Levaquin

Levofloxacin is used to treat certain infections such as pneumonia, and , kidney, prostate (a male reproductive gland), and skin infections. Levofloxacin is also used to prevent anthrax (a serious infection that may be spread on purpose as part of a bioterror attack) in people who may have been exposed to anthrax germs in the air, and treat and prevent plague (a serious infection that may be spread on purpose as part of a bioterror attack. Levofloxacin may also be used to treat bronchitis, sinus infections, or urinary tract infections but should not be used for bronchitis and certain types of urinary tract infections if there are other treatment options available. Levofloxacin is in a class of antibiotics called fluoroquinolones. It works by killing bacteria that cause infections.

Antibiotics such as levofloxacin will not work for colds, flu, or other viral infections. Using antibiotics when they are not needed increases your risk of getting an infection later that resists antibiotic treatment.

Make sure you drink plenty of water or other fluids every day while you are taking levofloxacin.

In case of overdose, call your local poison control center at 1-800-222-1222. If the victim has collapsed or is not breathing, call local emergency services at 911.

• Levaquin^®

• The usual dose is 250-750 mg given once daily for 3-14 days depending on the type of infection.
• Anthrax is treated with 500 mg daily for 60 days.
• It is important to take oral formulations at least 2 hours before or 2 hours after any antacid or mineral supplement containing iron, calcium, zinc, or magnesium since these bind Levaquin and prevent its absorption into the body.

Levofloxacin is a synthetic broad-spectrum 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)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1- piperazinyl)-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid hemihydrate.

Figure 1: The Chemical Structure of Levofloxacin

The empirical formula is C18H20FN3O4• ½ H2O and the molecular weight is 370.38. Levofloxacin 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+3 > Cu+2 > Zn+2 > Mg+2 > Ca+2.

Excipients And Description Of Dosage Forms

Levofloxacin Oral Solution, 25 mg/mL, is a multi-use self-preserving aqueous solution of levofloxacin with pH ranging from 5.0 to 6.0. The appearance of Levofloxacin Oral Solution may range from clear yellow to clear greenish-yellow. This does not adversely affect product potency.

Levofloxacin Oral Solution contains the following inactive ingredients: artificial and natural flavors, ascorbic acid, benzyl alcohol, caramel color, glycerin, hydrochloric acid, propylene glycol, purified water, sucralose and sucrose. It may also contain a solution of sodium hydroxide for pH adjustment.

If you take too much Levaquin, call your doctor or poison control center right away, or get emergency treatment.

You should not use this medication if you are allergic to levofloxacin or similar antibiotics such as ciprofloxacin (Cipro), gemifloxacin (Factive), moxifloxacin (Avelox), ofloxacin (Floxin), norfloxacin (Noroxin), and others.

Before taking levofloxacin, tell your doctor if you have kidney or liver disease, muscle weakness or trouble breathing, joint problems, seizures, diabetes, myasthenia gravis, a history of head injury of brain tumor, a condition called pseudotumor cerebri, low levels of potassium in your blood, a personal or family history of Long QT syndrome, or if you have ever had an allergic reaction to an antibiotic.

Avoid taking antacids, vitamin or mineral supplements, sucralfate (Carafate), or didanosine (Videx) powder or chewable tablets within 2 hours before or after you take levofloxacin.

Levofloxacin may cause swelling or tearing of a tendon (the fiber that connects bones to muscles in the body), especially in the Achilles' tendon of the heel. These effects may be more likely to occur if you are over 60, if you take steroid medication, or if you have had a kidney, heart, or lung transplant. Stop taking levofloxacin and call your doctor at once if you have sudden pain, swelling, tenderness, stiffness, or movement problems in any of your joints. Rest the joint until you receive medical care or instructions.

Your pharmacist can provide more information about levofloxacin.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

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Serious And Otherwise Important Adverse Reactions

The following serious and otherwise important adverse drug reactions are discussed in greater detail in other sections of labeling:

• Tendon Effects [see WARNINGS AND PRECAUTIONS]
• Exacerbation of Myasthenia Gravis [see WARNINGS AND PRECAUTIONS]
• Hypersensitivity Reactions [see WARNINGS AND PRECAUTIONS]
• Other Serious and Sometimes Fatal Reactions [see WARNINGS AND PRECAUTIONS]
• Hepatotoxicity [see WARNINGS AND PRECAUTIONS]
• Central Nervous System Effects [see WARNINGS AND PRECAUTIONS]
• Clostridium difficile-Associated Diarrhea [see WARNINGS AND PRECAUTIONS]
• Peripheral Neuropathy that may be irreversible [see WARNINGS AND PRECAUTIONS]
• Prolongation of the QT Interval [see WARNINGS AND PRECAUTIONS]
• Musculoskeletal Disorders in Pediatric Patients [see WARNINGS AND PRECAUTIONS]
• Blood Glucose Disturbances [see WARNINGS AND PRECAUTIONS]
• Photosensitivity/Phototoxicity [see WARNINGS AND PRECAUTIONS]
• Development of Drug Resistant Bacteria [see WARNINGS AND PRECAUTIONS]

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].

Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described below reflect exposure to Levofloxacin in 7537 patients in 29 pooled Phase 3 clinical trials. The population studied had a mean age of 50 years (approximately 74% of the population was < 65 years of age), 50% were male, 71% were Caucasian, 19% were Black. Patients were treated with Levofloxacin for a wide variety of infectious diseases [see INDICATIONS AND USAGE]. Patients received Levofloxacin doses of 750 mg once daily, 250 mg once daily, or 500 mg once or twice daily. Treatment duration was usually 3-14 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

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

In clinical trials using multiple-dose therapy, ophthalmologic abnormalities, including cataracts and multiple punctate lenticular opacities, have been noted in patients undergoing treatment with quinolones, including Levofloxacin. The relationship of the drugs to these events is not presently established.

Postmarketing Experience

Table 6 lists adverse reactions that have been identified during post-approval use of Levofloxacin.� Because these reactions are reported voluntarily from a population of uncertain size, reliably estimating their frequency or establishing a causal relationship to drug exposure is not always possible.

Table 6: Postmarketing Reports Of Adverse Drug Reactions

Read the entire FDA prescribing information for Levaquin (Levofloxacin)

Absorption

Bioavailability

Approximately 99%.1

Rapidly absorbed from GI tract.1 Peak plasma concentrations usually attained 1–2 hours after an oral dose;1 steady-state plasma concentrations attained within 48 hours with once-daily regimens.1

Tablets and oral solution are bioequivalent.1

Plasma concentrations and AUC after oral administration are similar to those after IV administration.1

Food

Tablets: Food slightly prolongs time to peak plasma concentration and slightly decreases peak concentrations (approximately 14%);1 86 not considered clinically important.1

Oral solution: Food slightly prolongs time to peak plasma concentration and decreases peak concentrations by approximately 25%.1

Distribution

Extent

Widely distributed into body tissues and fluids, including skin, blister fluid, and lungs.1

Distributed into CSF.5 64 65 Following IV administration of 400 or 500 mg twice daily, CSF concentrations have been reported to be up to 47% of concurrent plasma concentrations.64 65

Distributed into milk following oral or IV administration.80

Plasma Protein Binding

24–38% bound to serum proteins, principally albumin.1

Elimination

Metabolism

Undergoes limited metabolism to inactive metabolites.1 Not metabolized by CYP isoenzymes.1

Elimination Route

Eliminated principally as unchanged drug in urine by glomerular filtration and active tubular secretion.1 Approximately 87% of an oral dose eliminated in urine and <4% eliminated in feces.1

Half-life

Terminal elimination half-life approximately 6–8 hours after oral or IV administration.1

Special Populations

Increased clearance and decreased plasma levofloxacin concentrations in pediatric patients ≥6 months of age relative to those in adults.1

Pharmacokinetics in geriatric individuals with normal renal function similar to that in younger adults.1

Pharmacokinetics not studied in patients with hepatic impairment, but pharmacokinetic alterations unlikely.1

Decreased clearance and prolonged half-life in patients with impaired renal function.1 Half-life may be 27 hours in those with Clcr 20–49 mL/minute and 35 hours in those with Clcr <20 mL/minute.1

Storage

Oral

25°C (may be exposed to 15–30°C).1

15–30°C in well-closed containers.1

Parenteral

15–30°C; protect from light.2 After dilution to a concentration of 5 mg/mL with compatible IV solution, stable for up to 72 hours at ≤25°C or up to 14 days at 5°C.2

Diluted solutions containing 5 mg/mL may be frozen in glass or plastic IV containers for ≤6 months at -20°C;2 after thawing at room temperature or in a refrigerator, do not refreeze.2

Contains no preservatives; discard any unused portions.2

≤25°C (may be exposed to ≤40°C); do not freeze.1 Protect from light and excessive heat.1

Contains no preservatives;1 discard any unused portions.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Levaquin® Tablets

Levaquin® Tablets are supplied as 250, 500, and 750 mg capsule-shaped, coated tablets. Levaquin® Tablets are packaged in bottles in the following configurations:

• 250 mg tablets are terra cotta pink and are imprinted: "Levaquin" on one side and "250" on the other side – bottles of 50 (NDC 50458-920-50)
• 500 mg tablets are peach and are imprinted: "Levaquin" on one side and "500" on the other side – bottles of 50 (NDC 50458-925-50)
• 750 mg tablets are white and are imprinted "Levaquin" on one side and "750" on the other side – bottles of 20 (NDC 50458-930-20)

Levaquin® Tablets should be stored at 15° to 30°C (59° to 86°F) in well-closed containers.

Levaquin® Tablets are manufactured for Janssen Pharmaceuticals, Inc., Titusville, NJ 08560 by Janssen Ortho LLC, Gurabo, Puerto Rico 00778.

Levaquin® Oral Solution

Levaquin® Oral Solution is supplied in a 16 oz. multi-use bottle (NDC 50458-170-01). Each bottle contains 480 mL of the 25 mg/mL levofloxacin oral solution.

Levaquin® Oral Solution should be stored at 25°C (77°F); excursions permitted to 15° – 30°C (59° to 86°F) [refer to USP controlled room temperature].

Levaquin® Oral Solution is manufactured for Janssen Pharmaceuticals, Inc., Titusville, NJ 08560 by Janssen Pharmaceutica N.V., Beerse, Belgium.

Levaquin® Injection Pre-Mixed Solution, Single-Use in Flexible Container

Levaquin® (levofloxacin in 5% dextrose) Injection is supplied as a single-use, premixed solution in flexible containers. Each bag contains a dilute solution with the equivalent of 250, 500, or 750 mg of levofloxacin, respectively, in 5% Dextrose (D5W).

• 5 mg/mL (250 mg), 100 mL flexible container, 50 mL fill (NDC 50458-167-01)
• 5 mg/mL (500 mg), 100 mL flexible container, 100 mL fill (NDC 50458-168-01)
• 5 mg/mL (750 mg), 150 mL flexible container, 150 mL fill (NDC 50458-166-01)

Levaquin® Injection Premix in Flexible Containers should be stored at or below 25°C (77°F); however, brief exposure up to 40°C (104°F) does not adversely affect the product. Avoid excessive heat and protect from freezing and light. Levaquin® Injection Premix in Flexible Containers is manufactured for Janssen Pharmaceuticals, Inc., Titusville, NJ 08560 by Hospira, Inc., Austin, TX 78728.

Keep out of reach of children.

Levaquin (levofloxacin) is a fluoroquinolone antibiotic that fights bacteria in the body.

Levaquin is used to treat bacterial infections of the skin, sinuses, kidneys, bladder, or prostate. Levaquin is also used to treat bacterial infections that cause bronchitis or pneumonia, and to treat people who have been exposed to anthrax.

Fluoroquinolone antibiotics can cause serious or disabling side effects that may not be reversible. Levaquin should be used only for infections that cannot be treated with a safer antibiotic.

Stop taking Levaquin and call your doctor at once if you have sudden pain, swelling, bruising, tenderness, stiffness, or movement problems in any of your joints. Rest the joint until you receive medical care or instructions.

Levofloxacin may cause swelling or tearing of a tendon, especially if you are over 60, if you take steroid medication, or if you have had a kidney, heart, or lung transplant.

You may not be able to use Levaquin if you have a muscle disorder. Tell your doctor if you have a history of myasthenia gravis.

Tell your doctor about all your current medicines and any you start or stop using, especially:

• a diuretic or "water pill";

• theophylline;

• heart rhythm medication - amiodarone, disopyramide, dofetilide, dronedarone, procainamide, quinidine, sotalol, and others;

• medicine to treat depression or mental illness - amitriptylline, clomipramine, desipramine, iloperidone, imipramine, nortriptyline, and others; or

• NSAIDs (nonsteroidal anti-inflammatory drugs) - aspirin, ibuprofen (Advil, Motrin), naproxen (Aleve), celecoxib, diclofenac, indomethacin, meloxicam, and others.

This list is not complete. Other drugs may interact with levofloxacin, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

More frequent side effects include: diarrhea and insomnia. See below for a comprehensive list of adverse effects.

WARNINGS: Levaquin may rarely cause tendon damage (such as tendinitis, tendon rupture) during or after treatment. Your risk for tendon problems is greater if you are over 60 years of age, if you are taking corticosteroids (such as prednisone), or if you have had a kidney, heart or lung transplant. Stop exercising, rest, and get medical help right away if you develop joint/muscle/tendon pain or swelling.

Levaquin should not be used in patients with myasthenia gravis. It may cause the condition to become worse. Seek immediate medical attention if you develop muscle weakness or trouble breathing.

• Oral Levaquin tablets can be administered without regard to food. Take oral Levaquin solution one hour before or two hours after food.
• Take at least two hours before or two hours after antacids or preparations containing iron or zinc.
• Should be taken exactly as directed and for the time period indicated to reduce the risk of resistant bacteria developing, unless side effects force early discontinuation.
• Ensure you keep hydrated while taking Levaquin to prevent crystal formation in your urine.
• Discontinue Levaquin immediately if you experience tendon pain, swelling, inflammation or rupture and contact your healthcare provider.
• Discontinue Levaquin immediately and contact your healthcare provider if you experience pain, tingling, or numbness in your fingers and toes; severe diarrhea; any central nervous system effects (such as paranoia, depression, hallucinations); a severe rash, jaundice (skin yellowing) or any sign of an allergic reaction.
• Avoid excessive sun or UV light exposure, and wear sunblock when outdoors. Report any apparent sunburn to your doctor immediately.

• Peak levels are reached within one to two hours but it may take up to three days before symptoms of the infection begin to resolve.
• Take Levaquin for the entire course prescribed, unless side effects prevent you from doing so and your doctor has advised you to stop taking it.

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