1.LEVAQUIN HISTORY
How was Levaquin discovered?

Levaquin is a fluoroquinolone antibiotic, marketed by Ortho-McNeil under the brand name Levaquin. Chemically, levofloxacin is the S-enantiomer (L-isomer) of ofloxacin. 

Levaquin received U.S. Food and Drug Administration (FDA) approval in 1997.

Ortho-McNeil Neurologics is a division of Johnson & Johnson Corporation.

Note: World-drugs.net sells generic version of Levaquin

2.LEVAQUIN FACTS

Ortho-McNeil Pharmaceuticals currently markets products for Alzheimer's disease, epilepsy, and migraine prevention and treatment. Ortho-McNeil Neurologics continues to explore new opportunities to develop solutions for unmet health care needs in neurology in conjunction with internal and external research partners.

With more than 1,000 employees, Ortho-McNeil Neurologics is headquartered in Titusville, New Jersey. 

3.ABOUT LEVAQUIN MEDICATION

What are antibiotics?

An antibiotic is a drug that kills or slows the growth of bacteria. Antibiotics are one class of "antimicrobials", a larger group, which also includes anti-viral, anti-fungal, and anti-parasitic drugs. They are relatively harmless to the host, and therefore can be used to treat infections. The term originally described only those formulations derived from living organisms, in contradistinction to "chemotherapeutic agents", which were purely synthetic. Nowadays the term "antibiotic" is also applied also to synthetic antimicrobials, such as the sulfonamides.

Antibiotics are labeled as "magic bullets": drugs, which target disease without harming the host. Antibiotics are not effective in viral, fungal and other nonbacterial infections, and individual antibiotics vary widely in their effectiveness on various types of bacteria. Some specific antibiotics target either gram-negative or gram-positive bacteria, and others are more wide-spectrum antibiotics.

The effectiveness of individual antibiotics varies with the location of the infection, the ability of the antibiotic to reach the site of infection, and the ability of the bacteria to resist or inactivate the antibiotic. Some antibiotics actually kill the bacteria (bactericidal), whereas others merely prevent the bacteria from multiplying (bacteriostatic) so that the host's immune system can overcome them.

Classes of Antibiotics?

There are many ways to classify antibiotics.

One such classification is by chemical structure:

Aminoglycosides

•   Amikacin
•   Dibekacin
•   Gentamicin
•   Kanamycin
•   Neomycin
•   Netilmicin
•   Paromomycin
•   Sisomycin
•   Streptomycin
•   Tobramycin

Beta-lactam ring antibiotics

Carbapenems

•   Ertapenem
•   Imipenem
•   Meropenem

Cephalosporins and cephamycins

•   Cephalexin
•   Cefazolin
•   Cefuroxime
•   Cefadroxil
•   Ceftazidime

Penicillins

•   Amoxicillin

Monocyclic beta-lactams

Glycopeptide antibiotics

•   Vancomycin
•   Teicoplanin
•   Ramoplanin
•   Decaplanin

Oxazolidinones

•   Linezolid
•   Quinupristin/dalfopristin

Polyketides

Macrolides

•   Erythromycin
•   Azithromycin
•   Clarithromycin
•   Roxithromycin

Ketolides

•   Telithromycin

Tetracyclines

•   Doxycycline
•   Oxytetracycline
•   Chlortetracycline

Polymyxins

•   Polymyxin B
•   Colistin

Quinolones (fluoroquinolones)

•   Nalidixic acid
•   Ciprofloxacin (Cipro)
•   Ofloxacin
•   Norfloxacin (Norflox)
•   Levofloxacin (Levaquin)
•   Trovafloxacin (Trovan)

Streptogramins

Sulfonamides

•   Prontosil

Other important antibiotics:

•   Chloramphenicol
•   Clindamycin
•   Fusidic acid
•   Trimethoprim

Another such classification is by their mechanism of action

Antibiotics, which interfere with cell-wall synthesis

Beta-lactams, including penicillins like Amoxicillin and cephalosporins; mono-lactams, such as Imipenem; vancomycin, bacitracin

Antibiotics that interfere with bacterial protein synthesis

Antibiotics that bind to the 50S ribosomal unit

Lincosamides/lincosides including clindamycin and lincomycin; chloramphenicol, macrolides

Antibiotics, which interfere the 30S ribosomal unit

Tetracyclines; aminoglycosides including gentamicin

Drugs that inhibit folate synthesis

Sulfonamides and trimethoprim

Drugs that interfere with DNA synthesis

Metronidazole, quinolones, novobiocin

Drugs that interfere with RNA synthesis

Rifampin (rifampicin)

Drugs that interfere with cell membrane function

Polymyxin B, gramicidin

Antibiotics can also be classified by the organisms against which they are effective, and by the type of infection in which they are useful, which depends on the sensitivities of the organisms that most commonly cause the infection and the concentration of antibiotic obtainable in the affected tissue.

How does Levaquin work?

Levaquin is effective against a number of gram-positive and gram-negative bacteria.

Levaquin works by entering the bacterial cell and inhibiting a chemical called DNA-gyrase, which is involved in the production of genetic material (DNA). This therefore prevents the bacteria from reproducing and their growth is stopped.

Uses of Levaquin

Levaquin tablets or capsules are indicated for the treatment of adults (= 18 years of age) with mild, moderate, and severe infections caused by susceptible strains of the designated microorganisms in the conditions listed below.

Acute bacterial sinusitis due to Streptococcus pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis.

 

The sinuses are air-filled spaces in the skull (behind the forehead, cheeks, and eyes) that are lined with mucous membranes. Healthy sinuses are sterile (meaning that they contain no bacteria or other organisms) and open, allowing mucus to drain and air to circulate.

In Acute Bacterial Sinusitis, the sinuses become blocked with mucus and can become infected. Each year, over 30 million adults and children get sinusitis.

Sinusitis can be acute (lasting anywhere from 2 - 8 weeks) or chronic, with symptoms lingering much longer.

• Acute bacterial exacerbation of chronic bronchitis due to Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, Haemophilus parainfluenzae, or Moraxella catarrhalis.

Chronic bronchitis is an inflammation of the bronchi, the main air passages in the lungs, which persists for a long period or repeatedly recurs.

The condition is characterized by excessive bronchial mucus and a productive cough that produces sputum for 3 months or more in at least 2 consecutive years, without any other disease that could account for this symptom. 

• 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 a clinically indicated. Where Pseudomonas aeruginosa is a documented or presumptive pathogen, combination therapy with an anti-pseudomonal ß-lactam is recommended.

• Community-acquired pneumonia due to Staphylococcus aureus, Streptococcus pneumoniae (including multi-drug-resistant strains [MDRSP]), Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Moraxells catarrhalis, Chlamydia pneumoniae, Legionella pneumophila, or Mycoplasma pneumoniae.

• MDRSP (Multi-drug resistant Streptococcus pneumoniae) are strains resistant to two or more of the following antibiotics: penicillin (MIC =2 µg/mL), 2nd generation cephalosporins, e.g., cefuroxime, macroides, tetracyclines and trimethoprim/sulfamethoxazole.

• Complicated skin and skin structure infections due to methicillin-susceptible Staphylococcus aureus, Enterococcus faecalis, Streptococcus pyogenes, or Porteus mirabilis.

• Uncomplicated skin and skin structure infections (mild to moderate) including abscesses, cellulites, furuncles, impetigo, pyoderma, wound infections, due to Staphylococcus aureus or Streptococcus pyogenes.

• Chronic bacterial prostatitis due to Escherichia coli, Enterococcus faecalis, or Staphylococcus epidermidis.

• Complicated urinary tract infections (mild to moderate) due to Enterococcus faecalis, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, or Pseudomonas aeruginosa.

• Acute pyelonephritis (mild to moderate) caused by Escherichia coli.

• Uncomplicated urinary tract infections (mild to moderate) due to Escherichia coli, Klebsiella penumoniae, or Staphylococcus saprophyticus.

Most urinary tract infections (UTI) occur in the lower urinary tract, which includes the bladder and urethra. Cystitis (lower urinary tract infection) is caused when the normally sterile lower urinary tract is infected by bacteria and becomes inflamed. Cystitis is very common.

Most of the time, symptoms of cystitis disappear within 24 to 48 hours after treatment begins with Levaquin. Chronic or recurrent urinary tract infection includes repeated episodes of cystitis (more than 2 in 6 months), or urinary tract infection that does not respond to the usual treatment or that lasts longer than 2 weeks.

4.LEVAQUIN EFFECTIVENESS
When is Levaquin best taken?

Absorption

Levaquin 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 a 500 mg tablet and a 750 mg tablet of levofloxacin are both approximately 99%, demonstrating complete oral absorption of Levaquin.

Distribution

The mean volume of distribution of Levaquin generally ranges from 74 to 112 L after single and multiple 500 mg or 750 mg Levaquin doses, indicating widespread distribution into body tissues. Levaquin reaches its peak levels in skin tissues and in blister fluid of healthy subjects at approximately 3 hours after Levaquin dosing.

Metabolism

Levaquin is stereochemically stable in plasma and urine and does not invert metabolically to its enantiomer, D-ofloxacin. Levaquin undergoes limited metabolism in humans and is primarily excreted as unchanged drug in the urine. Following oral administration, approximately 87% of an administered Levaquin dose was recovered as unchanged drug in urine within 48 hours, whereas less than 4% of the Levaquin dose was recovered in feces in 72 hours. Less than 5% of an administered Levaquin 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

Levaquin is excreted largely as unchanged drug in the urine. The mean terminal plasma elimination half-life of Levaquin ranges from approximately 6 to 8 hours following single or multiple doses of Levaquin 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 Levaquin occurs in addition to its glomerular filtration.

5.LEVAQUIN EFFECTS ON SPECIAL POPULATION
How do different people react to Levaquin?

Geriatric

There are no significant differences in Levaquin pharmacokinetics between young and elderly subjects when the subjects' differences in creatinine clearance are taken into consideration. Following a 500 mg oral dose of Levaquin to healthy elderly subjects (66 - 80 years of age), the mean terminal plasma elimination half-life of Levaquin 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. Levaquin dose adjustment based on age alone is not necessary.

Pediatric

The pharmacokinetics of Levaquin in pediatric subjects has not been studied.

Gender

There are no significant differences in Levaquin pharmacokinetics between male and female subjects when subjects' differences in creatinine clearance are taken into consideration. Following a 500 mg oral doses of Levaquin to healthy male subjects, the mean terminal plasma elimination half-life of Levaquin 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.

Race

The effect of race on Levaquin pharmacokinetics was examined through a covariate analysis performed on data from 72 subjects: 48 white and 24 non-whites. The apparent total body clearance and apparent volume of distribution were not affected by the race of the subjects. 

6.LEVAQUIN EFFECTS ON MEDICAL CONDITIONS
(How does Levaquin affect your existing condition/ailment?)

Renal insufficiency:

Clearance of Levaquin is substantially reduced and plasma elimination half-life is substantially prolonged in 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 Levaquin from the body, indicating that supplemental doses of Levaquin are not required following hemodialysis or CAPD.

Hepatic insufficiency

Pharmacokinetic studies in hepatically impaired patients have not been conducted. Due to the limited extent of Levaquin metabolism, the pharmacokinetics of Levaquin are not expected to be affected by hepatic impairment.

Bacterial infection

The pharmacokinetics of Levaquin in patients with serious community-acquired bacterial infections are comparable to those observed in healthy subjects. 

7.OTHER/ALTERNATE USES OF LEVAQUIN
What else does Levaquin treat?

Levaquin may be prescribed for other uses; ask your doctor or pharmacist for more information.

8.ADVERSE/SIDE EFFECTS of LEVAQUIN
What are the side effects of Levaquin?

The incidence of drug-related adverse reactions in patients during Phase 3 clinical trials conducted in North America was 6. 2%. Among patients receiving Levaquin therapy, 4. 3% discontinued Levaquin therapy due to adverse experiences. The overall incidence, type and distribution of adverse events was similar in patients receiving Levaquin doses of 750 mg once daily compared to patients receiving Levaquin doses from 250 mg once daily to 500 mg twice daily.

In clinical trials, the following events were considered likely to be drug-related in patients receiving Levaquin: nausea 1. 2%, diarrhea 1. 0%, vaginitis 0. 6%, insomnia 0. 4%, abdominal pain 0. 4%, flatulence 0. 3%, pruritus 0. 3%, dizziness 0. 3%, rash 0. 3%, dyspepsia 0. 2%, genital moniliasis 0. 2%, moniliasis 0. 2%, taste perversion 0. 2%, vomiting 0. 2%, injection site pain 0. 2%, injection site reaction 0. 2%, injection site inflammation 0. 1%, constipation 0. 1%, fungal infection 0. 1%, genital pruritis 0. 1%, headache 0. 1%, nervousness 0. 1%, rash erythematous 0. 1%, urticaria 0. 1%, anorexia 0. 1%, somnolence 0. 1%, agitation 0. 1%, rash maculo-papular 0. 1%, tremor 0. 1%, condi-tion aggravated 0. 1%, allergic reaction 0. 1%. 

In clinical trials, the following events occurred in >3% of patients, regardless of drug relationship: nausea 7. 1%, headache 6. 2%, diarrhea 5. 5%, insomnia 5. 1%, constipation 3. 5%.

In clinical trials, the following events occurred in 1 to 3% of patients, regardless of drug relationship: abdominal pain 2. 7%, dizziness 2. 5%, vomiting 2. 5%, dyspepsia 2. 3%, vaginitis 1. 7%, rash 1. 6%, chest pain 1. 4%, pruritus 1. 3%, sinusitis 1. 3%, dyspnea 1. 4%, fatigue 1. 4%, flatulence 1. 2%, pain 1. 6%, back pain 1. 2%, rhinitis 1. 2%, anxiety 1. 2%, pharyngitis 1. 2%.

In clinical trials, the following events, of potential medical importance, occurred at a rate of 0. 1% to 0. 9%, regardless of drug relationship:

Body as a Whole – General Disorders:	Ascites, allergic reaction, asthenia, drug level increase, edema, enlarged abdomen, fever, headache, hot flashes, influenza-like symptoms, leg pain, malaise, rigors, substernal chest pain, syncope, multiple organ failure, changed temperature sensation, withdrawal syndrome
Cardiovascular Disorders, General: Central and Peripheral Nervous System Disorders:	Cardiac failure, hypertension, hypertension aggravated, hypotension, postural hypotension Convulsions (seizures), dysphonia, hyperesthesia, hyperkinesia, hypertonia, hypoesthesia, involuntary muscle contractions, migraine, paresthesia, paralysis, speech disorder, stupor, tremor, vertigo, encephalopathy, abnormal gait, leg cramps, intracranial hypertension, ataxia
Gastro-Intestinal System Disorders:	Dry mouth, dysphagia, esophagitis, gastritis, gastroenteritis, gastroesophageal reflux, G. I. hemorrhage, glossitis, hemorrhoids, intestinal obstruction, pancreatitis, tongue edema, melena, stomatitis
Hearing and Vestibular Disorders: Heart Rate and Rhythm Disorders:	Earache, tinnitus Arrhythmia, arrhythmia ventricular, atrial fibrillation, bradycardia, cardiac arrest, ventricular fibrillation, heart block, palpitation, supraventricular tachycardia, ventricular tachycardia, tachycardia
Liver and Biliary System Disorders:	Abnormal hepatic function, cholecystitis, cholelithiasis, elevated bilirubin, hepatic enzymes increased, hepatic failure, jaundice
Metabolic and Nutritional Disorders:	Hypomagnesemia, thirst, dehydration, electrolyte abnormality, fluid overload, gout, hyper-glycemia, hyperkalemia, hypernatremia, hypoglycemia, hypokalemia, hyponatremia, hypophosphatemia, nonprotein nitrogen increase, weight decrease
Musculo-Skeletal System Disorders:	Arthralgia, arthritis, arthrosis, myalgia, osteomyelitis, skeletal pain, synovitis, tendonitis, tendon disorder
Myo, Endo, Pericardial and Valve Disorders:	Angina pectoris, endocarditis, myocardial infarction
Neoplasms:	Carcinoma, thrombocythemia
Other Special Senses Disorders:	Parosmia, taste perversion
Platelet, Bleeding and Clotting Disorders:	Hematoma, epistaxis, prothrombin decreased, pulmonary embolism, purpura, thrombocytopenia
Psychiatric Disorders:	Abnormal dreaming, agitation, anorexia, confusion, depression, hallucination, impotence, nervousness, paroniria, sleep disorder, somnolence
Red Blood Cell Disorders:	Anemia
Reproductive Disorders:	Dysmenorrhea, leukorrhea
Resistance Mechanism Disorders:	Abscess, bacterial infection, fungal infection, herpes simplex, moniliasis, otitis media, sepsis, viral infection
Respiratory System Disorders:	Airways obstruction, aspiration, asthma, bronchitis, bronchospasm, chronic obstructive airway disease, coughing, hemoptysis, epistaxis, hypoxia, laryngitis, pharyngitis, pleural effusion, pleurisy, pneumonitis, pneumonia, pneumothorax, pulmonary collapse, pulmonary edema, respiratory depression, respiratory insufficiency, upper respiratory tract infection
Skin and Appendages Disorders:	Alopecia, bullous eruption, dry skin, eczema, genital pruritus, increased sweating, rash, skin exfoliation, skin ulceration, urticaria
Urinary System Disorders:	Abnormal renal function, acute renal failure, dysuria, hematuria, oliguria, urinary incontinence, urinary retention, urinary tract infection
Vascular (Extracardiac) Disorders:	Flushing, gangrene, phlebitis, purpura, thrombophlebitis (deep)
Vision Disorders:	Abnormal vision, eye pain, conjunctivitis
White Cell and RES Disorders:	Agranulocytosis, granulocytopenia, leukocytosis, lymphadenopathy

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

The following markedly abnormal laboratory values appeared in >2% of patients receiving levofloxacin. It is not known whether these abnormalities were caused by Levaquin or the underlying condition being treated.

Blood Chemistry: decreased glucose (2. 2%)

Hematology: decreased lymphocytes (2. 2%)

Post-Marketing Adverse Reactions

Additional adverse events reported from worldwide post-marketing experience with Levaquin include: allergic pneumonitis, anaphylactic shock, anaphylactoid reaction, dysphonia, abnormal EEG, encephalopathy, eosinophilia, erythema multiforme, hemolytic anemia, multi-system organ failure, increased International Normalized Ratio (INR)/prothrombin time, peripheral neuropathy, rhabdomyolysis, Stevens-Johnson Syndrome, tendon rupture, torsades de pointes, vasodilation.