CRAVIT Tablet

1. Patients with a history of hypersensitivity to levofloxacin, ofloxacin or any excipients of this product

2. Patients with epilepsy

3. Patients with history of tendon disorder related to fluoroquinolones administration

4. Children or adolescents below the age of 16 years

5. Pregnant women or women suspected of being pregnant

6. Breast-feeding women

・Blood and lymphatic system disorders

Uncommon: anemia

Very rare: thrombocytopenia*

Unknown: pancytopenia*, agranulocytosis*, hemolytic anemia with hemoglobinuria*

・Immune system disorder

Unknown: anaphylactoid reaction*

・Metabolism and nutrition disorder

Uncommon: anorexia

Unknown: hypoglycemia (hypoglycaemic coma may occur)*, hyperglycemia

・Psychiatric disorders

Common: sleep loss

Unknown: psychiatric symptoms such as confusion*, delirium*, depression*, hallucination

・Nervous system disorders

Common: dizziness, headache

Uncommon: somnolence, numbness, tremor, mental dullness, dysgeusia

Rare: consciousness disturbed

Very rare: convulsion*, ageusia

Unknown: peripheral nerve disorder, extrapyramidal disorder, anosmia, parosmia

・Eye disorders

Rare: abnormal vision

・Ear and labyrinth disorders

Uncommon: tinnitus

Unknown: hearing losses

・Cardiac disorders

Uncommon: palpitations

Unknown: ventricular tachycardia (including Torsades de pointes)*, QT prolonged*, tachycardia

・Vascular disorders

Very rare: shock*

Unknown: hypotension

・Respiratory, thoracic and mediastinal disorders

Uncommon: dry throat

Unknown: interstitial pneumonia*, eosinophilic pneumonia*

・Gastrointestinal disorders

Common: nausea, vomiting, diarrhea, abdominal discomfort

Uncommon: abdominal pain dyspepsia, abdominal distension, constipation

Rare: stomatitis

Very rare: glossitis

Unknown: colitis with bloody stool, such as pseudomembranous colitis*

・Hepatobiliary disorders

Uncommon: hepatic function abnormal

Unknown: hepatitis fulminant*, Jaundice*

・Skin and subcutaneous tissue disorders

Uncommon: pruritus, rash

Rare: hyperhidrosis. urticaria

Very rare: photosensitivity

Unknown: toxic epidermal necrolysis (TEN)*, Oculomucocutaneous syndrome (Stevens-Johnson syndrome)*, hypersensitivity vasculitis*

・Musculoskeletal and connective tissue disorders

Uncommon: arthralgia, pain in extremity, back pain, weakness

Rare: arthropathy, myalgia

Unknown: rhabdomyolysis*, tendon disorders such as Achilles tendonitis or tendon rupture*, exacerbation of myasthenia gravis*, muscle rupture

・Renal and urinary disorders

Uncommon: hematuria

Rare: pollakisuria, oliguria, acute renal failure*

Unknown: interstitial nephritis*, anuria, dysuria, urinary retention

Ÿ General disorders and administration site conditions

Uncommon: thirst, chest discomfort, malaise, feeling hot, edema

Very rare: pyrexia

Unknown: chest pain

Ÿ Investigations

Common: AST increased, ALT increased, LDH increased, white blood cell count decreased, eosinophil count increased

Uncommon: creatinine increased, urinary protein positive, alkaline phosphatase increased, gamma-GTP increased, blood bilirubin increased, lymphocyte count decreased, neutrophil count decreased, CPK increased, glucose urine present, blood glucose decreased, platelet count decreased

Rare: BUN increased, urine output decreased

Very rare: blood glucose increased

See the package insert about the details below:

1. Antacid, Sucralfate, Metal Cations, Multivitamins

2. Theophylline, Fenbufen, or similar NSAIDs (phenylacetic acid/propionic acid derivatives)

3. Antidiabetic agents

4. Anticoagulant drug (warfarin and its derivatives)

5. ClassⅠA antiarrhythmics and ClassⅢantiarrhythmics

See the package insert about the details:

Contraindicated

This tablet should be administered with caution in the following patients:

1. Patients with impaired renal function

2. Patients exposed to direct sunlight

3. Patients with known or suspected CNS disorder that may predispose to seizures or lower the seizure threshold

4. Diabetic patients receiving concomitant treatment with an oral hypoglycemic agent (especially, sulfonylureas or with insulin preparations)

5. Patients with a history of hypersensitivity to quinolone antibiotics

6. Patients with serious heart diseases e.g. arrhythmia and ischemic heart disease. [QT prolonged may occur] patients with uncorrected electrolyte imbalance (e.g. hypokalemia, hypomagnesemia) and patients receiving Class ⅠA and Ⅲantiarrhythmic agents

7. Patients with myasthenia gravis [symptoms may be exacerbated]

WARNINGS

1. Levofloxacin is more soluble than other quinolones, adequate hydration of patients receiving levofloxacin should be maintained to prevent the formation of highly concentrated urine.

2. Acute renal failure or interstitial nephritis

3. Excessive exposure to sunlight should be avoided. However, phototoxicity has been observed very rare; incidence <0.01%. Therapy should be discontinued if phototoxicity (e.g. a skin eruption) occurs.

4. Dysglycemia: During post-marketing surveillance, hypoglycemia and hyperglycemia have been reported in patients taking levofloxacin. Serious symptoms such as hypoglycemic coma have been reported in patients receiving levofloxacin. Hypoglycemia may be prone to develop in patients with diabetes mellitus (especially, those receiving sulfonylureas or insulin preparations), patients with impaired renal function and elderly patients.

5. Serious colitis with bloody stool, such as pseudomembranous colitis

6. Rhabdomyolysis characterized by myalgia. weakness, elevated CK(PCK) and increased myoglobin in plasma and urine, etc., and accompanied with acute exacerbation of renal function

7. Tendon disorder such as Achilles tendonitis or tendon rupture: If symptoms such as pain and edema in the peritendinous region are observed, treatment with levofloxacin should be discontinued immediately and appropriate therapeutic measures taken. The risk of tendonitis and tendon rupture is increased in those over age 60, in those on concomitant corticosteroid therapy, and transplant recipients.

8. Levofloxacin may inhibit the growth of Mycobacterium tuberculosis, and therefore, may give false-negative results in the bacteriological diagnosis of tuberculosis.

9. Some undesirable effects may impair the patient’s ability to concentration and react and therefore may constitute a risk in situation where these abilities are of special importance (e.g. driving a car or operating machinery).

10. Shock or anaphylactoid reaction (initial symptoms: erythema, rigor, dyspnea, etc)

11. Toxic epidermal necrolysis (TEN) or Oculomucocutaneous syndrome (Stevens-Johnson syndrome)

12. Convulsion

13. QT prolonged and ventricular tachycardia (including Torsades de pointes): During post-marketing surveillance, prolonged QT which may sometimes lead to the occurrence of ventricular tachycardia including torsades de pointes have been reported spontaneously in patients taking levofloxacin. The risk of the events may be increased in patients with serious heart diseases (e.g. arrhythmia and ischemic heart disease), patients with uncorrected hypokalemia, patents receiving ClassⅠA (quinidine sulfate, procainamide hydrochloride) and ClassⅢ(amiodarone hydrochloride, sotalol hydrochloride) antiarrhythmic agents and in elderly patients

14. Hepatitis fulminant, hepatic function disorder or jaundice (initial symptoms: nausea, vomiting, anorexia, malaise, pruritus, etc.)

15. Pancytopenia, agranulocytosis (initial symptoms: pyrexia, pharynx pain, malaise, etc.), hemolytic anemia with hemoglobinuria or thrombocytopenia

16. Interstitial pneumonia or eosinophilic pneumonia accompanied with pyrexia, cough, dyspnea, abnormal chest X-ray, or eosinophilia, etc.

17. Psychiatric symptoms such as confusion,, delirium and depression.

18. Hypersensitivity vasculitis: If symptoms such as pyrexia, abdominal pain, arthralgia, purpura or maculopapules, and skin biopsy evidence of leukocytoclastic vasculitis are observed, treatment with levofloxacin should be discontinued immediately and appropriate therapeutic measures taken.

19. Exacerbation of myasthenia gravis.

20. Patients received Levofloxacin dose of 750mg may develop some adverse reaction such as dizziness, headache, nausea or vomiting more than Levofloxacin dose of 500mg.

Levofloxacin is the -isomer of the racemate, ofloxacin, a quinolone antimicrobial agent. The antibacterial activity of ofloxacin resides primarily in the L-isomer. It is two folds stronger than that of ofloxacin.

The mechanism of action of levofloxacin and other fluoroquinolone antimicrobials involve inhibition of bacterial topoisomeraseⅣand DNA gyrase (both of which are typeⅡtopoisomerases), enzymes required for DNA replication, transcription, repair and recombination.

Levofloxacin has in vitro activity against a wide range of gram-negative and gram-positive microorganisms. Levofloxacin is often bactericidal at concentrations equal to or slightly greater than inhibitory concentrations.

Fluoroquinolones, including levofloxacin, differ in chemical structure and mode of action from aminoglycosides, macrolides and beta-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. Although cross-resistance has been observed between levofloxacin and some other fluoroquinolones, some microorganisms resistant to other fluoroquinolones may be susceptible to levofloxacin.

Levofloxacin has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section:

Aerobic gram-positive microorganisms

Enterococcus faecalis, Staphylococcus aureus, Staphylococcus saprophyticus, Streptococcus pneumoniae (including penicillin-resistant strains), Streptococcus pyogenes

Aerobic gram-negative microorganisms

Enterobacter cloacae, Escherichia coli, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Legionella pneumophila, Moraxella catarrhalis, Proteus mirabillis, Pseudomonas aeruginosa

Other microorganisms

Chlamydia pneumoniae, Mycoplasma pneumoniae

The following in vitro data are available, but their clinical significance is unknown.

Aerobic gram-positive microorganisms

Staphylococcus epidermidis, Streptococcus (Group C/F), Streptococcus (Group G), Streptococcus agalactiae, Streptococcus milleri, Viridans group streptococci

Aerobic gram-negative microorganisms

Acinetobacter baumannii, Acinetobacter lwoffii, Bordetella pertussis, Citrobacter (diversus) koseri, Citrobacter freundii, Enterobacter aerogenes, Enterobacter sakazakii, Klebsiella oxytoca, Morganella morganii, Pantoea (Enterobacter) agglomerans, Proteus vulgaris, Providencia rettgeri, Providencia stuartii, Pseudomonas fluorescens, Serratia marcescens

Anaerobic gram-positive microorganisms

Clostridium perfringens