouble sleeping

nightmares

feel lightheaded or dizzy

feel more suspicious (paranoia)

suicidal thoughts or acts

headaches that will not go away, with or without blurred vision

memory problems

false or strange thoughts or beliefs (delusions)

The CNS changes may be permanent

4. Worsening of myasthenia gravis (a problem that causes muscle weakness). Fluoroquinolones like

levofloxacin tablets may cause worsening of myasthenia gravis symptoms, including muscle weakness and

breathing problems. Tell your healthcare provider if you have a history of myasthenia gravis before you start

taking levofloxacin tablets. Call your healthcare provider right away if you have any worsening muscle

weakness or breathing problems.

What are levofloxacin tablets?

Levofloxacin tablet is a fluoroquinolone antibiotic medicine used in adults age 18 years or older to treat

certain infections caused by certain germs called bacteria. These bacterial infections include:

nosocomial pneumonia

community-acquired pneumonia

skin infections, complicated and uncomplicated

chronic prostate infection

inhalation anthrax germs

plague

urinary tract infections, complicated and uncomplicated

acute kidney infection (pyelonephritis)

acute worsening or chronic bronchitis

acute sinus infection

Studies of levofloxacin tablets for use in the treatment of plague and anthrax were done in animals only,

because plague and anthrax could not be studied in people.

Levofloxacin tablets should not be used in people with uncomplicated urinary tract infections, acute bacterial

exacerbation of chronic bronchitis, or acute bacterial sinusitis if there are other treatment options available.

Levofloxacin tablets are also used to treat children who weigh at least 66 pounds (or at least 30 kilograms)

and may have breathed in anthrax germs, have plague, or been exposed to plague germs.

It is not known if levofloxacin tablets are safe and effective in children under 6 months of age.

The safety and effectiveness in children treated with levofloxacin tablets for more than 14 days is not

known.

Who should not take levofloxacin tablets?

Do not take levofloxacin tablets if you have ever had a severe allergic reaction to an antibiotic known as a

fluoroquinolone, or if you are allergic to levofloxacin or any of the ingredients in levofloxacin tablets. See

the end of this leaflet for a complete list of ingredients in levofloxacin tablets.

Before you take levofloxacin tablets, tell your healthcare provider about all of your medical conditions,

including if you:

have tendon problems. Levofloxacin tablets should not be used in people who have a history of

tendon problems

have a problem that causes muscle weakness (myasthenia gravis). Levofloxacin tablets should not be

used in people who have a known history of myasthenia gravis

have a history of mental health problems, including depression

have central nervous system problems such as seizures (epilepsy)

have nerve problems. Levofloxacin tablets should not be used in people who have a history of a nerve

problem called peripheral neuropathy

have or anyone in your family has an irregular heartbeat, especially a condition called “QT

prolongation.”

have low blood potassium (hypokalemia)

have bone problems

have joint problems including rheumatoid arthritis (RA)

have kidney problems. You may need a lower dose of levofloxacin tablets if your kidneys do not

work well.

have liver problems

have diabetes or problems with low blood sugar (hypoglycemia)

are pregnant or plan to become pregnant. Levofloxacin passes into your breast milk. You should not

breastfeed during treatment with levofloxacin and for 2 days after taking your last dose of

levofloxacin. You may pump your breast milk and throw it away during treatment with levofloxacin

and for 2 days after taking your last dose of levofloxacin.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter

medicines, vitamins, and herbal supplements.

Levofloxacin tablets and other medicines can affect each other causing side effects.

Especially tell your healthcare provider if you take:

a steroid medicine.

an anti-psychotic medicine

a tricyclic antidepressant

a water pill (diuretic)

certain medicines may keep levofloxacin tablets from working correctly. Take levofloxacin tablets

either 2 hours before or 2 hours after taking these medicines or supplements:

an antacid, multivitamin, or other medicines or supplements that have magnesium, aluminum,

iron, or zinc

sucralfate (Carafate®)

didanosine (Videx®,Videx® EC)

a blood thinner (warfarin, Coumadin, Jantoven)

an oral anti-diabetes medicine or insulin

an NSAID (Non-Steroidal Anti-Inflammatory Drug). Many common medicines for pain relief are

NSAIDs. Taking an NSAID while you take levofloxacin tablets or other fluoroquinolones may

increase your risk of central nervous system effects and seizures.

theophylline (Theo-24®, Elixophyllin®, Theochron®, Uniphyl®, Theolair®)

a medicine to control your heart rate or rhythm (antiarrhythmics)

Ask your healthcare provider if you are not sure if any of your medicines are listed above.

Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and

pharmacist when you get a new medicine.

How should I take levofloxacin tablets?

Take levofloxacin tablets exactly as your healthcare provider tells you to take it.

Take levofloxacin tablets at the same time each day.

Drink plenty of fluids while you take levofloxacin tablets.

Levofloxacin tablets can be taken with or without food.

If you miss a dose of levofloxacin tablets and it is:

8 hours or more until your next scheduled dose, take your missed dose right away. Then take the next

dose at your regular time.

less than 8 hours until your next scheduled dose, do not take the missed dose. Take the next dose at

your regular time.

Do not skip any doses of levofloxacin tablets, or stop taking it, even if you begin to feel better, until

you finish your prescribed treatment unless:

you have tendon problems. See “What is the most important information I should know about

levofloxacin tablets?”.

you have a nerve problem. See “What is the most important information I should know about

levofloxacin tablets?”.

you have a central nervous system problem. See "What are the possible side effects of

levofloxacin tablets?".

you have a serious allergic reaction. See “What are the possible side effects oflevofloxacin

tablets?”.

your healthcare provider tells you to stop taking levofloxacin tablets.

Taking all of your levofloxacin tablets doses will help make sure that all of the bacteria are killed. Taking all

of your levofloxacin tablets doses will help you lower the chance that the bacteria will become resistant to

levofloxacin tablets. If your infection does not get better while you take levofloxacin tablets, it may mean

that the bacteria causing your infection may be resistant to levofloxacin tablets. If your infection does not get

better, call your healthcare provider. If your infection does not get better, levofloxacin tablets and other

similar antibiotic medicines may not work for you in the future.

If you take too much levofloxacin tablets, call your healthcare provider or get medical help right

away.

What should I avoid while taking levofloxacin tablets?

Levofloxacin tablets can make you feel dizzy and lightheaded. Do not drive, operate machinery, or do

other activities that require mental alertness or coordination until you know how levofloxacin tablets

affects you.

Avoid sunlamps, tanning beds, and try to limit your time in the sun. Levofloxacin tablets can make

your skin sensitive to the sun (photosensitivity) and the light from sunlamps and tanning beds. You

could get severe sunburn, blisters or swelling of your skin. If you get any of these symptoms while

you take levofloxacin tablets, call your healthcare provider right away. You should use sunscreen and

wear a hat and clothes that cover your skin if you have to be in sunlight.

What are the possible side effects of levofloxacin tablets?

Levofloxacin tablets may cause serious side effects, including:

See “What is the most important information I should know about levofloxacin tablets?”

Serious allergic reactions. Allergic reactions can happen in people taking fluoroquinolones, including

levofloxacin tablets, even after only 1 dose. Stop taking levofloxacin tablets and get emergency

medical help right away if you have any of the following symptoms of a severe allergic reaction:

hives

trouble breathing or swallowing

swelling of the lips, tongue, face

throat tightness, hoarseness

rapid heartbeat

faint

skin rash

Skin rash may happen in people taking levofloxacin tablets, even after only 1 dose. Stop taking levofloxacin

tablets at the first sign of a skin rash and immediately call your healthcare provider. Skin rash may be a sign

of a more serious reaction to levofloxacin tablets.

Liver damage (hepatotoxicity): Hepatotoxicity can happen in people who take levofloxacin tablets.

Call your healthcare provider right away if you have unexplained symptoms such as:

nausea or vomiting

stomach pain

fever

weakness

pain or tenderness in the upper right side of your stomach-area

itching

unusual tiredness

loss of appetite

light colored bowel movements

dark colored urine

yellowing of your skin or the whites of your eyes

Stop taking levofloxacin tablets and tell your healthcare provider right away if you have yellowing of your

skin or white part of your eyes, or if you have dark urine. These can be signs of a serious reaction to

levofloxacin tablets (a liver problem).

Aortic aneurysm and dissection: Tell your healthcare provider if you have ever been told that you

have an aortic aneurysm, a swelling of the large artery that carries blood from the heart to the body.

Get emergency medical help right away if you have sudden chest, stomach, or back pain.

Intestine infection (Clostridium difficile-associated diarrhea). Clostridium difficile-associated

diarrhea (CDAD) can happen with many antibiotics, including levofloxacin tablets. Call your

healthcare provider right away if you get watery diarrhea, diarrhea that does not go away, or bloody

stools. You may have stomach cramps and a fever. CDAD can happen 2 or more months after you

have finished your antibiotic.

Serious heart rhythm changes (QT prolongation and torsades de pointes). Tell your healthcare

provider right away if you have a change in your heart beat (a fast or irregular heartbeat), or if you

faint. Levofloxacin tablets may cause a rare heart problem known as prolongation of the QT interval.

This condition can cause an abnormal heartbeat and can be very dangerous. The chances of this

happening are higher in people:

who are elderly

with a family history of prolonged QT interval

with low blood potassium (hypokalemia)

who take certain medicines to control heart rhythm (antiarrhythmics)

Joint Problems. Increased chance of problems with joints and tissues around joints in children can

happen. Tell your child’s healthcare provider if your child has any joint problems during or after

treatment with levofloxacin tablets.

Changes in blood sugar. People who take levofloxacin tablets and other fluoroquinolone medicines

with oral anti-diabetes medicines or with insulin can get low blood sugar (hypoglycemia) and high

blood sugar (hyperglycemia). Follow your healthcare provider’s instructions for how often to check

your blood sugar. If you have diabetes and you get low blood sugar while taking levofloxacin tablets,

stop taking levofloxacin tablets and call your healthcare provider right away. Your antibiotic

medicine may need to be changed.

Sensitivity to sunlight (photosensitivity). See “What should I avoid while taking levofloxacin

tablets?"

The most common side effects of levofloxacin tablets include:

nausea

headache

diarrhea

insomnia

constipation

dizziness

In children 6 months and older who take levofloxacin tablets to treat anthrax disease or plague, vomiting is

also common.

Levofloxacin tablets may cause false-positive urine screening results for opiates when testing is done with

some commercially available kits. A positive result should be confirmed using a more specific test.

These are not all the possible side effects of levofloxacin tablets.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-

1088.

How should I store levofloxacin tablets?

Store levofloxacin tablets at 20° to 25°C (68° to 77°F).

Keep levofloxacin tablets in a tightly closed container.

General information about the safe and effective use of levofloxacin tablets

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use

levofloxacin tablets for a condition for which it is not prescribed. Do not give levofloxacin tablets to other

people, even if they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about levofloxacin tablets. If you would

like more information about levofloxacin tablets, talk with your healthcare provider. You can ask your

healthcare provider or pharmacist for information about levofloxacin tablets that is written for health

professionals.

For more information go to call 1-888-375-3784.

What are the ingredients in levofloxacin tablets?

Levofloxacin Film-Coated Tablets:

Active ingredient: levofloxacin

Inactive ingredients:

250 mg (as expressed in the anhydrous form): colloidal silicon dioxide, corn starch, crospovidone,

hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol and titanium dioxide.

500 mg (as expressed in the anhydrous form): colloidal silicon dioxide, corn starch, crospovidone, FD&C

yellow no. 5 aluminum lake, FD&C yellow no. 6 aluminum lake, hypromellose, magnesium stearate,

microcrystalline cellulose, polyethylene glycol and titanium dioxide.

750 mg (as expressed in the anhydrous form): colloidal silicon dioxide, corn starch, crospovidone,

hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, synthetic yellow iron

oxide and titanium dioxide.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Rx Only

Manufactured by:

Dr. Reddy’s Laboratories Limited

Bachupally – 500 090 INDIA

Revised: 0719

Dispense the Medication Guide available at: www.drreddys.com/medguide/levofloxacintabs.pdf

Revised: 8/2019

Document Id: 92348d00-be12-49bd-8bfd-04ab3346cb92

34391-3

Set id: 780b4252-c1ee-4568-b0c2-69d7baf907f4

Version: 1

Effective Time: 20190807

Bryant Ranch Prepack

LEVOFLOXACIN- levofloxacin tablet, film coated

Bryant Ranch Prepack

----------

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use LEVOFLOXACIN TABLETS safely and

effectively. See full prescribing information for LEVOFLOXACIN TABLETS.

LEVOFLOXACIN tablets, for oral use

Initial U.S. Approval: 1996

WARNING: SERIOUS ADVERSE REACTIONS INCLUDING TENDINITIS, TENDON RUPTURE,

PERIPHERAL NEUROPATHY, CENTRAL NERVOUS SYSTEM EFFECTS AND EXACERBATION OF

MYASTHENIA GRAVIS

See full prescribing information for complete boxed warning.

Fluoroquinolones, including levofloxacin, have been associated with disabling and potentially

irreversible serious adverse reactions that have occurred together (5.1), including:

o Tendinitis and tendon rupture (5.2)

o Peripheral neuropathy (5.3)

o Central nervous system effects (5.4)

Discontinue levofloxacin immediately and avoid the use of fluoroquinolones, including levofloxacin, in

patients who experience any of these serious adverse reactions (5.1)

Fluoroquinolones, including levofloxacin, may exacerbate muscle weakness in patients with myasthenia

gravis. Avoid levofloxacin in patients with a known history of myasthenia gravis [see Warnings and

Precautions (5.5)].

Because fluoroquinolones, including levofloxacin, have been associated with serious adverse reactions

(5.1-5.15), reserve levofloxacin for use in patients who have no alternative treatment options for the

following indications:

o Uncomplicated urinary tract infection (1.12)

o Acute bacterial exacerbation of chronic bronchitis (1.13)

o Acute bacterial sinusitis (1.14)

RECENT MAJOR CHANGES

Warnings and Precautions,– Risk of Aortic Aneurysm and Dissection (5.9) 5/2019

Warnings and Precautions -Central Nervous System Effects (5.4) 10/2018

Warnings and Precautions – Blood Glucose Disturbances (5.13) 10/2018

INDICATIONS AND USAGE

Levofloxacin tablet is a fluoroquinolone antibacterial indicated in adults (18 years of age and older) with infections caused

by designated, susceptible bacteria and in pediatric patients where indicated (1, 12.4).

Pneumonia: Nosocomial (1.1) and Community Acquired (1.2, 1.3)

Skin and Skin Structure Infections (SSSI): Complicated (1.4) and Uncomplicated (1.5)

Chronic bacterial prostatitis (1.6)

Inhalational Anthrax, Post-Exposure in adult and pediatric patients(1.7)

Plague in adult and pediatric patients (1.8)

Urinary Tract Infections (UTI) : Complicated (1.9, 1.10) and Uncomplicated (1.12)

Acute Pyelonephritis (1.11)

Acute Bacterial Exacerbation of Chronic Bronchitis (1.13)

Acute Bacterial Sinusitis (1.14)

Usage

To reduce the development of drug-resistant bacteria and maintain the effectiveness of levofloxacin tablets and other

antibacterial drugs, levofloxacin tablets should be used only to treat or prevent infections that are proven or strongly

suspected to be caused by bacteria (1.15).

DOSAGE AND ADMINISTRATION

Administer levofloxacin tablets to pediatric patients weighing 30 kg and greater only (2.1, 2.2).

Levofloxacin 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 (2.2).

Dosage in Adult and Pediatric Patients with Creatinine Clearance greater than or equal to 50 mL/minute (2.1.

2.2)

Type of Infection

Dose Every 24 hours

Duration (days)

Nosocomial Pneumonia (1.1)

750 mg

7 to 14

Community Acquired Pneumonia (1.2)

500 mg

7 to 14

Community Acquired Pneumonia (1.3)

750 mg

Complicated SSSI (1.4)

750 mg

7 to 14

Uncomplicated SSSI (1.5)

500 mg

7 to 10

Chronic Bacterial Prostatitis (1.6)

500 mg

Inhalational Anthrax (Post-Exposure) (1.7)

Adults and Pediatric Patients 50 kg or greater

Pediatric Patients 30 kg to less than 50 kg (2.2)

500 mg

250 mg every 12 hours

Plague (1.8)

Adults and Pediatric Patients 50 kg or greater

Pediatric Patients 30 kg to less than 50 kg (2.2)

500 mg

250 mg every 12 hours

10 to 14

10 to 14

Complicated UTI (1.9) or Acute Pyelonephritis (1.11)

750 mg

Complicated UTI (1.10) or Acute Pyelonephritis (1.11)

250 mg

Uncomplicated UTI (1.12)

250 mg

Acute Bacterial Exacerbation of Chronic Bronchitis (1.13)

500 mg

Acute Bacterial Sinusitis (1.14)

750 mg

500 mg

10 to 14

Adjust dose for creatinine clearance less than 50 mL/minute (2.3, 8.6, 12.3)

DOSAGE FORMS AND STRENGTHS

Tablets: 250 mg, 500 mg, and 750 mg (3)

CONTRAINDICATIONS

Known hypersensitivity to levofloxacin or other quinolones (4, 5.7)

WARNINGS AND PRECAUTIONS

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)

ADVERSE REACTIONS

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

To report SUSPECTED ADVERSE REACTIONS, contact Dr. Reddy’s Laboratories Inc. at 1-888-375-3784 or

FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

Interacting Drug

Inte rac tio n

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, watch for

bleeding (7.2)

Antidiabetic agents

Carefully monitor blood glucose (5.13, 7.3)

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

levofloxacin-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.

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

Revised: 8/2019

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: SERIOUS ADVERSE REACTIONS INCLUDING TENDINITIS, TENDON

RUPTURE, PERIPHERAL NEUROPATHY, CENTRAL NERVOUS SYSTEM EFFECTS

AND EXACERBATION OF MYASTHENIA GRAVIS

1 INDICATIONS AND USAGE

1.1Nosocomial Pneumonia

1.2 Community-Acquired Pneumonia: 7 to 14 day Treatment Regimen

1.3Community-Acquired Pneumonia: 5 day Treatment Regimen

1.4 Complicated Skin and Skin Structure Infections

1.5 Uncomplicated Skin and Skin Structure Infections

1.6 Chronic Bacterial Prostatitis

1.7Inhalational Anthrax (Post-Exposure)

1.8 Plague

1.9 Complicated Urinary Tract Infections: 5 day Treatment Regimen

1.10 Complicated Urinary Tract Infections: 10 day Treatment Regimen

1.11 Acute Pyelonephritis: 5 or 10 day Treatment Regimen

1.12 Uncomplicated Urinary Tract Infections

1.13 Acute Bacterial Exacerbation of Chronic Bronchitis

1.14 Acute Bacterial Sinusitis: 5-day and 10 to 14 day Treatment Regimens

1.15 Usage

2 DOSAGE AND ADMINISTRATION

2.1 Dosage of Levofloxacin Tablets in Adult Patients with Creatinine Clearance ≥ 50 mL/minute

2.2 Dosage of Levofloxacin Tablets in Pediatric Patients with Inhalational Anthrax or Plague

2.3 Dosage Adjustment in Adults with Renal Impairment

2.4 Drug Interaction With Chelation Agents: Antacids, Sucralfate, Metal Cations, Multivitamins

2.5 Important Administration Instructions

2.6 Hydration for Patients Receiving Levofloxacin Tablets

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Disabling and Potentially Irreversible Serious Adverse Reactions Including Tendinitis and

Tendon Rupture, Peripheral Neuropathy, and Central Nervous System Effects

5.2 Tendinitis and Tendon Rupture

5.3 Peripheral Neuropathy

5.4 Central Nervous System Effects

5.5 Exacerbation of Myasthenia Gravis

5.6 Other Serious and Sometimes Fatal Adverse Reactions

5.7 Hypersensitivity Reactions

5.8 Hepatotoxicity

5.9 Risk of Aortic Aneurysm and Dissection

5.10 Clostridium difficile-Associated Diarrhea

5.11 Prolongation of the QT Interval

5.12 Musculoskeletal Disorders in Pediatric Patients and Arthropathic Effects in Animals

5.13 Blood Glucose Disturbances

5.14 Photosensitivity/Phototoxicity

5.15 Development of Drug Resistant Bacteria

6 ADVERSE REACTIONS

6.1 Clinical Trial Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 Chelation Agents: Antacids, Sucralfate, Metal Cations, Multivitamins

7.2 Warfarin

7.3 Antidiabetic Agents

7.4 Non-Steroidal Anti-Inflammatory Drugs

7.5 Theophylline

7.6 Cyclosporine

7.7 Digoxin

7.8 Probenecid and Cimetidine

7.9 Interactions with Laboratory or Diagnostic Testing

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Renal Impairment

8.7 Hepatic Impairment

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.3 Pharmacokinetics

12.4 Microbiology

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

13.2 Animal Pharmacology and/or Toxicology

14 CLINICAL STUDIES

14.1 Nosocomial Pneumonia

14.2 Community-Acquired Pneumonia: 7 to 14 day Treatment Regimen

14.3 Community-Acquired Pneumonia: 5 Day Treatment Regimen

14.4 Acute Bacterial Sinusitis: 5 day and 10 to 14 day Treatment Regimens

14.5 Complicated Skin and Skin Structure Infections

14.6 Chronic Bacterial Prostatitis

14.7 Complicated Urinary Tract Infections and Acute Pyelonephritis: 5 day Treatment Regimen

14.8 Complicated Urinary Tract Infections and Acute Pyelonephritis: 10 day Treatment Regimen

14.9 Inhalational Anthrax (Post-Exposure)

14.10 Plague

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

Sections or subsections omitted from the full prescribing information are not listed.

FULL PRESCRIBING INFORMATION

WARNING: SERIOUS ADVERSE REACTIONS INCLUDING TENDINITIS, TENDON

RUPTURE, PERIPHERAL NEUROPATHY, CENTRAL NERVOUS SYSTEM EFFECTS

AND EXACERBATION OF MYASTHENIA GRAVIS

Fluoroquinolones, including levofloxacin, have been associated with disabling and

potentially irreversible serious adverse reactions that have occurred together [see

Warnings and Precautions (5.1)], including:

o Tendinitis and tendon rupture [see Warnings and Precautions (5.2)]

o Peripheral neuropathy [see Warnings and Precautions (5.3)]

o Central nervous system effects [see Warnings and Precautions (5.4)]

Discontinue levofloxacin immediately and avoid the use of fluoroquinolones, including

levofloxacin, in patients who experience any of these serious adverse reactions [see

Warnings and Precautions (5.1)]

Fluoroquinolones, including levofloxacin, may exacerbate muscle weakness in

patients with myasthenia gravis. Avoid levofloxacin in patients with a known history

of myasthenia gravis [see Warnings and Precautions (5.5)].

Because fluoroquinolones, including levofloxacin, have been associated with serious

adverse reactions [see Warnings and Precautions (5.1-5.15)], reserve levofloxacin for

use in patients who have no alternative treatment options for the following indications:

o Uncomplicated urinary tract infection [see Indications and Usage (1.12)]

o Acute bacterial exacerbation of chronic bronchitis [see Indications and Usage (1.13)]

o Acute bacterial sinusitis [see Indications and Usage (1.14)].

1 INDICATIONS AND USAGE

1.1Nosocomial Pneumonia

Levofloxacin tablets are indicated in adult patients for the treatment of nosocomial pneumonia due to

methicillin-susceptible Staphylococcus aureus, Pseudomonas aeruginosa, Serratia marcescens,

Escherichia coli, Klebsiella pneumoniae, Haemophilus influenzae, or Streptococcus pneumoniae.

Adjunctive therapy should be used as clinically indicated. Where Pseudomonas aeruginosa is a

documented or presumptive pathogen, combination therapy with an anti-pseudomonal β-lactam is

recommended [see ClinicalStudies (14.1 )].

1.2 Community-Acquired Pneumonia: 7 to 14 day Treatment Regimen

Levofloxacin tablets are indicated in adult patients for the treatment of community-acquired pneumonia

due to methicillin-susceptible Staphylococcus aureus, Streptococcus pneumoniae (including multi-drug-

resistant Streptococcus pneumoniae [MDRSP]), Haemophilus influenzae, Haemophilus parainfluenzae,

Klebsiella pneumoniae, Moraxella catarrhalis, Chlamydophila pneumoniae, Legionella pneumophila, or

Mycoplasma pneumoniae [seeDosageand Administration (2.1) and Clinical Studies (14.2)].

MDRSP isolates are isolates resistant to two or more of the following antibacterials: penicillin (MIC ≥2

mcg/mL), 2

generation cephalosporins, e.g., cefuroxime, macrolides, tetracyclines and

trimethoprim/sulfamethoxazole.

1.3Community-Acquired Pneumonia: 5 day Treatment Regimen

Levofloxacin tablets are indicated in adult patients for the treatment of community-acquired pneumonia

due to Streptococcus pneumoniae (excluding multi-drug-resistant isolates [MDRSP]), Haemophilus

influenzae, Haemophilus parainfluenzae, Mycoplasma pneumoniae, or Chlamydophila pneumoniae

[seeDosageand Administration (2.1) and Clinical Studies (14.3)].

1.4 Complicated Skin and Skin Structure Infections

Levofloxacin tablets are indicated in adult patients for the treatment of complicated skin and skin

structure infections due to methicillin-susceptible Staphylococcus aureus, Enterococcus faecalis,

Streptococcus pyogenes, or Proteus mirabilis [see ClinicalStudies(14.5)].

1.5 Uncomplicated Skin and Skin Structure Infections

Levofloxacin tablets are indicated in adult patients for the treatment of uncomplicated skin and skin

structure infections (mild to moderate) including abscesses, cellulitis, furuncles, impetigo, pyoderma,

wound infections, due to methicillin-susceptible Staphylococcus aureus, or Streptococcus pyogenes.

1.6 Chronic Bacterial Prostatitis

Levofloxacin tablets are indicated in adult patients for the treatment of chronic bacterial prostatitis due

to Escherichia coli, Enterococcus faecalis, or methicillin-susceptible Staphylococcus epidermidis [see

ClinicalStudies (14.6)].

1.7Inhalational Anthrax (Post-Exposure)

Levofloxacin tablets are indicated for inhalational anthrax (post-exposure) to reduce the incidence or

progression of disease following exposure to aerosolized Bacillus anthracis in adults and pediatric

patients, 6 months of age and older [see Dosage and Administration (2.2)]. The effectiveness of

levofloxacin is based on plasma concentrations achieved in humans, a surrogate endpoint reasonably

likely to predict clinical benefit.

Levofloxacin has not been tested in humans for the post-exposure prevention of inhalation anthrax. The

safety of levofloxacin in adults for durations of therapy beyond 28 days or in pediatric patients for

durations of therapy beyond 14 days has not been studied. Prolonged levofloxacin therapy should only

be used when the benefit outweighs the risk [see Clinical Studies (14.9)].

1.8 Plague

Levofloxacin tablets are indicated for treatment of plague, including pneumonic and septicemic plague,

due to Yersinia pestis (Y. pestis) and prophylaxis for plague in adults and pediatric patients, 6 months of

age and older [see Dosage and Administration (2.2)].

Efficacy studies of levofloxacin tablets could not be conducted in humans with plague for ethical and

feasibility reasons. Therefore, approval of this indication was based on an efficacy study conducted in

animals [see Clinical Studies (14.10)].

1.9 Complicated Urinary Tract Infections: 5 day Treatment Regimen

Levofloxacin tablets are indicated in adult patients for the treatment of complicated urinary tract

infections due to Escherichia coli, Klebsiella pneumoniae, or Proteus mirabilis [see Clinical Studies

(14.7)].

1.10 Complicated Urinary Tract Infections: 10 day Treatment Regimen

Levofloxacin tablets are indicated in adult patients for the treatment of complicated urinary tract

infections (mild to moderate) due to Enterococcus faecalis, Enterobacter cloacae, Escherichia coli,

Klebsiella pneumoniae, Proteus mirabilis, or Pseudomonas aeruginosa [see Clinical Studies (14.8)].

1.11 Acute Pyelonephritis: 5 or 10 day Treatment Regimen

Levofloxacin tablets are indicated in adult patients for the treatment of acute pyelonephritis caused by

Escherichia coli, including cases with concurrent bacteremia [see Clinical Studies (14.8)].

1.12 Uncomplicated Urinary Tract Infections

Levofloxacin tablets are indicated in adult patients for the treatment of uncomplicated urinary tract

infections (mild to moderate) due to Escherichia coli, Klebsiella pneumoniae, or Staphylococcus

saprophyticus.

Because fluoroquinolones, including levofloxacin tablets, have been associated with serious adverse

reactions [see Warnings and Precautions (5.1 - 5.15)] and for some patients uncomplicated urinary tract

infection is self-limiting, reserve levofloxacin tablets for treatment of uncomplicated urinary tract

infections in patients who have no alternative treatment options.

1.13 Acute Bacterial Exacerbation of Chronic Bronchitis

Levofloxacin tablets are indicated in adult patients for the treatment of acute bacterial exacerbation of

chronic bronchitis (ABECB) due to methicillin-susceptible Staphylococcus aureus, Streptococcus

pneumoniae, Haemophilus influenzae, Haemophilus parainfluenzae, or Moraxella catarrhalis.

Because fluoroquinolones, including levofloxacin tablets, have been associated with serious adverse

reactions [see Warnings and Precautions (5.1 - 5.15)] and for some patients ABECB is self-limiting,

reserve levofloxacin tablets for treatment of ABECB in patients who have no alternative treatment

options.

1.14 Acute Bacterial Sinusitis: 5-day and 10 to 14 day Treatment Regimens

Levofloxacin tablets are indicated in adult patients for the treatment of acute bacterial sinusitis (ABS)

due to Streptococcus pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis [see Clinical

Studies (14.4)].

Because fluoroquinolones, including levofloxacin tablets, have been associated with serious adverse

reactions [see Warnings and Precautions (5.1 - 5.15)] and for some patients ABS is self-limiting, reserve

levofloxacin tablets for treatment of ABS in patients who have no alternative treatment options.

1.15 Usage

To reduce the development of drug-resistant bacteria and maintain the effectiveness of levofloxacin

tablets and other antibacterial drugs, levofloxacin tablets should be used only to treat or prevent

infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and

susceptibility information are available, they should be considered in selecting or modifying

antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may

contribute to the empiric selection of therapy.

Culture and susceptibility testing

Appropriate culture and susceptibility tests should be performed before treatment in order to isolate and

identify organisms causing the infection and to determine their susceptibility to levofloxacin [see

Microbiology (12.4)]. Therapy with levofloxacin tablets may be initiated before results of these tests

are known; once results become available, appropriate therapy should be selected.

As with other drugs in this class, some isolates of Pseudomonas aeruginosa may develop resistance

fairly rapidly during treatment with levofloxacin tablets. Culture and susceptibility testing performed

periodically during therapy will provide information about the continued susceptibility of the pathogens

to the antimicrobial agent and also the possible emergence of bacterial resistance.

2 DOSAGE AND ADMINISTRATION

2.1 Dosage of Levofloxacin Tablets in Adult Patients with Creatinine Clearance ≥ 50

mL/minute

The usual dose of levofloxacin tablets is 250 mg, 500 mg, or 750 mg administered orally every 24

hours, as indicated by infection and described in Table 1.

These recommendations apply to patients with creatinine clearance ≥ 50 mL/minute. For patients with

creatinine clearance less than 50 mL/min, adjustments to the dosing regimen are required [see Dosage

and Administration (2.3)].

Table 1: Dosageof Levofloxacin Tablets in Adult Patients with Creatinine Clearance greater than

or equal to 50 mL/minute)

Type of Infection

Dosed Every 24

hours

Duration

(days)

Nosocomial Pneumonia

750 mg

7 to 14

Community Acquired Pneumonia

500 mg

7 to 14

Community Acquired Pneumonia

750 mg

Complicated Skin and Skin Structure Infections (SSSI)

750 mg

7 to 14

Uncomplicated SSSI

500 mg

7 to 10

Chronic Bacterial Prostatitis

500 mg

Inhalational Anthrax (Post-Exposure), adult and

pediatric patients weighing 50 kg

or greater

Pediatric patients weighing 30 kg to less than 50 kg

500 mg see

Table 2 below

(2.2)

Plague, adult and pediatric patients weighing 50 kg or

greater

Pediatric Patients weighing 30 kg to less than 50 kg

500 mg see Table

2 below (2.2)

10 to 14

10 to 14

Complicated Urinary Tract Infection (cUTI) or Acute

Pyelonephritis (AP)

750 mg

Complicated Urinary Tract Infection (cUTI) or Acute

Pyelonephritis (AP)

250 mg

Uncomplicated Urinary Tract Infection

250 mg

Acute Bacterial Exacerbation of Chronic Bronchitis

(ABECB)

500 mg

Acute Bacterial Sinusitis (ABS)

750 mg

500 mg

10 to 14

Due to the designated pathogens [see Indications and Usage (1)].

Sequential therapy (intravenous levofloxacin to oral levofloxacin tablets) may be instituted at the

discretion of the healthcare provider.

Due to methicillin-susceptible Staphylococcus aureus, Streptococcus pneumoniae (including multi-

drug-resistant isolates [MDRSP]), Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella

pneumoniae, Moraxella catarrhalis, Chlamydophila pneumoniae, Legionella pneumophila, or

Mycoplasma pneumoniae [see Indications and Usage (1.2)].

Due to Streptococcus pneumoniae (excluding multi-drug-resistant isolates [MDRSP]), Haemophilus

influenzae, Haemophilus parainfluenzae, Mycoplasma pneumoniae, or Chlamydophila pneumoniae [see

Indications and Usage (1.3)].

*

Þ,ß

Þ ß

Indications and Usage (1.3)].

¶This regimen is indicated for cUTI due to Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis

and AP due to E. coli, including cases with concurrent bacteremia.

This regimen is indicated for cUTI due to Enterococcus faecalis, Enterococcus cloacae, Escherichia

coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa; and for AP due to E. coli.

ÞDrug administration should begin as soon as possible after suspected or confirmed exposure to

aerosolized B. anthracis. This indication is based on a surrogate endpoint. Levofloxacin plasma

concentrations achieved in humans are reasonably likely to predict clinical benefit [see Clinical Studies

(14.9)].

ßThe safety of levofloxacin in adults for durations of therapy beyond 28 days or in pediatric patients

for durations beyond 14 days has not been studied. An increased incidence of musculoskeletal adverse

events compared to controls has been observed in pediatric patients [see Warnings and Precautions

(5.11), Use in Specific Populations (8.4), and Clinical Studies (14.9)]. Prolonged levofloxacin

therapy should only be used when the benefit outweighs the risk.

Drug administration should begin as soon as possible after suspected or confirmed exposure to

Yersinia pestis. Higher doses of levofloxacin typically used for treatment of pneumonia can be used for

treatment of plague, if clinically indicated.

2.2 Dosage of Levofloxacin Tablets in Pediatric Patients with Inhalational Anthrax or Plague

The dosage of levofloxacin tablets for inhalational anthrax (post-exposure) and plague in pediatric

patients who weigh 30 kg or greater is described below in Table 2. Levofloxacin tablets cannot be

administered to patients who weigh less than 30 kg because of the limitations of the available strength.

Alternative formulations of levofloxacin may be considered for pediatric patients who weigh less than

30 kg..

Table 2: Levofloxacin Tablets Dosage in Pediatric Patients Weighing 30 kg or greater with

Inhalational Anthrax (Post-Exposure) and Plague*

Type of Infection

Dos e

Frequency

Duration

Inhalational Anthrax (post-exposure)

Pediatric patients weighing 50 kg or

greater

500 mg every 24

hours

every 24

hours

60 days

Pediatric patients weighing 30 kg to less

than 50 kg

250 mg

every 12

hours

60 days

Plague

Pediatric patients weighing 50 kg or

greater

500 mg

every 24

hours

10 to 14

days

Pediatric patients weighing 30 kg to less

than 50 kg

250 mg

every 12

hours

10 to 14

days

Due to Bacillus anthracis [see Indications and Usage (1.13)] and Yersinia pestis [see Indications and

Usage (1.14)].

Sequential therapy (intravenous levofloxacin injection to oral levofloxacin tablets) may be instituted at

the discretion of the healthcare provider.

Begin levofloxacin tablets as soon as possible after suspected or confirmed exposure to aerosolized

B. anthracis.

The safety of levofloxacin in pediatric patients for durations of therapy beyond 14 days has not been

*

‡,§

studied [see Warnings and Precautions (5.11), Use in Specific Populations (8.4), and Clinical Studies

(14.9)]. Begin levofloxacin tablets as soon as possible after suspected or confirmed exposure to

Yersinia pestis.

2.3 Dosage Adjustment in Adults with Renal Impairment

Administer levofloxacin with caution in patients with renal impairment. Careful clinical observation and

appropriate laboratory studies should be performed prior to and during therapy since elimination of

levofloxacin may be reduced in these patients.

In patients with renal impairment (creatinine clearance less than 50 mL/min), adjustment of the dosage

regimen is necessary to avoid the accumulation of levofloxacin due to decreased clearance [seeUse in

Specific Populations (8.6)]. No adjustment is necessary for patients with a creatinine clearance greater

than or equal to 50 mL/minute.

Table 3 shows how to adjust dose based on creatinine clearance.

Table 3: Dosage Adjustment in Adult Patients with Renal Impairment (Creatinine Clearance less

than 50 mL/minute)

Creatinine

Clearance greater

than or equal to 50

mL/minute

Creatinine

Clearance 20

to 49

mL/minute

Creatinine Clearance 10 to

19 mL/minute

Hemodialysis or

Chronic Ambulatory

Peritoneal Dialysis

(CAPD)

750 mg every 24

hours

750 mg every

48 hours

750 mg initial dose, then 500

mg every 48 hours

750 mg initial dose,

then 500 mg every 48

hours

500 mg every 24

hours

500 mg initial

dose, then

250 mg every

24 hours

500 mg initial dose, then

250 mg every 48 hours

500 mg initial dose,

then

250 mg every 48 hours

250 mg every 24

hours

No dosage

adjustment

required

250 mg every 48 hours. If

treating uncomplicated UTI,

then no dosage adjustment is

required

No information on

dosing adjustment is

available

2.4 Drug Interaction With Chelation Agents: Antacids, Sucralfate, Metal Cations,

Multivitamins

Levofloxacin tablets should be administered at least two hours before or two hours after antacids

containing magnesium, aluminum, as well as sucralfate, metal cations such as iron, and multivitamin

preparations with zinc or didanosine chewable/buffered tablets or the pediatric powder for oral

solution [see Drug Interactions (7.1) and Patient Counseling Information (17)].

2.5 Important Administration Instructions

Levofloxacin tablets can be administered without regard to food.

If patients miss a dose, they should take it as soon as possible anytime up to 8 hours prior to their next

scheduled dose. If less than 8 hours remain before the next dose, wait until their next scheduled dose.

2.6 Hydration for Patients Receiving Levofloxacin Tablets

Adequate hydration of patients receiving levofloxacin should be maintained to prevent the formation of

highly concentrated urine. Crystalluria and cylindruria have been reported with quinolones [ see

Adverse Reactions (6.1) and Patient Counseling Information (17)]

3 DOSAGE FORMS AND STRENGTHS

Levofloxacin tablets USP, 250 mg are white colored, modified capsule shaped, biconvex, film coated

tablets debossed with ‘RDY’ on one side and ‘279’ on other side.

Levofloxacin tablets USP, 500 mg are orange colored, modified capsule shaped, biconvex, film coated

tablets debossed with ‘RDY’ on one side and ‘280’ on other side.

Levofloxacin tablets USP, 750 mg are yellow colored, modified capsule shaped, biconvex, film coated

tablets debossed with ‘RDY’ on one side and ‘281’ on other side.

4 CONTRAINDICATIONS

Levofloxacin tablets are contraindicated in persons with known hypersensitivity to levofloxacin, or

other quinolone antibacterials [seeWarningsandPrecautions (5.3)].

5 WARNINGS AND PRECAUTIONS

5.1 Disabling and Potentially Irreversible Serious Adverse Reactions Including Tendinitis and

Tendon Rupture, Peripheral Neuropathy, and Central Nervous System Effects

Fluoroquinolones, including levofloxacin, 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

levofloxacin. 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 levofloxacin immediately at the first signs or symptoms of any serious adverse reaction. In

addition, avoid the use of fluoroquinolones, including levofloxacin, in patients who have experienced

any of these serious adverse reactions associated with fluoroquinolones.

5.2 Tendinitis and Tendon Rupture

Fluoroquinolones, including levofloxacin, 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 levofloxacin 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 levofloxacin 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 levofloxacin in patients who have a history of tendon disorders or tendon

rupture [see Adverse Reactions (6.3) and Patient Counseling Information (17)].

5.3 Peripheral Neuropathy

Fluoroquinolones, including levofloxacin, 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 levofloxacin. Symptoms may occur soon after initiation of

levofloxacinand may be irreversible in some patients [see Warnings and Precautions (5.1) and Adverse

Reactions (6.1, 6.2)].

Discontinue levofloxacin 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

levofloxacin, 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 levofloxacin, 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 levofloxacin, discontinue levofloxacin and institute appropriate measures.

Central Nervous System Adverse Reactions

Fluoroquinolones, including levofloxacin, have been associated with an increased risk of seizures

(convulsions), increased intracranial pressure (including pseudotumor cerebri), tremors, and

lightheadedness. As with other fluoroquinolones, levofloxacin 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 levofloxacin, discontinue

levofloxacin, and institute appropriate measures [see Adverse Reactions (6); Drug Interactions (7.4, 7.5)

and Patient Counseling Information (17)].

5.5 Exacerbation of Myasthenia Gravis

Fluoroquinolones, including levofloxacin, 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 levofloxacin in patients with a known history of myasthenia

gravis [see Adverse Reactions (6.3) and Patient Counseling Information (17)].

5.6 Other 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 levofloxacin. 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 levofloxacin 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)].

5.7 Hypersensitivity Reactions

Serious and occasionally fatal hypersensitivity and/or anaphylactic reactions have been reported in

patients receiving therapy with fluoroquinolones, including levofloxacin. 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. Levofloxacin

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)].

5.8 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

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 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 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

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)].

6.1 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 levofloxacin in 7,537 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

Psychiatric Disorders

insomnia [see Warnings and

Precautions (5.4)]

Nervous System Disorders

headache

dizziness [see Warnings and

Precautions (5.4)]

Respiratory, Thoracic andMediastinal

Dis orders

dyspnea [see Warnings and

Precautions (5.7)].

Gastrointestinal Disorders

nausea

diarrhea

constipation

abdominal pain

vomiting

dyspepsia

Skin and SubcutaneousTissue

Dis orders

rash [see Warnings and Precautions

(5.7)]

pruritus

Reproductive System andBreast

Dis orders

Vaginitis

General Disorders andAdministration

SiteConditions

edema

injection site reaction

chest pain

* N = 7274

N=3758 (women)

# pool of studies included IV and oral

administration

Table 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

Sys temDis orders

anemia

thrombocytopenia

granulocytopenia

[see Warnings and Precautions (5.6)]

Immune System Disorders

allergic reaction [see Warnings and Precautions

(5.6, 5.7)]

Metabolism and

NutritionDis orders

hyperglycemia

hypoglycemia

[see Warnings and Precautions (5.13)]

hyperkalemia

Psychiatric Disorders

anxiety

agitation

confusion

depression

hallucination

nightmare

[see Warnings and Precautions (5.4)]

sleep disorder

anorexia

abnormal dreaming

Nervous System Disorders

tremor

convulsions

[see Warnings and Precautions (5.4)]

paresthesia [see Warnings and Precautions (5.3)]

vertigo

hypertonia

hyperkinesias

abnormal gait

somnolence

syncope

Respiratory, Thoracic

andMediastinal Disorders

epistaxis

Cardiac Disorders

cardiac arrest

palpitation

ventricular tachycardia

ventricular arrhythmia

Vascular Disorders

phlebitis

Gastrointestinal Disorders

gastritis

stomatitis

pancreatitis

esophagitis

gastroenteritis

glossitis

pseudomembranous/ C. difficile colitis [see

Warnings and Precautions (5.10)]

Hepatobiliary Disorders

abnormal hepatic function

increased hepatic enzymes

increased alkaline phosphatase

Skin and Subcutaneous

Tis s ueDis orders

urticaria [see Warnings and Precautions (5.7)]

Musculoskeletal and

ConnectiveTissue Disorders

arthralgia

tendinitis

[see Warnings and Precautions (5.2)]

myalgia

skeletal pain

Renal and Urinary Disorders

abnormal renal function

acute 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.

6.2 Postmarketing Experience

Table 6 lists adverse reactions that have been identified during post-approval use of levofloxacin.

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

Dis orders

pancytopenia

aplastic anemia

leukopenia

hemolytic 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

psychosis

paranoia

isolated 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)]

anosmia

ageusia

parosmia

dysgeusia

peripheral neuropathy (may be irreversible)

[see Warnings and Precautions (5.3)]

isolated reports of encephalopathy

abnormal electroencephalogram (EEG)

dysphonia

pseudotumor cerebri

[see Warnings and Precautions (5.4)]

Eye Disorders

uveitis

vision disturbance, including diplopia

visual acuity reduced

vision blurred

scotoma

Ear and Labyrinth Disorders

hypoacusis

tinnitus

Cardiac Disorders

isolated reports of torsade de pointes

electrocardiogram QT prolonged

[see Warnings and Precautions (5.11)]

tachycardia

Vascular Disorders

vasodilatation

Respiratory, Thoracic

andMediastinal Disorders

isolated reports of allergic pneumonitis

[see Warnings and Precautions (5.6)]

Hepatobiliary Disorders

hepatic failure (including fatal cases)

hepatitis

jaundice

[see Warnings and Precautions (5.6), (5.8)]

Skin and Subcutaneous

Tis s ueDis orders

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

ConnectiveTissue Disorders

tendon rupture [see Warnings and Precautions (5.2)]

muscle injury, including rupture

rhabdomyolysis

Renal and Urinary Disorders

interstitial nephritis [see Warnings and Precautions (5.6)]

General Disorders

andAdministration Site Conditions

multi-organ failure

pyrexia

Inves tigations

prothrombin time prolonged

international normalized ratio prolonged

muscle enzymes increased

7 DRUG INTERACTIONS

7.1 Chelation Agents: Antacids, Sucralfate, Metal Cations, Multivitamins

While the chelation by divalent cations is less marked than with other fluoroquinolones, concurrent

administration of levofloxacin 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 multivitamins 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 levofloxacin

administration.

7.2 Warfarin

No significant effect of levofloxacin 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 levofloxacin

enhances the effects of warfarin. Elevations of the prothrombin time in the setting of concurrent

warfarin and levofloxacin use have been associated with episodes of bleeding. Prothrombin time,

International Normalized Ratio (INR), or other suitable anticoagulation tests should be closely

monitored if levofloxacin is administered concomitantly with warfarin. Patients should also be

monitored for evidence of bleeding [see Adverse Reactions (6.3) and Patient Counseling

Information (17)].

7.3 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 [see Warnings and

Precautions (5.13), Adverse Reactions (6.2) and Patient Counseling Information (17)].

7.4 Non-Steroidal Anti-Inflammatory Drugs

The concomitant administration of a non-steroidal anti-inflammatory drug with a fluoroquinolone,

including levofloxacin, may increase the risk of CNS stimulation and convulsive seizures [see Warnings

and Precautions (5.4)]

7.5 Theophylline

No significant effect of levofloxacin 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 levofloxacin is co-administered.

Adverse reactions, including seizures, may occur with or without an elevation in serum theophylline

levels [see Warnings and Precautions (5.4)]

7.6 Cyclosporine

No significant effect of levofloxacin 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 Cmax and k were slightly lower while

Tmax and t

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 levofloxacin or cyclosporine when

administered concomitantly.

7.7 Digoxin

No significant effect of levofloxacin 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 levofloxacin or digoxin is required when administered concomitantly.

7.8 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

of levofloxacin were higher while CL/F

and CL were lower during concomitant treatment of levofloxacin with probenecid or cimetidine

compared to levofloxacin alone. However, these changes do not warrant dosage adjustment for

levofloxacinwhen probenecid or cimetidine is co-administered.

7.9 Interactions with Laboratory or Diagnostic Testing

Some fluoroquinolones, including levofloxacin, 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

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 to 4% and 15 to 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 levofloxacin on milk production

or the breastfed infant. Because of the potential risks of serious adverse reactions, in breastfed infants,

a lactating woman may consider pumping and discarding breast milk during treatment with levofloxacin

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 levofloxacin 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)].

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 levofloxacin 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 levofloxacin tablets 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 levofloxacin tablet dosage in pediatric patients with inhalational anthrax or

plague, see Dosage and Administration (2.2). Levofloxacin 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, 1,534 children (6 months to 16 years of age) were treated with oral and intravenous

levofloxacin. Pediatric patients 6 months to 5 years of age received levofloxacin10 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. Levofloxacin 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 (1,340 levofloxacin-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

levofloxacin had a significantly higher incidence of musculoskeletal disorders when compared to the

non-fluoroquinolone-treated children as illustrated in Table 7. Levofloxacin 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

Levofloxacin

N = 1340

Non-Fluoroquinolone

N = 893

p-value

60 days

28 (2.1%)

8 (0.9%)

p = 0.038

1 year

46 (3.4%)

16 (1.8%)

p = 0.025

Non-Fluoroquinolone: ceftriaxone, amoxicillin/ clavulanate, clarithromycin

2-sided Fisher’s Exact Test

There were 1199 levofloxacin-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 completedthe 1-year evaluation visit.

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%) levofloxacin-treated pediatric patients

and most were treated with analgesics. The median time to resolution was 7 days for levofloxacin-

treated pediatric patients and 9 for non-fluoroquinolone-treated children (approximately 80% resolved

within 2 months in both groups). No pediatric patients 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 levofloxacin-treated and non-fluoroquinolone-treated pediatric patients.

In addition to the adverse reactions reported in pediatric patients in clinical trials, adverse reactions in

adults during clinical trials or post-marketing experience [seeAdverse 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 levofloxacin. 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 levofloxacin to elderly patients especially those on corticosteroids.

Patients should be informed of this potential side effect and advised to discontinue levofloxacin 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 levofloxacin-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 levofloxacin. 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 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 levofloxacin 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 [seeClinical

Pharmacology (12.3)].

8.6 Renal 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 levofloxacin are not required following hemodialysis or CAPD [seeDosage and

Administration (2.3)].

8.7 Hepatic Impairment

Pharmacokinetic studies in 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.

10 OVERDOSAGE

In the event of an acute overdosage, the stomach should be emptied. The patient should be observed and

appropriate hydration maintained. Levofloxacin is not efficiently removed by hemodialysis or peritoneal

dialysis.

Levofloxacin exhibits a low potential for acute toxicity. Mice, rats, dogs and monkeys exhibited the

following clinical signs after receiving a single high dose of levofloxacin: ataxia, ptosis, decreased

locomotor activity, dyspnea, prostration, tremors, and convulsions. Doses in excess of 1500 mg/kg

orally (approximately 10 or 19 times MRHD in mice and rats, respectively) and 250 mg/kg IV produced

significant mortality (estimated to be greater than or equal to 50%) in rodents.

11 DESCRIPTION

Levofloxacin tablets are synthetic antibacterial agent for oral administration. Chemically, levofloxacin,

a chiral fluorinated carboxyquinolone, is the pure (-)-(S)-enantiomer of the racemic drug substance

ofloxacin. The chemical name is (-)-(S)-9fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-

oxo-7H-pyrido[1,2,3-de]-1,4benzoxazine-6-carboxylic acid hemihydrate.

Figure 1: The Chemical Structure of Levofloxacin

The molecular formula is C

H FN O ½ H O and the molecular weight is 370.38. Levofloxacin

USP is a light yellowish-white to yellow-white crystal or crystalline powder. The molecule exists as a

zwitterion at the pH conditions in the small intestine.

The data demonstrate that from pH 0.6 to 5.8, the solubility of levofloxacin is essentially constant

(approximately 100 mg/mL). Levofloxacin is considered soluble to freely soluble in this pH range, as

defined by USP nomenclature. Above pH 5.8, the solubility increases rapidly to its maximum at pH 6.7

(272 mg/mL) and is considered freely soluble in this range. Above pH 6.7, the solubility decreases and

reaches a minimum value (about 50 mg/mL) at a pH of approximately 6.9.

Levofloxacin has the potential to form stable coordination compounds with many metal ions. This in

vitro chelation potential has the following formation order: Al

>Cu

>Zn

>Mg

>Ca

Levofloxacin tablets USP are available as film-coated tablets and contain the following inactive

ingredients:

250 mg (as expressed in the anhydrous form): colloidal silicon dioxide, corn starch, crospovidone,

hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol and titanium

dioxide.

500 mg (as expressed in the anhydrous form): colloidal silicon dioxide, corn starch, crospovidone,

FD&C yellow no. 5 aluminum lake, FD&C yellow no. 6 aluminum lake, hypromellose, magnesium

stearate, microcrystalline cellulose, polyethylene glycol and titanium dioxide.

750 mg (as expressed in the anhydrous form): colloidal silicon dioxide, corn starch, crospovidone,

hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, synthetic

yellow iron oxide and titanium dioxide.

Levofloxacin tablets meets USP Dissolution Test 2.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Levofloxacin is a member of the fluoroquinolone class of antibacterial agents [see Microbiology

(12.4)].

12.3 Pharmacokinetics

The mean ±SD pharmacokinetic parameters of levofloxacin determined under single and steady-state

conditions following administration of the oral tablets, are summarized in Table 8.

Table 8: Mean ±SD Levofloxacin PK Parameters

Cmax

Tmax AUC

CL/F (mL/min) Vd/F (L) t

CL

1/2

R

Regimen

(mcg/mL)

(h)

(mcgh/mL)

(h) (mL/min)

Single dose

250 mg oral

tablet

2.8 ± 0.4

1.6 ± 1 27.2 ± 3.9

156 ± 20

142 ± 21

500 mg oral

tablet

5.1 ± 0.8

1.3 ±

47.9 ± 6.8

178 ± 28

103 ± 30

750 mg oral

tablet

9.3 ± 1.6

1.6 ±

101 ± 20

129 ± 24

83 ± 17

Multiple dose

500 mg every

24h oral tablet

5.7 ± 1.4

1.1 ±

47.5 ± 6.7

175 ± 25

102 ± 22

116 ± 31

750 mg every 24h

oral tablet

8.6 ± 1.9

1.4 ±

90.7 ± 17.6

143 ± 29

100 ± 16

116 ± 28

500 mg oral tablet single dose,

effects of gender and age:

Male

5.5 ± 1.1

1.2 ±

54.4 ± 18.9

166 ± 44

89 ± 13

126 ± 38

Female

7.0 ± 1.6

1.7 ±

67.7 ± 24.2

136 ± 44

62 ± 16

106 ± 40

Young

5.5 ± 1

1.5 ±

47.5 ± 9.8

182 ± 35

83 ± 18

140 ± 33

Elderly

7.0 ± 1.6

1.4 ±

74.7 ± 23.3

121 ± 33

67 ± 19

± 2

91 ± 29

500 mg oral single dose tablet,

patients with renal impairment:

CLCR 50 to 80

mL/min

7.5 ± 1.8

1.5 ±

95.6 ± 11.8

88 ± 10

57 ± 8

CLCR 20 to 49

mL/min

7.1 ± 3.1

2.1 ±

182.1 ± 62.6 51 ± 19

26 ± 13

CLCR <20

mL/min

8.2 ± 2.6

1.1 ± 1 263.5 ± 72.5 33 ± 8

± 5

13 ± 3

Hemodialysis

5.7 ± 1

2.8 ±

CAPD

6.9 ± 2.3

1.4 ±

clearance /bioavailability

volume of distribution/bioavailability

healthy males 18 to 53 years of age

1/2

R

healthy male and female subjects 18 to 54 years of age

healthy males 22 to 75 years of age

healthy females 18 to 80 years of age

young healthy male and female subjects 18 to 36 years of age

healthy elderly male and female subjects 66 to 80 years of age

* Absolute bioavailability; F=0.99 ± 0.08 from a 500 mg tablet and F=0.99 ± 0.06 from a 750 mg tablet;

ND= not determine

Levofloxacin pharmacokinetics are linear and predictable after single and multiple oral or IV dosing

regimens. Steady-state conditions are reached within 48 hours following a 500 mg or 750 mg once-

daily dosage regimen. The mean ±SD peak and trough plasma concentrations attained following multiple

once-daily oral dosage regimens were approximately 5.7 ± 1.4 and 0.5 ± 0.2 mcg/mL after the 500 mg

doses, and 8.6 ±1.9 and 1.1 ± 0.4 mcg/mL after the 750 mg doses, respectively. The mean ±SD peak and

trough plasma concentrations attained following multiple once-daily IV regimens were approximately

6.4 ±0.8 and 0.6 ±0.2 mcg/mL after the 500 mg doses, and 12.1 ± 4.1 and 1.3 ± 0.71 mcg/mL after the

750 mg doses, respectively.

Absorption

Levofloxacin is rapidly and essentially completely absorbed after oral administration. Peak plasma

concentrations are usually attained one to two hours after oral dosing. The absolute bioavailability of

levofloxacin from a 500 mg tablet and a 750 mg tablet of levofloxacin are both approximately 99%,

demonstrating complete oral absorption of levofloxacin. Following a single intravenous dose of

levofloxacin to healthy volunteers, the mean ±SD peak plasma concentration attained was 6.2 ±1 mcg/mL

after a 500 mg dose infused over 60 minutes and 11.5 ±4 mcg/mL after a 750 mg dose infused over 90

minutes. Oral administration of a 500 mg dose of levofloxacinwith food prolongs the time to peak

concentration by approximately 1 hour and decreases the peak concentration by approximately 14%

following tablet and approximately 25% following oral solution administration. Therefore,

levofloxacintablets can be administered without regard to food.

The plasma concentration profile of levofloxacin after IV administration is similar and comparable in

extent of exposure (AUC) to that observed for levofloxacin tablets when equal doses (mg/mg) are

administered. Therefore, the oral and IV routes of administration can be considered interchangeable.

Distribution

The mean volume of distribution of levofloxacin generally ranges from 74 to 112 L after single and

multiple 500 mg or 750 mg doses, indicating widespread distribution into body tissues. Levofloxacin

reaches its peak levels in skin tissues and in blister fluid of healthy subjects at approximately 3 hours

after dosing. The skin tissue biopsy to plasma AUC ratio is approximately 2 and the blister fluid to

plasma AUC ratio is approximately 1 following multiple once-daily oral administration of 750 mg and

500 mg doses of levofloxacin, respectively, to healthy subjects. Levofloxacin also penetrates well into

lung tissues. Lung tissue concentrations were generally 2- to 5- fold higher than plasma concentrations

and ranged from approximately 2.4 to 11.3 mcg/g over a 24-hour period after a single 500 mg oral

dose.

In vitro, over a clinically relevant range (1 to 10 mcg/mL) of serum/plasma levofloxacin concentrations,

levofloxacin is approximately 24 to 38% bound to serum proteins across all species studied, as

determined by the equilibrium dialysis method. Levofloxacin is mainly bound to serum albumin in

humans. Levofloxacin binding to serum proteins is independent of the drug concentration.

Elimination

Metabolism

Levofloxacin is stereochemically stable in plasma and urine and does not invert metabolically to its

enantiomer, D-ofloxacin. Levofloxacin undergoes limited metabolism in humans and is primarily

excreted as unchanged drug in the urine. Following oral administration, approximately 87% of an

administered dose was recovered as unchanged drug in urine within 48 hours, whereas less than 4% of

the dose was recovered in feces in 72 hours. Less than 5% of an administered dose was recovered in

the urine as the desmethyl and N-oxide metabolites, the only metabolites identified in humans. These

metabolites have little relevant pharmacological activity.

Excretion

Levofloxacin is excreted largely as unchanged drug in the urine. The mean terminal plasma elimination

half-life of levofloxacin ranges from approximately 6 to 8 hours following single or multiple doses of

levofloxacin given orally or intravenously. The mean apparent total body clearance and renal clearance

range from approximately 144 to 226 mL/min and 96 to 142 mL/min, respectively. Renal clearance in

excess of the glomerular filtration rate suggests that tubular secretion of levofloxacin occurs in

addition to its glomerular filtration. Concomitant administration of either cimetidine or probenecid

results in approximately 24% and 35% reduction in the levofloxacin renal clearance, respectively,

indicating that secretion of levofloxacin occurs in the renal proximal tubule. No levofloxacin crystals

were found in any of the urine samples freshly collected from subjects receiving levofloxacin.

Specific Populations

Geriatric Patients

There are no significant differences in levofloxacin pharmacokinetics between young and elderly

subjects when the subjects’ differences in creatinine clearance are taken into consideration. Following a

500 mg oral dose of levofloxacin to healthy elderly subjects (66 to 80 years of age), the mean terminal

plasma elimination half-life of levofloxacin was about 7.6 hours, as compared to approximately 6 hours

in younger adults. The difference was attributable to the variation in renal function status of the subjects

and was not believed to be clinically significant. Drug absorption appears to be unaffected by age.

Levofloxacin dose adjustment based on age alone is not necessary [see Use in Specific Populations

(8.5)].

Pediatric Patients

The pharmacokinetics of levofloxacin following a single 7 mg/kg intravenous dose were investigated in

pediatric patients ranging in age from 6 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.

Subsequent pharmacokinetic analyses predicted that a dosage regimen of 8 mg/kg every 12 hours (not to

exceed 250 mg per dose) for pediatric patients 6 months to 17 years of age would achieve comparable

steady state plasma exposures (AUC

and C

) to those observed in adult patients administered 500

mg of levofloxacin once every 24 hours. Levofloxacin 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)].

Male and Female Subjects

There are no significant differences in levofloxacin pharmacokinetics between male and female

subjects when subjects’ differences in creatinine clearance are taken into consideration. Following a

500 mg oral dose of levofloxacin to healthy male subjects, the mean terminal plasma elimination half-

life of levofloxacin was about 7.5 hours, as compared to approximately 6.1 hours in female subjects.

This difference was attributable to the variation in renal function status of the male and female subjects

and was not believed to be clinically significant. Drug absorption appears to be unaffected by the

gender of the subjects. Dose adjustment based on gender alone is not necessary.

Racial or Ethnic Groups

The effect of race on levofloxacin pharmacokinetics was examined through a covariate analysis

0-24

performed on data from 72 subjects: 48 white and 24 non-white. The apparent total body clearance and

apparent volume of distribution were not affected by the race of the subjects.

Patients with Renal Impairment

Clearance of levofloxacin is substantially reduced and plasma elimination half-life is substantially

prolonged in adult patients with impaired renal function (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 levofloxacin are not required following hemodialysis or CAPD [see

Dosage and Administration (2.3) and Use in Specific Populations (8.6)].

Patients with Hepatic Impairment

Pharmacokinetic studies in hepatically impaired patients 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 [see Use in Specific Populations (8.7)].

Patients with Bacterial Infection

The pharmacokinetics of levofloxacin in patients with serious community-acquired bacterial infections

are comparable to those observed in healthy subjects.

Drug Interaction Studies

The potential for pharmacokinetic drug interactions between levofloxacin and antacids, warfarin,

theophylline, cyclosporine, digoxin, probenecid, and cimetidine has been evaluated [seeDrug

Interactions (7)].

12.4 Microbiology

Mechanism of Action

Levofloxacin is the L-isomer of the racemate, ofloxacin, a quinolone antimicrobial agent. The

antibacterial activity of ofloxacin resides primarily in the L-isomer. The mechanism of action of

levofloxacin and other fluoroquinolone antimicrobials involves inhibition of bacterial topoisomerase

IV and DNA gyrase (both of which are type II topoisomerases), enzymes required for DNA replication,

transcription, repair and recombination.

Res is tance

Fluoroquinolone resistance can arise through mutations in defined regions of DNA gyrase or

topoisomerase IV, termed the Quinolone-Resistance Determining Regions (QRDRs), or through altered

efflux.

Fluoroquinolones, including levofloxacin, differ in chemical structure and mode of action from

aminoglycosides, macrolides and β-lactam antibiotics, including penicillins. Fluoroquinolones may,

therefore, be active against bacteria resistant to these antimicrobials.

Resistance to levofloxacin due to spontaneous mutation in vitro is a rare occurrence (range: 10

to 10

). Cross-resistance has been observed between levofloxacin and some other fluoroquinolones, some

microorganisms resistant to other fluoroquinolones may be susceptible to levofloxacin.

Antimicrobial Activity

Levofloxacin has in vitro activity against Gram-negative and Gram-positive bacteria.

Levofloxacin has been shown to be active against most isolates of the following bacteria both in vitro

and in clinical infections as described in Indications and Usage (1):

Aerobic bacteria

Gram-Positive Bacteria

Enterococcus faecalis

Staphylococcus aureus (methicillin-susceptible isolates)

Staphylococcus epidermidis (methicillin-susceptible isolates)

Staphylococcus saprophyticus

Streptococcus pneumoniae (including multi-drug resistant isolates [MDRSP])

Streptococcus pyogenes

MDRSP (Multi-drug resistant Streptococcus pneumoniae) isolates are isolates resistant to two or more

of the following antibiotics: penicillin (MIC ≥2 mcg/mL), 2nd generation cephalosporins, e.g.,

cefuroxime; macrolides, tetracyclines and trimethoprim/sulfamethoxazole.

Gram-Negative Bacteria

Enterobacter cloacae

Escherichia coli

Haemophilus influenzae

Haemophilus parainfluenzae

Klebsiella pneumoniae

Legionella pneumophila

Moraxella catarrhalis

Proteus mirabilis

Pseudomonas aeruginosa

Serratia marcescens

Other microorganisms

Chlamydophila pneumoniae

Mycoplasma pneumoniae

The following in vitro data are available, but their clinical significance is unknown: At least 90 percent

of the following bacteria exhibit an in vitro minimum inhibitory concentrations (MIC) less than or equal

to the susceptible breakpoint for levofloxacin against isolates of similar genus or organism group.

However, efficacy of levofloxacin in treating clinical infections caused by these bacteria has not been

established in adequate and well-controlled clinical trials.

Aerobic bacteria

Gram-Positive Bacteria

Staphylococcus haemolyticus

β-hemolytic Streptococcus (Group C/F)

β-hemolytic Streptococcus (Group G)

Streptococcus agalactiae

Streptococcus milleri

Viridans group streptococci

Bacillus anthracis

Gram-Negative Bacteria

Acinetobacter baumannii

Acinetobacter lwoffii

Bordetella pertussis

Citrobacter koseri

Citrobacter freundii

Enterobacter aerogenes

Enterobacter sakazakii

Klebsiella oxytoca

Morganella morganii

Pantoea agglomerans

Proteus vulgaris

Providencia rettgeri

Providencia stuartii

Pseudomonas fluorescens

Yersinia pestis

Anaerobic bacteria

Gram-Positive Bacteria

Clostridium perfringens

Susceptibility Tests

For specific information regarding susceptibility test interpretive criteria and associated test methods

and quality control standards recognized by FDA for this drug, please see: http:/www.fda.gov/STIC.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

In a lifetime bioassay in rats, levofloxacin exhibited no carcinogenic potential following daily dietary

administration for 2 years; the highest dose (100 mg/kg/day) was 1.4 times the Maximum Recommended

Human Dose (MRHD) (750 mg) after normalization for total body surface area. Levofloxacin did not

shorten the time to tumor development of UV-induced skin tumors in hairless albino (Skh-1) mice at any

levofloxacin dose level and was therefore not photo-carcinogenic under conditions of this study.

Dermal levofloxacin concentrations in the hairless mice ranged from 25 to 42 mcg/g at the highest

levofloxacin dose level (300 mg/kg/day) used in the photo-carcinogenicity study. By comparison,

dermal levofloxacin concentrations in human subjects receiving 750 mg of levofloxacin averaged

approximately 11.8 mcg/g at C

Levofloxacin was not mutagenic in the following assays: Ames bacterial mutation assay (S. typhimurium

and E. coli), CHO/HGPRT forward mutation assay, mouse micronucleus test, mouse dominant lethal test,

rat unscheduled DNA synthesis assay, and the mouse sister chromatid exchange assay. It was positive in

the in vitro chromosomal aberration (CHL cell line) and sister chromatid exchange (CHL/IU cell line)

assays.

Levofloxacin caused no impairment of fertility or reproductive performance in rats at oral doses as

high as 360 mg/kg/day, corresponding to 4.2 times the MRHD and intravenous doses as high as 100

mg/kg/day, corresponding to 1.2 times the MRHD after normalization for total body surface area.

13.2 Animal Pharmacology and/or Toxicology

max.

Levofloxacin and other quinolones have been shown to cause arthropathy in immature animals of most

species tested [see Warnings and Precautions (5.12)]. In immature dogs (4 to 5 months old), oral doses of

10 mg/kg/day for 7 days and intravenous doses of 4 mg/kg/day for 14 days of levofloxacin resulted in

arthropathic lesions. Administration at oral doses of 300 mg/kg/day for 7 days and intravenous doses of

60 mg/kg/day for 4 weeks produced arthropathy in juvenile rats. Three-month old beagle dogs dosed

orally with levofloxacin at 40 mg/kg/day exhibited clinically severe arthrotoxicity resulting in the

termination of dosing at Day 8 of a 14 day dosing routine(dosing was terminated in the low and mid-

dose groups on Day 9 due to similar findings at the mid-dose). Slight musculoskeletal clinical effects,

in the absence of gross pathological or histopathological effects, resulted from the lowest dose level

of 2.5 mg/kg/day (approximately 0.2-fold the pediatric dose based upon AUC comparisons). Synovitis

and articular cartilage lesions were observed at the 10 and 40 mg/kg dose levels (approximately 0.7-

fold and 2.4-fold the pediatric dose, respectively, based on AUC comparisons). Articular cartilage

gross pathology and histopathology persisted to the end of the 18-week recovery period for those

dogs from the 10 and 40 mg/kg/day dose levels. The low and mid-dose groups in that study were also

evaluated by electron microscopy, revealing compound-related ultrastructural effects in articular

cartilage chondrocytes at the end of treatment and at the end of recovery in both of those doses.

When tested in a mouse ear swelling bioassay, levofloxacin exhibited phototoxicity similar in

magnitude to ofloxacin, but less phototoxicity than other quinolones. While crystalluria has been

observed in some intravenous rat studies, urinary crystals are not formed in the bladder, being present

only after micturition and are not associated with nephrotoxicity.

In mice, the CNS stimulatory effect of quinolones is enhanced by concomitant administration of non-

steroidal anti-inflammatory drugs.

In dogs, levofloxacin administered at 6 mg/kg or higher by rapid intravenous injection produced

hypotensive effects. These effects were considered to be related to histamine release.

In vitro and in vivo studies in animals indicate that levofloxacin is neither an enzyme inducer nor inhibitor

in the human therapeutic plasma concentration range; therefore, no drug metabolizing enzyme-related

interactions with other drugs or agents are anticipated.

14 CLINICAL STUDIES

14.1 Nosocomial Pneumonia

Adult patients with clinically and radiologically documented nosocomial pneumonia were enrolled in a

multicenter, randomized, open-label study comparing intravenous levofloxacin (750 mg once daily)

followed by oral levofloxacin (750 mg once daily) for a total of 7 to 15 days to intravenous

imipenem/cilastatin (500 to 1000 mg every 6 to 8 hours daily) followed by oral ciprofloxacin (750 mg

every 12 hours daily) for a total of 7 to 15 days. Levofloxacin-treated patients received an average of 7

days of intravenous therapy (range: 1 to 16 days); comparator-treated patients received an average of 8

days of intravenous therapy (range: 1 to 19 days).

Overall, in the clinically and microbiologically evaluable population, adjunctive therapy was

empirically initiated at study entry in 56 of 93 (60.2%) patients in the levofloxacin arm and 53 of 94

(56.4%) patients in the comparator arm. The average duration of adjunctive therapy was 7 days in the

levofloxacin arm and 7 days in the comparator. In clinically and microbiologically evaluable patients

with documented Pseudomonas aeruginosa infection, 15 of 17 (88.2%) received ceftazidime (N=11) or

piperacillin/tazobactam (N=4) in the levofloxacin arm and 16 of 17 (94.1%) received an aminoglycoside

in the comparator arm. Overall, in clinically and microbiologically evaluable patients, vancomycin was

added to the treatment regimen of 37 of 93 (39.8%) patients in the levofloxacin arm and 28 of 94

(29.8%) patients in the comparator arm for suspected methicillin-resistant S. aureus infection.

Clinical success rates in clinically and microbiologically evaluable patients at the post-therapy visit

(primary study endpoint assessed on day 3 to 15 after completing therapy) were 58.1% for levofloxacin

and 60.6% for comparator. The 95% CI for the difference of response rates (levofloxacin minus

comparator) was [-17.2, 12]. The microbiological eradication rates at the posttherapy visit were 66.7%

for levofloxacin and 60.6% for comparator. The 95% CI for the difference of eradication rates

(levofloxacin minus comparator) was [-8.3, 20.3]. Clinical success and microbiological eradication

rates by pathogen are detailed in Table 9

Table 9: Clinical Success Rates and Bacteriological Eradication Rates (Nosocomial Pneumonia)

Pathogen

N Levofloxacin No. (%) of

Patients Microbiologic/ Clinical

Outcomes

N Imipenem/Cilastatin No. (%) of

Patients Microbiologic/ Clinical

Outcomes

MSSA

21 14 (66.7)/13 (61.9)

19 13 (68.4)/15 (78.9)

P.

aeruginosa

17 10 (58.8)/11 (64.7)

17 5 (29.4)/7 (41.2)

S.

marcescens

11 9 (81.8)/7 (63.6)

2 (28.6)/3 (42.9)

E. coli

12 10 (83.3)/7 (58.3)

11 7 (63.6)/8 (72.7)

K.

pneumoniae

11 9 (81.8)/5 (45.5)

6 (85.7)/3 (42.9)

H. influenzae 16 13 (81.3)/10 (62.5)

15 14 (93.3)/11 (73.3)

S.

pneumoniae

3 (75.0)/3 (75.0)

5 (71.4)/4 (57.1)

Methicillin-susceptible S. aureus

See above text for use of combination therapy

The observed differences in rates for the clinical and microbiological outcomes may reflect other

factors that were not accounted for in the study

14.2 Community-Acquired Pneumonia: 7 to 14 day Treatment Regimen

Adult inpatients and outpatients with a diagnosis of community-acquired bacterial pneumonia were

evaluated in 2 pivotal clinical studies. In the first study, 590 patients were enrolled in a prospective,

multi-center, unblinded randomized trial comparing levofloxacin 500 mg once daily orally or

intravenously for 7 to 14 days to ceftriaxone 1 to 2 grams intravenously once or in equally divided

doses twice daily followed by cefuroxime axetil 500 mg orally twice daily for a total of 7 to 14 days.

Patients assigned to treatment with the control regimen were allowed to receive erythromycin (or

doxycycline if intolerant of erythromycin) if an infection due to atypical pathogens was suspected or

proven. Clinical and microbiologic evaluations were performed during treatment, 5 to 7 days

posttherapy, and 3 to 4 weeks posttherapy. Clinical success (cure plus improvement) with levofloxacin

at 5 to 7 days posttherapy, the primary efficacy variable in this study, was superior (95%) to the control

group (83%). The 95% CI for the difference of response rates (levofloxacin minus comparator) was [-

6, 19]. In the second study, 264 patients were enrolled in a prospective, multi-center, non-comparative

trial of 500 mg levofloxacin administered orally or intravenously once daily for 7 to 14 days. Clinical

success for clinically evaluable patients was 93%. For both studies, the clinical success rate in patients

with atypical pneumonia due to Chlamydophila pneumoniae, Mycoplasma pneumoniae, and Legionella

pneumophila were 96%, 96%, and 70%, respectively. Microbiologic eradication rates across both

studies are presented in Table 10.

Table 10: Bacteriological Eradication Rates Across 2 Community Acquired Pneumonia Clinical

Studies

*

Pathogen

No. Pathogens

Bacteriological Eradication Rate (%)

H. influenzae

S. pneumoniae

S. aureus

M. catarrhalis

H. parainfluenzae

K. pneumoniae

Community-Acquired Pneumonia Due to Multi-Drug Resistant Streptococcus pneumoniae

Levofloxacin was effective for the treatment of community-acquired pneumonia caused by multi-drug

resistant Streptococcus pneumoniae (MDRSP). MDRSP isolates are isolates resistant to two or more of

the following antibacterials: penicillin (MIC ≥2 mcg/mL), 2

generation cephalosporins (e.g.,

cefuroxime, macrolides, tetracyclines and trimethoprim/sulfamethoxazole). Of 40 microbiologically

evaluable patients with MDRSP isolates, 38 patients (95%) achieved clinical and bacteriologic success

at post-therapy. The clinical and bacterial success rates are shown in Table 11.

Table 11: Clinical and Bacterial Success Rates for Levofloxacin-Treated MDRSP in Community

Acquired Pneumonia Patients (Population Valid for Efficacy)

Screening Susceptibility

Clinical Success Bacteriological Success

n/N

%

n/N

%

Penicillin-res is tant

16/17

94.1

16/17

94.1

2nd generation Cephalosporin resistant

31/32

96.9

31/32

96.9

Macrolide-res is tant

28/29

96.6

28/29

96.6

Trimethoprim/ Sulfamethoxazole resistant

17/19

89.5

17/19

89.5

T etracycline-res is tant

12/12

12/12

* One patient had a respiratory isolate that was resistant to tetracycline, cefuroxime, macrolides and

TMP/SMX and intermediate to penicillin and a blood isolate that was intermediate to penicillin and

cefuroxime and resistant to the other classes. The patient is included in the database based on

respiratory isolate.

n=the number of microbiologically evaluable patients who were clinical successes; N=number of

microbiologically evaluable patients in the designated resistance group.

n=the number of MDRSP isolates eradicated or presumed eradicated in microbiologically evaluable

patients;

N=number of MDRSP isolates in a designated resistance group.

Not all isolates were resistant to all antimicrobial classes tested. Success and eradication rates are

summarized in Table 12.

Table 12: Clinical Success and Bacteriologic Eradication Rates for Resistant Streptococcus

pneumoniae (Community Acquired Pneumonia)

Type of Resistance

Clinical Success Bacteriologic Eradication

Resistant to 2 antibacterials 17/18 (94.4%)

17/18 (94.4%)

Resistant to 3 antibacterials 14/15 (93.3%)

14/15 (93.3%)

Resistant to 4 antibacterials7/7 (100%)

7/7 (100%)

Resistant to 5 antibacterials 0

Bacteremia with MDRSP

8/9 (89%)

8/9 (89%)

*

14.3 Community-Acquired Pneumonia: 5 Day Treatment Regimen

To evaluate the safety and efficacy of the higher dose and shorter course of levofloxacin, 528

outpatient and hospitalized adults with clinically and radiologically determined mild to severe

community-acquired pneumonia were evaluated in a double-blind, randomized, prospective, multicenter

study comparing levofloxacin 750 mg, IV or orally, every day for five days or levofloxacin 500 mg IV

or orally, every day for 10 days.

Clinical success rates (cure plus improvement) in the clinically evaluable population were 90.9% in the

levofloxacin 750 mg group and 91.1% in the levofloxacin 500 mg group. The 95% CI for the

difference of response rates (levofloxacin 750 minus levofloxacin 500) was [-5.9, 5.4]. In the clinically

evaluable population (31 to 38 days after enrollment) pneumonia was observed in 7 out of 151 patients in

the levofloxacin 750 mg group and 2 out of 147 patients in the levofloxacin 500 mg group. Given the

small numbers observed, the significance of this finding cannot be determined statistically. The

microbiological efficacy of the 5-day regimen was documented for infections listed in Table 13.

Table 13: Bacteriological Eradication Rates (Community-Acquired Pneumonia)

S. pneumoniae

19/20 (95%)

Haemophilus influenzae

12/12 (100%)

Haemophilus parainfluenzae

10/10 (100%)

Mycoplasma pneumoniae

26/27 (96%)

Chlamydophila pneumoniae

13/15 (87%)

14.4 Acute Bacterial Sinusitis: 5 day and 10 to 14 day Treatment Regimens

Levofloxacin is approved for the treatment of acute bacterial sinusitis (ABS) using either 750 mg by

mouth x 5 days or 500 mg by mouth once daily x 10 to 14 days. To evaluate the safety and efficacy of a

high dose short course of levofloxacin, 780 outpatient adults with clinically and radiologically

determined acute bacterial sinusitis were evaluated in a double-blind, randomized, prospective,

multicenter study comparing levofloxacin 750 mg by mouth once daily for five days to levofloxacin

500 mg by mouth once daily for 10 days.

Clinical success rates (defined as complete or partial resolution of the pre-treatment signs and

symptoms of ABS to such an extent that no further antibiotic treatment was deemed necessary) in the

microbiologically evaluable population were 91.4% (139/152) in the levofloxacin 750 mg group and

88.6% (132/149) in the levofloxacin 500 mg group at the test-of-cure (TOC) visit (95% CI [-4.2, 10]

for levofloxacin 750 mg minus levofloxacin 500 mg).

Rates of clinical success by pathogen in the microbiologically evaluable population who had

specimens obtained by antral tap at study entry showed comparable results for the five- and ten-day

regimens at the test-of-cure visit 22 days post treatment (see Table 14).

Table 14: Clinical Success Rate by Pathogen at the TOC in Microbiologically Evaluable Subjects

Who Underwent Antral Puncture (Acute Bacterial Sinusitis)

Pathogen

Levofloxacin 750 mg x 5 days Levofloxacin 500 mg x 10 days

Streptococcus pneumoniae*25/27 (92.6%)

26/27 (96.3%)

Haemophilus influenzae*

19/21 (90.5%)

25/27 (92.6%)

Moraxella catarrhalis*

10/11 (90.9%)

13/13 (100%)

Note: Forty percent of the subjects in this trial had specimens obtained by sinus endoscopy. The

efficacy data for subjects whose specimen was obtained endoscopically were comparable to those

presented in the above table

14.5 Complicated Skin and Skin Structure Infections

Three hundred ninety-nine patients were enrolled in an open-label, randomized, comparative study for

complicated skin and skin structure infections. The patients were randomized to receive either

levofloxacin 750 mg once daily (IV followed by oral), or an approved comparator for a median of 10 ±

4.7 days. As is expected in complicated skin and skin structure infections, surgical procedures were

performed in the levofloxacin and comparator groups. Surgery (incision and drainage or debridement)

was performed on 45% of the levofloxacin-treated patients and 44% of the comparator treated patients,

either shortly before or during antibiotic treatment and formed an integral part of therapy for this

indication.

Among those who could be evaluated clinically 2 to 5 days after completion of study drug, overall

success rates (improved or cured) were 116/138 (84.1%) for patients treated with levofloxacin and

106/132 (80.3%) for patients treated with the comparator.

Success rates varied with the type of diagnosis ranging from 68% in patients with infected ulcers to

90% in patients with infected wounds and abscesses. These rates were equivalent to those seen with

comparator drugs.

14.6 Chronic Bacterial Prostatitis

Adult patients with a clinical diagnosis of prostatitis and microbiological culture results from urine

sample collected after prostatic massage (VB3) or expressed prostatic secretion (EPS) specimens

obtained via the Meares-Stamey procedure were enrolled in a multicenter, randomized, double-blind

study comparing oral levofloxacin 500 mg, once daily for a total of 28 days to oral ciprofloxacin 500

mg, twice daily for a total of 28 days. The primary efficacy endpoint was microbiologic efficacy in

microbiologically evaluable patients. A total of 136 and 125 microbiologically evaluable patients were

enrolled in the levofloxacin and ciprofloxacin groups, respectively. The microbiologic eradication rate

by patient infection at 5 to 18 days after completion of therapy was 75% in the levofloxacin group and

76.8% in the ciprofloxacin group (95% CI [-12.58, 8.98] for levofloxacin minus ciprofloxacin). The

overall eradication rates for pathogens of interest are presented in Table 15.

Table 15: Bacteriological Eradication Rates (Chronic Bacterial Prostatitis)

Levofloxacin(N=136)

Ciprofloxacin (N=125)

Pathogen

N

Eradication

N

Eradication

E. coli

14 (93.3%)

9 (81.8%)

E. faecalis

39 (72.2%)

33 (75%)

S. epidermidis*

9 (81.8%)

11 (78.6%)

* Eradication rates shown are for patients who had a sole pathogen only; mixed cultures were excluded.

Eradication rates for S. epidermidis when found with other co-pathogens are consistent with rates seen

in pure isolates.

Clinical success (cure + improvement with no need for further antibiotic therapy) rates in

microbiologically evaluable population 5 to 18 days after completion of therapy were 75% for

levofloxacin-treated patients and 72.8% for ciprofloxacin-treated patients (95% CI [-8.87, 13.27] for

levofloxacin minus ciprofloxacin). Clinical long-term success (24 to 45 days after completion of

therapy) rates were 66.7% for the levofloxacin-treated patients and 76.9% for the ciprofloxacin-treated

patients (95% CI [-23.40, 2.89] for levofloxacin minus ciprofloxacin).

14.7 Complicated Urinary Tract Infections and Acute Pyelonephritis: 5 day Treatment Regimen

To evaluate the safety and efficacy of the higher dose and shorter course of levofloxacin, 1109

patients with cUTI and AP were enrolled in a randomized, double-blind, multicenter clinical trial

conducted in the US from November 2004 to April 2006 comparing levofloxacin 750 mg IV or orally

once daily for 5 days (546 patients) with ciprofloxacin 400 mg IV or 500 mg orally twice daily for 10

days (563 patients). Patients with AP complicated by underlying renal diseases or conditions such as

complete obstruction, surgery, transplantation, concurrent infection or congenital malformation were

excluded. Efficacy was measured by bacteriologic eradication of the baseline organism(s) at the post-

therapy visit in patients with a pathogen identified at baseline. The post-therapy (test-of-cure) visit

occurred 10 to 14 days after the last active dose of levofloxacin and 5 to 9 days after the last dose of

active ciprofloxacin.

The bacteriologic cure rates overall for levofloxacin and control at the test-of-cure (TOC) visit for the

group of all patients with a documented pathogen at baseline (modified intent to treat or mITT) and the

group of patients in the mITT population who closely followed the protocol (Microbiologically

Evaluable) are summarized in Table 16.

Table 16: Bacteriological Eradication at Test-of-Cure

Levofloxacin

750 mg orally orIV once

daily

for 5 days

Ciprofloxacin

400mg IV/500 mg orally twice

daily

for 10 days

Overall Difference

[95% CI]

Levofloxacin-

Ciprofloxacin

mITT Population

Overall (cUTI or

252/333

75.7

239/318

75.2

0.5 (-6.1, 7.1)

cUTI

168/230

73.0

157/213

73.7

84/103

81.6

82/105

78.1

Microbiologically Evaluable Population

Overall (cUTI or

228/265

86.0

215/241

89.2

-3.2 [-8.9, 2.5]

cUTI

154/185

83.2

144/165

87.3

74/80

92.5

71/76

93.4

The mITT population included patients who received study medication and who had a positive (≥10

CFU/mL) urine culture with no more than 2 uropathogens at baseline. Patients with missing response

were counted as failures in this analysis.

The Microbiologically Evaluable population included patients with a confirmed diagnosis of cUTI

or AP, a causative organism(s) at baseline present at ≥ 10

CFU/mL, a valid test-of-cure urine culture,

no pathogen isolated from blood resistant to study drug, no premature discontinuation or loss to follow-

up, and compliance with treatment (among other criteria).Microbiologic eradication rates in the

Microbiologically Evaluable population at TOC for individual pathogens recovered from patients

randomized to levofloxacin treatment are presented in Table 17.

Table 17: Bacteriological Eradication Rates for Individual Pathogens Recovered From Patients

Randomized to Levofloxacin 750 mg QD for 5 Days Treatment

Pathogen

Bacteriological Eradication Rate (n/N)

Escherichia coli*

155/172

Klebsiella pneumoniae

20/23

Klebsiella pneumoniae

20/23

Proteus mirabilis

12/12

* The predominant organism isolated from patients with AP was E. coli: 91% (63/69) eradication in AP

and 89% (92/103) in patients with cUTI.

14.8 Complicated Urinary Tract Infections and Acute Pyelonephritis: 10 day Treatment Regimen

To evaluate the safety and efficacy of the 250 mg dose, 10 day regimen of levofloxacin, 567 patients

with uncomplicated UTI, mild-to-moderate cUTI, and mild-to-moderate AP were enrolled in a

randomized, double-blind, multicenter clinical trial conducted in the US from June 1993 to January 1995

comparing levofloxacin 250 mg orally once daily for 10 days (285 patients) with ciprofloxacin 500 mg

orally twice daily for 10 days (282 patients). Patients with a resistant pathogen, recurrent UTI, women

over age 55 years, and with an indwelling catheter were initially excluded, prior to protocol amendment

which took place after 30% of enrollment. Microbiological efficacy was measured by bacteriologic

eradication of the baseline organism(s) at 1 to 12 days post-therapy in patients with a pathogen identified

at baseline.

The bacteriologic cure rates overall for levofloxacin and control at the test-of-cure (TOC) visit for the

group of all patients with a documented pathogen at baseline (modified intent to treat or mITT) and the

group of patients in the mITT population who closely followed the protocol (Microbiologically

Evaluable) are summarized in Table 18.

Table 18. Bacteriological Eradication Overall (cUTI or AP) at Test-Of-Cure*

Levofloxacin

250 mg once

daily

for 10 days

Ciprofloxacin

500 mg twice

daily

for 10 days

mITT Population

174/209

83.3

184/219

Microbiologically Evaluable

Population

164/177

92.7

159/171

1 to 9 days posttherapy for 30% of subjects enrolled prior to a protocol amendment; 5 to 12 days

posttherapy for 70% of subjects.

The mITT population included patients who had a pathogen isolated at baseline. Patients with

missingresponse were counted as failures in this analysis.

The Microbiologically Evaluable population included mITT patients who met protocol-specified

evaluability criteria.

14.9 Inhalational Anthrax (Post-Exposure)

The effectiveness of levofloxacin for this indication is based on plasma concentrations achieved in

humans, a surrogate endpoint reasonably likely to predict clinical benefit. Levofloxacin has not been

tested in humans for the post-exposure prevention of inhalation anthrax. The mean plasma concentrations

of levofloxacin associated with a statistically significant improvement in survival over placebo in the

rhesus monkey model of inhalational anthrax are reached or exceeded in adult and pediatric patients

receiving the recommended oral and intravenous dosage regimens [see Indications and Usage (1.13)

and Dosage and Administration (2.1, 2.2)].

Levofloxacin pharmacokinetics have been evaluated in adult and pediatric patients. The mean (± SD)

steady state peak plasma concentration in human adults receiving 500 mg orally or intravenously once

daily is 5.7 ± 1.4 and 6.4 ± 0.8 mcg/mL, respectively; and the corresponding total plasma exposure

(AUC0-24) is 47.5 ± 6.7 and 54.6 ± 11.1 mcg.h/mL, respectively. The predicted steady-state

pharmacokinetic parameters in pediatric patients ranging in age from 6 months to 17 years receiving 8

mg/kg orally every 12 hours (not to exceed 250 mg per dose) were calculated to be comparable to those

observed in adults receiving 500 mg orally once daily [see Clinical Pharmacology (12.3)].

Levofloxacin 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)].

In adults, the safety of levofloxacin for treatment durations of up to 28 days is well characterized.

However, information pertaining to extended use at 500 mg daily up to 60 days is limited. Prolonged

levofloxacin therapy in adults should only be used when the benefit outweighs the risk.

In pediatric patients, the safety of levofloxacin for treatment durations of more than 14 days has not been

studied. An increased incidence of musculoskeletal adverse events (arthralgia, arthritis, tendinopathy,

gait abnormality) compared to controls has been observed in clinical studies with treatment duration of

up to 14 days. Long-term safety data, including effects on cartilage, following the administration of

levofloxacin to pediatric patients is limited [seeWarnings and Precautions (5.12) and Use in Specific

Populations (8.4)].

A placebo-controlled animal study in rhesus monkeys exposed to an inhaled mean dose of 49 LD

(~2.7 X 10 ) spores (range 17 - 118 LD ) of B. anthracis (Ames strain) was conducted. The minimal

inhibitory concentration (MIC) of levofloxacin for the anthrax strain used in this study was 0.125

mcg/mL. In the animals studied, mean plasma concentrations of levofloxacin achieved at expected Tmax

(1 hour post-dose) following oral dosing to steady state ranged from 2.79 to 4.87 mcg/mL. Steady state

trough concentrations at 24 hours post-dose ranged from 0.107 to 0.164 mcg/mL. Mean (SD) steady

state AUC0-24 was 33.4 ± 3.2 mcg.h/mL (range 30.4 to 36 mcg.h/mL). Mortality due to anthrax for

animals that received a 30 day regimen of oral levofloxacin beginning 24 hrs post exposure was

significantly lower (1/10), compared to the placebo group (9/10) [P=0.0011, 2-sided Fisher’s Exact

Test]. The one levofloxacin treated animal that died of anthrax did so following the 30-day drug

administration period.

14.10 Plague

Efficacy studies of levofloxacin 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 mean plasma concentrations of levofloxacin associated with a statistically significant improvement

in survival over placebo in an African green monkey model of pneumonic plague are reached or

exceeded in adult and pediatric patients receiving the recommended oral and intravenous dosage

regimens [see Indications and Usage (1.14), Dosage and Administration (2.1), (2.2)].

Levofloxacin pharmacokinetics have been evaluated in adult and pediatric patients. The mean (± SD)

steady state peak plasma concentration in human adults receiving 500 mg orally or intravenously once

daily is 5.7 ± 1.4 and 6.4 ± 0.8 mcg/mL, respectively; and the corresponding total plasma exposure

(AUC

) is 47.5 ± 6.7 and 54.6 ± 11.1 mcg.h/mL, respectively. The predicted steady-state

pharmacokinetic parameters in pediatric patients ranging in age from 6 months to 17 years receiving 8

mg/kg orally every 12 hours (not to exceed 250 mg per dose) were calculated to be comparable to those

observed in adults receiving 500 mg orally once daily [see Clinical Pharmacology (12.3)].

Levofloxacin 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 placebo-controlled animal study in African green monkeys exposed to an inhaled mean dose of 65

LD (range 3 to 145 LD ) of Yersinia pestis (CO92 strain) was conducted. The minimal inhibitory

concentration (MIC) of levofloxacin for the Y. pestis strain used in this study was 0.03 mcg/mL. Mean

plasma concentrations of levofloxacin achieved at the end of a single 30-min infusion ranged from 2.84

0-24

to 3.50 mcg/mL in African green monkeys. Trough concentrations at 24 hours post-dose ranged from

<0.03 to 0.06 mcg/mL. Mean (SD) AUC

was 11.9 (3.1) mcg.h/mL (range 9.50 to 16.86 mcg.h/mL).

Animals were randomized to receive either a 10-day regimen of i.v. levofloxacin or placebo beginning

within 6 hrs of the onset of telemetered fever (≥ 39°C for more than 1 hour). Mortality in the

levofloxacin group was significantly lower (1/17) compared to the placebo group (7/7) [p<0.001,

Fisher’s Exact Test; exact 95% confidence interval (-99.9%, -55.5%) for the difference in mortality].

One levofloxacin-treated animal was euthanized on Day 9 post-exposure to Y. pestis due to a gastric

complication; it had a blood culture positive for Y. pestis on Day 3 and all subsequent daily blood

cultures from Day 4 through Day 7 were negative.

16 HOW SUPPLIED/STORAGE AND HANDLING

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NDC: 71335-1277-1 30 TABLET, FILM COATED in a BOTTLE

NDC: 71335-1277-2 10 TABLET, FILM COATED in a BOTTLE

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NDC: 71335-1277-4 14 TABLET, FILM COATED in a BOTTLE

NDC: 71335-1277-5 5 TABLET, FILM COATED in a BOTTLE

NDC: 71335-1277-6 20 TABLET, FILM COATED in a BOTTLE

NDC: 71335-1277-7 60 TABLET, FILM COATED in a BOTTLE

NDC: 71335-1277-8 3 TABLET, FILM COATED in a BOTTLE

NDC: 71335-1277-9 50 TABLET, FILM COATED in a BOTTLE

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Serious Adverse Reactions

Advise patients to stop taking levofloxacin if they experience an adverse reaction and to call their

healthcare provider for advice on completing the full course of treatment with another antibacterial

drug.

Inform patients of the following serious adverse reactions that have been associated with levofloxacin

or other fluoroquinolone use:

Disabling and Potentially Irreversible Serious Adverse Reactions That May Occur Together:

Inform patients that disabling and potentially irreversible serious adverse reactions, including tendinitis

and tendon rupture, peripheral neuropathies, and central nervous system effects, have been associated

with use of levofloxacin and may occur together in the same patient. Inform patients to stop taking

levofloxacin immediately if they experience an adverse reaction and to call their healthcare provider.

Tendinitis and Tendon Rupture: Instruct patients to contact their healthcare provider if they

experience pain, swelling, or inflammation of a tendon, or weakness or inability to use one of their

joints; rest and refrain from exercise; and discontinue levofloxacin treatment. Symptoms may be

irreversible. The risk of severe tendon disorder with fluoroquinolones is higher in older patients

usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or

lung transplants.

Peripheral Neuropathies: Inform patients that peripheral neuropathies have been associated with

levofloxacin use, symptoms may occur soon after initiation of therapy and may be irreversible. If

symptoms of peripheral neuropathy including pain, burning, tingling, numbness and/or weakness

0-24

develop, immediately discontinue levofloxacin and tell them to contact their physician.

Central Nervous System Effects (for example, convulsions, dizziness, lightheadedness, increased

intracranial pressure): Inform patients that convulsions have been reported in patients receiving

fluoroquinolones, including levofloxacin. Instruct patients to notify their physician before taking this

drug if they have a history of convulsions. Inform patients that they should know how they react to

levofloxacin before they operate an automobile or machinery or engage in other activities requiring

mental alertness and coordination. Instruct patients to notify their physician if persistent headache with

or without blurred vision occurs.

Exacerbation of Myasthenia Gravis: Instruct patients to inform their physician of any history of

myasthenia gravis. Instruct patients to notify their physician if they experience any symptoms of muscle

weakness, including respiratory difficulties.

Hypersensitivity Reactions: Inform patients that levofloxacin can cause hypersensitivity reactions,

even following a single dose, and to discontinue the drug at the first sign of a skin rash, hives or other

skin reactions, a rapid heartbeat, difficulty in swallowing or breathing,any swelling suggesting

angioedema (for example, swelling of the lips, tongue, face, tightness of the throat, hoarseness), or

other symptoms of an allergic reaction.

Hepatotoxicity: Inform patients that severe hepatotoxicity (including acute hepatitis and fatal events)

has been reported in patients taking levofloxacin. Instruct patients to inform their physician if they

experience any signs or symptoms of liver injury including: loss of appetite, nausea, vomiting, fever,

weakness, tiredness, right upper quadrant tenderness, itching, yellowing of the skin and eyes, light

colored bowel movements or dark colored urine.

Aortic aneurysm and dissection: Inform patients to seek emergency medical care if they experience

sudden chest, stomach, or back pain.

Diarrhea: Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic

is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and

bloody stools (with or without stomach cramps and fever) even as late as two or more months after

having taken the last dose of the antibiotic. If this occurs, instruct patients to contact their physician as

soon as possible.

Prolongation of the QT Interval: Instruct patients to inform their physician of any personal or family

history of QT prolongation or proarrhythmic conditions such as hypokalemia, bradycardia, or recent

myocardial ischemia; if they are taking any Class IA (quinidine, procainamide), or Class III (amiodarone,

sotalol) antiarrhythmic agents. Instruct patients to notify their physician if they have any symptoms of

prolongation of the QT interval, including prolonged heart palpitations or a loss of consciousness.

Musculoskeletal Disorders in Pediatric Patients: Instruct parents to inform their child’s physician if

the child has a history of joint-related problems before taking this drug. Inform parents of pediatric

patients to notify their child’s physician of any joint-related problems that occur during or following

levofloxacin therapy [see Warnings and Precautions (5.12) and Use in Specific Populations (8.4)].

Photosensitivity/Phototoxicity: Inform patients that photosensitivity/phototoxicity has been reported

in patients receiving fluoroquinolones. Inform patients to minimize or avoid exposure to natural or

artificial sunlight (tanning beds or UVA/B treatment) while taking fluoroquinolones. If patients need to

be outdoors while using fluoroquinolones, instruct them to wear loose-fitting clothes that protect skin

from sun exposure and discuss other sun protection measures with their physician. If a sunburn-like

reaction or skin eruption occurs, instruct patients to contact their physician.

Lactation: Advise a lactating woman that she may pump and discard during treatment with levofloxacin

and for an additional 2 days after the last dose. Alternatively, advise a lactating woman that breastfeeding

is not recommended during treatment with levofloxacin and for an additional 2 days after the last dose

[see Use in Specific Populations (8.2)].

Antibacterial Resistance

Antibacterial drugs including levofloxacin should only be used to treat bacterial infections. They do not

treat viral infections (e.g., the common cold). When levofloxacin is prescribed to treat a bacterial

infection, patients should be told that although it is common to feel better early in the course of therapy,

the medication should be taken exactly as directed. Skipping doses or not completing the full course of

therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood

that bacteria will develop resistance and will not be treatable by levofloxacin or other antibacterial

drugs in the future.

Administration with Food, Fluids, and Concomitant Medications

Patients should be informed that levofloxacin tablets may be taken with or without food. The tablet

should be taken at the same time each day.

Patients should drink fluids liberally while taking levofloxacin to avoid formation of a highly

concentrated urine and crystal formation in the urine.

Antacids containing magnesium, or aluminum, as well as sucralfate, metal cations such as iron, and

multivitamin preparations with zinc or didanosine should be taken at least two hours before or two hours

after oral levofloxacin administration.

Drug Interactions with Insulin, Oral Hypoglycemic Agents, and Warfarin

Patients should be informed that if they are diabetic and are being treated with insulin or an oral

hypoglycemic agent and a hypoglycemic reaction occurs, they should discontinue levofloxacin and

consult a physician.

Patients should be informed that concurrent administration of warfarin and levofloxacin has been

associated with increases of the International Normalized Ratio (INR) or prothrombin time and clinical

episodes of bleeding. Patients should notify their physician if they are taking warfarin, be monitored for

evidence of bleeding, and also have their anticoagulation tests closely monitored while taking warfarin

concomitantly.

Plague and Anthrax Studies

Patients given levofloxacin for these conditions should be informed that efficacy studies could not be

conducted in humans for ethical and feasibility reasons. Therefore, approval for these conditions was

based on efficacy studies conducted in animals.

MEDICATION GUIDE

Levofloxacin Tablets USP, 250 mg, 500 mg and 750 mg

(lee'' voe flox' a sin)

What is the most important information I should know about levofloxacin tablets?

Levofloxacin tablets, a fluoroquinolone antibiotic, can cause serious side effects. Some of these

serious side effects can happen at the same time and could result in death.

If you have any of the following serious side effects while you take levofloxacin tablets, you should

stop taking levofloxacin tablets immediately and get medical help right away.

1. Tendon rupture or swelling of the tendon (tendinitis).

Tendon problems can happen in people of all ages who takelevofloxacin tablets. Tendons are

tough cords of tissue that connect muscles to bones. Some tendon problems include:

pain

swelling

tears and swelling of tendons including the back of the ankle (Achilles), shoulder, hand, or other

tendon sites.

The risk of getting tendon problems while you take levofloxacin if you:

are over 60 years of age

are taking steroids (corticosteroids)

have had a kidney, heart or lung transplant.

Tendon problems can happen in people who do not have the above risk factors when they take

levofloxacin tablets.

Other reasons that can increase your risk of tendon problems can include:

physical activity or exercise

kidney failure

tendon problems in the past, such as in people with rheumatoid arthritis (RA).

Stop taking levofloxacin tablets immediately and get medical help right away at the first sign of

tendon pain, swelling or inflammation. Avoid exercise and using the affected area.

The most common area of pain and swelling is the Achilles tendon at the back of your ankle. This

can also happen with other tendons. You may need a different antibiotic that is not a fluoroquinolone

to treat your infection.

Tendon rupture can happen while you are taking or after you have finished taking levofloxacin

tablets. Tendon ruptures can happen within hours or days of taking levofloxacin tablets and have

happened up to several months after people have finished taking their fluoroquinolone.

Stop taking levofloxacin tablets immediately and get medical help right away if you get any of the

following signs or symptoms of a tendon rupture:

hear or feel a snap or pop in a tendon area

bruising right after an injury in a tendon area

unable to move the affected area or bear weight

The tendon problems may be permanent.

2. Changes in sensation and possible nerve damage (Peripheral Neuropathy). Damage to the

nerves in arms, hands, legs, or feet can happen in people who take fluoroquinolones, including

levofloxacin tablets. Stop taking levofloxacin tablets immediately and talk to your healthcare provider

right away if you get any of the following symptoms of peripheral neuropathy in your arms, hands, legs,

or feet:

pain

burning

numbness

weakness

tingling

The nerve damage may be permanent.

3. Central Nervous System (CNS) effects. Mental health problems and seizures have been reported in

people who take fluoroquinolone antibacterial medicines, including levofloxacin tablets. Tell your

healthcare provider if you have a history of mental health problems, including depression, or have a

history of seizures before you start taking levofloxacin tablets. CNS side effects may happen as soon as

after taking the first dose of levofloxacin tablets. Stop taking levofloxacin tablets immediately and talk

to your healthcare provider right away if you get any of these side effects, or other changes in mood or

behavior:

seizures

hear voices, see things, or sense things that are not there (hallucinations)

feel restless or agitated

tremors

feel anxious or nervous

confusion

depression

reduced awareness of surroundings

trouble sleeping

nightmares

feel lightheaded or dizzy

feel more suspicious (paranoia)

suicidal thoughts or acts

headaches that will not go away, with or without blurred vision

memory problems

false or strange thoughts or beliefs (delusions)

The CNS changes may be permanent

4. Worsening of myasthenia gravis (a problem that causes muscle weakness). Fluoroquinolones

like levofloxacin tablets may cause worsening of myasthenia gravis symptoms, including muscle

weakness and breathing problems. Tell your healthcare provider if you have a history of myasthenia

gravis before you start taking levofloxacin tablets. Call your healthcare provider right away if you have

any worsening muscle weakness or breathing problems.

What are levofloxacin tablets?

Levofloxacin tablet is a fluoroquinolone antibiotic medicine used in adults age 18 years or older to

treat certain infections caused by certain germs called bacteria. These bacterial infections include:

nosocomial pneumonia

community-acquired pneumonia

skin infections, complicated and uncomplicated

chronic prostate infection

inhalation anthrax germs

plague

urinary tract infections, complicated and uncomplicated

acute kidney infection (pyelonephritis)

acute worsening or chronic bronchitis

acute sinus infection

Studies of levofloxacin tablets for use in the treatment of plague and anthrax were done in animals only,

because plague and anthrax could not be studied in people.

Levofloxacin tablets should not be used in people with uncomplicated urinary tract infections, acute

bacterial exacerbation of chronic bronchitis, or acute bacterial sinusitis if there are other treatment

options available.

Levofloxacin tablets are also used to treat children who weigh at least 66 pounds (or at least 30

kilograms) and may have breathed in anthrax germs, have plague, or been exposed to plague germs.

It is not known if levofloxacin tablets are safe and effective in children under 6 months of age.

The safety and effectiveness in children treated with levofloxacin tablets for more than 14 days is not

known.

Who should not take levofloxacin tablets?

Do not take levofloxacin tablets if you have ever had a severe allergic reaction to an antibiotic known

as a fluoroquinolone, or if you are allergic to levofloxacin or any of the ingredients in levofloxacin

tablets. See the end of this leaflet for a complete list of ingredients in levofloxacin tablets.

Before you take levofloxacin tablets, tell your healthcare provider about all of your medical

conditions, including if you:

have tendon problems. Levofloxacin tablets should not be used in people who have a history of

tendon problems

have a problem that causes muscle weakness (myasthenia gravis). Levofloxacin tablets should not be

used in people who have a known history of myasthenia gravis

have a history of mental health problems, including depression

have central nervous system problems such as seizures (epilepsy)

have nerve problems. Levofloxacin tablets should not be used in people who have a history of a

nerve problem called peripheral neuropathy

have or anyone in your family has an irregular heartbeat, especially a condition called “QT

prolongation.”

have low blood potassium (hypokalemia)

have bone problems

have joint problems including rheumatoid arthritis (RA)

have kidney problems. You may need a lower dose of levofloxacin tablets if your kidneys do not

work well.

have liver problems

have diabetes or problems with low blood sugar (hypoglycemia)

are pregnant or plan to become pregnant. Levofloxacin passes into your breast milk. You should not

breastfeed during treatment with levofloxacin and for 2 days after taking your last dose of

levofloxacin. You may pump your breast milk and throw it away during treatment with levofloxacin

and for 2 days after taking your last dose of levofloxacin.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-

counter medicines, vitamins, and herbal supplements.

Levofloxacin tablets and other medicines can affect each other causing side effects.

Especially tell your healthcare provider if you take:

a steroid medicine.

an anti-psychotic medicine

a tricyclic antidepressant

a water pill (diuretic)

certain medicines may keep levofloxacin tablets from working correctly. Take levofloxacin tablets

either 2 hours before or 2 hours after taking these medicines or supplements:

an antacid, multivitamin, or other medicines or supplements that have magnesium, aluminum, iron,

or zinc

sucralfate (Carafate

didanosine (Videx

,Videx

a blood thinner (warfarin, Coumadin, Jantoven)

an oral anti-diabetes medicine or insulin

an NSAID (Non-Steroidal Anti-Inflammatory Drug). Many common medicines for pain relief are

NSAIDs. Taking an NSAID while you take levofloxacin tablets or other fluoroquinolones may

increase your risk of central nervous system effects and seizures.

theophylline (Theo-24

, Elixophyllin , Theochron , Uniphyl

, Theolair

a medicine to control your heart rate or rhythm (antiarrhythmics)

Ask your healthcare provider if you are not sure if any of your medicines are listed above.

Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and

pharmacist when you get a new medicine.

How should I take levofloxacin tablets?

Take levofloxacin tablets exactly as your healthcare provider tells you to take it.

Take levofloxacin tablets at the same time each day.

Drink plenty of fluids while you take levofloxacin tablets.

Levofloxacin tablets can be taken with or without food.

If you miss a dose of levofloxacin tablets and it is:

8 hours or more until your next scheduled dose, take your missed dose right away. Then take the

next dose at your regular time.

less than 8 hours until your next scheduled dose, do not take the missed dose. Take the next dose at

your regular time.

Do not skip any doses of levofloxacin tablets, or stop taking it, even if you begin to feel better, until

you finish your prescribed treatment unless:

you have tendon problems. See “What is the most important information I should know

about levofloxacin tablets?”.

you have a nerve problem. See “What is the most important information I should know

about levofloxacin tablets?”.

you have a central nervous system problem. See "What are the possible side effects of

levofloxacin tablets?".

you have a serious allergic reaction. See “What are the possible side effects oflevofloxacin

tablets ?”.

your healthcare provider tells you to stop taking levofloxacin tablets.

Taking all of your levofloxacin tablets doses will help make sure that all of the bacteria are killed.

Taking all of your levofloxacin tablets doses will help you lower the chance that the bacteria will

become resistant to levofloxacin tablets. If your infection does not get better while you take

levofloxacin tablets, it may mean that the bacteria causing your infection may be resistant to

levofloxacin tablets. If your infection does not get better, call your healthcare provider. If your

infection does not get better, levofloxacin tablets and other similar antibiotic medicines may not work

for you in the future.

If you take too much levofloxacin tablets, call your healthcare provider or get medical help right

away.

What should I avoid while taking levofloxacin tablets?

Levofloxacin tablets can make you feel dizzy and lightheaded. Do not drive, operate machinery, or

do other activities that require mental alertness or coordination until you know how levofloxacin

tablets affects you.

Avoid sunlamps, tanning beds, and try to limit your time in the sun. Levofloxacin tablets can make

your skin sensitive to the sun (photosensitivity) and the light from sunlamps and tanning beds. You

could get severe sunburn, blisters or swelling of your skin. If you get any of these symptoms while

you take levofloxacin tablets, call your healthcare provider right away. You should use sunscreen

and wear a hat and clothes that cover your skin if you have to be in sunlight.

What are the possible side effects of levofloxacin tablets?

Levofloxacin tablets may cause serious side effects, including:

See “What is the most important information I should know about levofloxacin tablets?”

Serious allergic reactions. Allergic reactions can happen in people taking fluoroquinolones,

including levofloxacin tablets, even after only 1 dose. Stop taking levofloxacin tablets and get

emergency medical help right away if you have any of the following symptoms of a severe allergic

reaction:

hives

trouble breathing or swallowing

swelling of the lips, tongue, face

throat tightness, hoarseness

rapid heartbeat

faint

skin rash

Skin rash may happen in people taking levofloxacin tablets, even after only 1 dose. Stop taking

levofloxacin tablets at the first sign of a skin rash and immediately call your healthcare provider. Skin

rash may be a sign of a more serious reaction to levofloxacin tablets.

Liver damage (hepatotoxicity): Hepatotoxicity can happen in people who take levofloxacin tablets.

Call your healthcare provider right away if you have unexplained symptoms such as:

nausea or vomiting

stomach pain

fever

weakness

pain or tenderness in the upper right side of your stomach-area

itching

unusual tiredness

loss of appetite

light colored bowel movements

dark colored urine

yellowing of your skin or the whites of your eyes

Stop taking levofloxacin tablets and tell your healthcare provider right away if you have yellowing of

your skin or white part of your eyes, or if you have dark urine. These can be signs of a serious reaction

to levofloxacin tablets (a liver problem).

Aortic aneurysm and dissection: Tell your healthcare provider if you have ever been told that you

have an aortic aneurysm, a swelling of the large artery that carries blood from the heart to the body.

Get emergency medical help right away if you have sudden chest, stomach, or back pain.

Intestine infection (Clostridium difficile-associated diarrhea). Clostridium difficile-associated

diarrhea (CDAD) can happen with many antibiotics, including levofloxacin tablets. Call your

healthcare provider right away if you get watery diarrhea, diarrhea that does not go away, or bloody

stools. You may have stomach cramps and a fever. CDAD can happen 2 or more months after you

have finished your antibiotic.

Serious heart rhythm changes (QT prolongation and torsades de pointes). Tell your

healthcare provider right away if you have a change in your heart beat (a fast or irregular heartbeat),

or if you faint. Levofloxacin tablets may cause a rare heart problem known as prolongation of the

QT interval. This condition can cause an abnormal heartbeat and can be very dangerous. The chances

of this happening are higher in people:

who are elderly

with a family history of prolonged QT interval

with low blood potassium (hypokalemia)

who take certain medicines to control heart rhythm (antiarrhythmics)

who take certain medicines to control heart rhythm (antiarrhythmics)

Joint Problems. Increased chance of problems with joints and tissues around joints in children can

happen. Tell your child’s healthcare provider if your child has any joint problems during or after

treatment with levofloxacin tablets.

Changes in blood sugar. People who take levofloxacin tablets and other fluoroquinolone

medicines with oral anti-diabetes medicines or with insulin can get low blood sugar (hypoglycemia)

and high blood sugar (hyperglycemia). Follow your healthcare provider’s instructions for how

often to check your blood sugar. If you have diabetes and you get low blood sugar while taking

levofloxacin tablets, stop taking levofloxacin tablets and call your healthcare provider right away.

Your antibiotic medicine may need to be changed.

Sensitivity to sunlight (photosensitivity). See “What should I avoid while taking levofloxacin

tablets ?"

The most common side effects of levofloxacin tablets include:

nausea

headache

diarrhea

insomnia

constipation

dizziness

In children 6 months and older who take levofloxacin tablets to treat anthrax disease or plague, vomiting

is also common.

Levofloxacin tablets may cause false-positive urine screening results for opiates when testing is done

with some commercially available kits. A positive result should be confirmed using a more specific

test.

These are not all the possible side effects of levofloxacin tablets.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-

FDA-1088.

How should I store levofloxacin tablets?

Store levofloxacin tablets at 20° to 25°C (68° to 77°F).

Keep levofloxacin tablets in a tightly closed container.

General information about the safe and effective use of levofloxacin tablets

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not

use levofloxacin tablets for a condition for which it is not prescribed. Do not give levofloxacin tablets

to other people, even if they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about levofloxacin tablets. If you

would like more information about levofloxacin tablets, talk with your healthcare provider. You can ask

your healthcare provider or pharmacist for information about levofloxacin tablets that is written for

health professionals.

For more information go to call 1-888-375-3784.

What are the ingredients in levofloxacin tablets?

Levofloxacin Film-Coated Tablets:

Active ingredient: levofloxacin

Inactive ingredients:

250 mg (as expressed in the anhydrous form): colloidal silicon dioxide, corn starch, crospovidone,

hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol and titanium

dioxide.

500 mg (as expressed in the anhydrous form): colloidal silicon dioxide, corn starch, crospovidone,

FD&C yellow no. 5 aluminum lake, FD&C yellow no. 6 aluminum lake, hypromellose, magnesium

stearate, microcrystalline cellulose, polyethylene glycol and titanium dioxide.

750 mg (as expressed in the anhydrous form): colloidal silicon dioxide, corn starch, crospovidone,

hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, synthetic yellow

iron oxide and titanium dioxide.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Rx Only

Manufactured by:

Dr. Reddy’s Laboratories Limited

Bachupally – 500 090 INDIA

Revised: 0719

Dispense the Medication Guide available at: www.drreddys.com/medguide/levofloxacintabs.pdf

Levofloxacin 500mg Tablet

LEVOFLOXACIN

levofloxacin tablet, film coated

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:71335-1277(NDC:55111-28 0 )

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

LEVO FLO XACIN (UNII: 6 GNT3Y5LMF) (LEVOFLOXACIN ANHYDROUS -

LEVOFLOXACIN

50 0 mg

UNII:RIX4E8 9 Y14)

ANHYDROUS

50 0 mg

Inactive Ingredients

Ingredient Name

Stre ng th

Silico n Dio xide (UNII: ETJ7Z6 XBU4)

STARCH, CO RN (UNII: O8 232NY3SJ)

Cro spo vido ne, Unspecified (UNII: 2S78 30 E56 1)

FD&C YELLO W NO . 5 (UNII: I753WB2F1M)

FD&C YELLO W NO . 6 (UNII: H77VEI9 3A8 )

HYPRO MELLO SE, UNSPECIFIED (UNII: 3NXW29 V3WO)

ma g nesium stea ra te (UNII: 70 0 9 7M6 I30 )

MICRO CRYSTALLINE CELLULO SE (UNII: OP1R32D6 1U)

PO LYETHYLENE GLYCO L, UNSPECIFIED (UNII: 3WJQ0 SDW1A)

tita nium dio xide (UNII: 15FIX9 V2JP)

Product Characteristics

Color

ORANGE

S core

no sco re

S hap e

CAPSULE

S iz e

18 mm

Flavor

Imprint Code

RDY;28 0

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:71335-1277-1

30 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 7/0 6 /20 11

2

NDC:71335-1277-2

10 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 7/0 6 /20 11

3

NDC:71335-1277-3

7 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 7/0 6 /20 11

4

NDC:71335-1277-4

14 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 7/0 6 /20 11

5

NDC:71335-1277-5

5 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 7/0 6 /20 11

6

NDC:71335-1277-6

20 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 7/0 6 /20 11

7

NDC:71335-1277-7

6 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 7/0 6 /20 11

8

NDC:71335-1277-8

3 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 7/0 6 /20 11

9

NDC:71335-1277-9

50 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 7/0 6 /20 11

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 76 710

0 6 /20 /20 11

Labeler -

Bryant Ranch Prepack (171714327)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Bryant Ranch Prepack

171714327

REPACK(71335-1277) , RELABEL(71335-1277)

Bryant Ranch Prepack

Revised: 8/2019

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