COMPOSITION:

Each film coated tablet contains:

Levofloxacin hemihydrate equivalent to Levofloxacin 250/500/750 mg

Other inactive ingredients:

Microcrystalline cellulose, povidone, crospovidone, colloidal silicon dioxide, magnesium stearate, opadry pink 03B84681, isopropyl alcohol, purified water.

DESCRIPTION: Pink colored film coated capsule shaped tablet with 250/500/750 engraved on one side & other side plain.

INDICATIONS:

In adults with infections of mild or moderate severity, Tigeron tablets are indicated for the treatment of the following infections when due to levofloxacin-susceptible microorganisms:

Acute bacterial sinusitis (adequately diagnosed according to national and/or local guidelines on the treatment of respiratory tract infections)

 Acute bacterial exacerbations of chronic bronchitis (adequately diagnosed according to national and/or local guidelines on the treatment of respiratory tract infections)

 Community-acquired pneumonia

 Uncomplicated urinary tract infections

 Complicated urinary tract infections including pyelonephritis

 Chronic bacterial prostatitis.

 Skin and soft tissue infections.

Before prescribing Tigeron, consideration should be given to national and/or local guidance on the appropriate use of fluoroquinolones.

RECOMMENDED DOSE:

Recommended doses for adult patients with normal kidney function with creatinine clearance more than 50 ml/min

Dosage for patients with kidney function disorders and creatinine clearance less than 50 ml/min:

* In combination with an antibiotic with anaerobic coverage.1After hemodialysis or chronic ambulatory peritoneal dialysis (CAPD) additional doses are not required.Dosage for patients with liver function disorders: Dosage adjustment is not necessary because levofloxacin is insignificantly metabolised in liver.

UNDESIRABLE EFFECTS:

The information given below is based on data from clinical studies in more than 5000 patients and on extensive post marketing experience.

The adverse reactions are described according to the MedDRA system organ class below.

Frequencies are defined using the following convention: very common (1/10), common (1/100, <1/10), uncommon (1/1000, 1/100), rare (1/10000, 1/1000), very rare (1/10000), not known (cannot be estimated from the available data).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Infections and infestations

Uncommon:

Fungal infection (and proliferation of other resistant microorganisms)




Blood and lymphatic system disordersUncommon:

Leukopenia, eosinophilia

Rare:

Thrombocytopenia, neutropenia

Very rare:

Agranulocytosis

Not Known: Pancytopenia, haemolytic anaemia.

Immune system disorders

Very rare: Anaphylactic shock

Anaphylactic and anaphylactoid reactions may sometimes occur even after the first dose.

Not known:

Hypersensitivity

Metabolism and nutrition disorders

Uncommon:

Anorexia

Very rare:

Hypoglycemia, particularly in diabetic patients.

Psychiatric disorders

Uncommon:

Insomnia, nervousness

Rare:

Psychotic disorder, Depression, confusional state, agitation, anxiety

Very rare:

Psychotic reactions with self-endangering behaviour including suicidal ideation or acts , hallucination.

Nervous system disorders

Uncommon:

Dizziness, headache, somnolence

Rare: Convulsion, tremor, paraesthesia,

Very rare:

Sensory or sensorimotor peripheral neuropathy, dysgeusia including ageusia, parosmia including anosmia.

Cardiac disorders

Rare:

Tachycardia

Not Known:

Electrocardiogram QT prolonged.

Vascular disorders

Rare:

Hypotension

Respiratory, thoracic and mediastinal disorders

Rare:

Bronchospasm, dyspnoea

Very rare:

Pneumonitis allergic

Gastrointestinal disorders

Common:

Diarrhoea, nausea

Uncommon:

Vomiting, abdominal pain, dyspepsia, flatulence, constipation.

Rare:

Diarrhoea haemorrhagic which in very rare cases may be indicative of enterocolitis, including pseudomembranous colitis

Hepatobiliary disorders

Common:

Hepatic enzyme increased (ALT/AST, alkaline phosphatase, GGT).

Uncommon: Blood bilirubin increased

Very rare:

Hepatitis

Not known:

Jaundice and severe liver injury, including cases with acute liver failure, have been reported with levofloxacin, primarily in patients with severe underlying diseases

Skin and subcutaneous tissue disorders

Uncommon:

Rash, pruritus

Rare:

Urticaria

Very rare:

Angioneurotic oedema, photosensitivity reaction

Not Known:

Toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, hyperhidrosis Mucocutaneous reactions may sometimes occur even after the first dose.

Musculoskeletal and Connective tissue disorders


Rare: Tendon disorder including tendinitis (e.g. Achilles tendon), arthralgia, myalgia.

Very rare:

Tendon rupture. This undesirable effect may occur within 48 hours of starting treatment and may be bilateral, muscular weakness which may be of special importance in patients with myasthenia gravis.

Not Known:

Rhabdomyolysis

Renal and urinary disorders

Uncommon:

Blood creatinine increased

Very rare:

Renal failure acute (e.g. due to nephritis interstitial).

INTERACTION WITH OTHER MEDICAMENTS: Iron salts, magnesium- or aluminium-containing antacids

Levofloxacin absorption is significantly reduced when iron salts, or magnesium- or aluminium-containing antacids are administered concomitantly with Tigeron tablets. It is recommended that preparations containing divalent or trivalent cations such as iron salts, or magnesium- or aluminium-containing antacids should not be taken 2 hours before or after Tigeron tablet administration. No interaction was found with calcium carbonate.

Sucralfate

The bioavailability of Tigeron tablets is significantly reduced when administered together with sucralfate. If the patient is to receive both sucralfate and Tigeron, it is best to administer sucralfate 2 hours after the Tigeron tablet administration.

Theophylline, fenbufen or similar non-steroidal anti-inflammatory drugs

No pharmacokinetic interactions of levofloxacin were found with theophylline in a clinical study. However a pronounced lowering of the cerebral seizure threshold may occur when quinolones are given concurrently with theophylline, non-steroidal anti-inflammatory drugs, or other agents which lower the seizure threshold.

Levofloxacin concentrations were about 13% higher in the presence of fenbufen than when administered alone.

Probenecid and cimetidine

Probenecid and cimetidine had a statistically significant effect on the elimination of levofloxacin. The renal clearance of levofloxacin was reduced by cimetidine (24%) and probenecid (34%). This is because both drugs are capable of blocking the renal tubular secretion of levofloxacin. However, at the tested doses in the study, the statistically significant kinetic differences are unlikely to be of clinical relevance.

Caution should be exercised when levofloxacin is coadministered with drugs that affect the tubular renal secretion such as probenecid and cimetidine, especially in renally impaired patients.

Other relevant information:

Clinical pharmacology studies have shown that the pharmacokinetics of levofloxacin were not affected to any clinically relevant extent when levofloxacin was administered together with the following drugs: calcium carbonate, digoxin, glibenclamide, ranitidine.

WARNINGS AND PRECAUTIONS:

In the most severe cases of pneumococcal pneumonia Tigeron may not be the optimal therapy. Nosocomial infections due to P. aeruginosa may require combination therapy.

Tendinitis and tendon rupture

Tendinitis may rarely occur. It most frequently involves the Achilles tendon and may lead to tendon rupture.Close monitoring of these patients is therefore necessary if they are prescribed Tigeron. All patients should consult their physician if they experience symptoms of tendinitis. If tendinitis is suspected, treatment with Tigeron must be halted immediately, and appropriate treatment (e.g. immobilisation) must be initiated for the affected tendon.

Clostridium difficile-associated disease

Diarrhoea, particularly if severe, persistent and/or bloody, during or after treatment with Tigeron tablets, may be symptomatic of Clostridium difficile-associated disease, the most severe form of which is pseudomembranous colitis. If pseudomembranous colitis is suspected, Tigeron tablets must be stopped immediately and patients should be treated with supportive measures

± specific therapy without delay (e.g. oral vancomycin).

Patients predisposed to seizures

Tigeron tablets are contraindicated in patients with a history of epilepsy and, as with other quinolones, should be used with extreme caution in patients predisposed to seizures, such as patients with pre-existing central nervous system lesions, concomitant treatment with fenbufen and similar non-steroidal anti-inflammatory drugs or with drugs which lower the cerebral seizure threshold, such as theophylline.In case of convulsive seizures, treatment with levofloxacin should be discontinued.

Patients with G-6- phosphate dehydrogenase deficiency

Patients with latent or actual defects in glucose-6-phosphate dehydrogenase activity may be prone to haemolytic reactions when treated with quinolone antibacterial agents, and so levofloxacin should be used with caution.

Patients with renal impairment

Since levofloxacin is excreted mainly by the kidneys, the dose of Tigeron should be adjusted in patients with renal impairment.

Hypersensitivity reactions

Levofloxacin can cause serious, potentially fatal hypersensitivity reactions (e.g. angioedema up to anaphylactic shock), occasionally following the initial dose. Patients should discontinue treatment immediately and contact their physician or an emergency physician, who will initiate appropriate emergency measures.

Hypoglycemia

As with all quinolones, hypoglycemia has been reported, usually in diabetic patients receiving concomitant treatment with an oral hypoglycemic agent (e.g., glibenclamide) or with insulin. In these diabetic patients, careful monitoring of blood glucose is recommended.

Prevention of photosensitisation

Although photosensitisation is very rare with levofloxacin, patients should not expose themselves unnecessarily to strong sunlight or to artificial UV rays in order to prevent photosensitisation.

Patients treated with Vitamin K antagonists

Due to possible increase in coagulation tests (PT/INR) and/or bleeding in patients treated with Tigeron in combination with a vitamin K antagonist (e.g. warfarin), coagulation tests should be monitored when these drugs are given concomittantly .

Psychotic reactions

Psychotic reactions have been reported in patients receiving quinolones, including levofloxacin. In very rare cases these have progressed to suicidal thoughts and self-endangering behaviour- sometimes after only a single dose of levofloxacin .

QT interval prolongation

Caution should be taken when using fluoroquinolones, including levofloxacin, in patients with known risk factors for prolongation of the QT interval such as, for example:

 congenital long QT syndrome

 concomitant use of drugs that are known to prolong the QT interval (e.g. Class IA and III antiarrhythmics, tricyclic antidepressants, macrolides).

 uncorrected electrolyte imbalance (e.g. hypokalemia, hypomagnesemia)

 elderly

 cardiac disease (e.g. heart failure, myocardial infarction, bradycardia)

Peripheral neuropathy

Sensory or sensorimotor peripheral neuropathy has been reported in patients receiving fluoroquinolones, including levofloxacin, which can be rapid in its onset.

Opiates

In patients treated with levofloxacin, determination of opiates in urine may give false-positive results. It may be necessary to confirm positive opiate screens by more specific method.

Hepatobiliary disorders

Cases of hepatic necrosis up to life threatening hepatic failure have been reported with levofloxacin, primarily in patients with severe underlying diseases, e.g. sepsis. Patients should be advised to stop treatment and contact their doctor if signs and symptoms of hepatic disease develop such as anorexia, jaundice, dark urine, pruritus or tender abdomen.

OVERDOSE AND TREATMENT:

According to toxicity studies in animals or clinical pharmacology studies performed with supra-therapeutic doses, the most important signs to be expected following acute over dosage of Tigeron tablets are central nervous system symptoms such as confusion, dizziness, impairment of consciousness, and convulsive seizures, increases in QT interval as well as gastro-intestinal reactions such as nausea and mucosal erosions.

In the event of overdose, symptomatic treatment should be implemented. ECG monitoring should be undertaken, because of the possibility of QT interval prolongation. Antacids may be used for protection of gastric mucosa. Haemodialysis, including peritoneal dialysis and CAPD, are not effective in removing levofloxacin from the body. No specific antidote exists.

CONTRAINDICATIONS:

Tigeron tablets must not be used in:

 patients hypersensitive to levofloxacin or other quinolones or any of the excipients,

 patients with epilepsy,

 patients with history of tendon disorders related to fluoroquinolone administration,

 children or growing adolescents,

 during pregnancy,

 breast-feeding women.

PHARMACODYNAMICS:

Pharmacotherapeutic group:

Quinolone antibacterials, fluoroquinolones.

ATC code: J01MA12

Levofloxacin is a synthetic antibacterial agent of the fluoroquinolone class and is the S (-) enantiomer of the racemic drug substance ofloxacin.

Mechanism of action

As a fluoroquinolone antibacterial agent, levofloxacin acts on the DNA-DNA-gyrase complex and topoisomerase IV.

PK/PD relationship

The degree of the bactericidal activity of levofloxacin depends on the ratio of the maximum concentration in serum (Cmax) or the area under the curve (AUC) and the minimal inhibitory concentration (MIC).

Mechanism of resistance

The main mechanism of resistance is due to a gyr-A mutation. In vitro there is a cross-resistance between levofloxacin and other fluoroquinolones. Due to the mechanism of action, there is generally no cross-resistance between levofloxacin and other classes of antibacterial agents.

Antibacterial spectrum

The prevalence of resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.

Commonly susceptible species

Aerobic Gram-positive bacteria

Staphylococcus aureus methicillin-susceptible, Staphylococcus saprophyticus,Streptococci, group C and G, Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes.

Aerobic Gram- negative bacteria

Burkholderia cepacia, Eikenella, Haemophilus influenzae, Haemophilus para-influenzae, Klebsiella pneumoniae, Moraxella, Pasteurella multocida, Proteus vulgaris, Providencia rettgeri.

Anaerobic bacteria: Peptostreptococcus.

Others: Chlamydophila pneumoniae, Chlamydophila psittaci, Chlamydia trachomatis, Legionella pneumophila, Mycoplasma pneumoniae, Mycoplasma hominis, Ureaplasma urealyticum.

Species for which acquired resistance may be a problem

Aerobic Gram-positive bacteria

Enterococcus faecalis, Staphylococcus aureus methicillin-resistant, Staphylococcus coagulase spp.

Aerobic Gram- negative bacteria

Acinetobacter baumannii, Citrobacter freundii, Enterobacter, Escherichia coli, Morganella morganii, Proteus mirabilis, Providencia stuartii, Pseudomonas aeruginosa, Serratia marcescens.

Anaerobic bacteria

Bacteroides fragilis, Bacteroides ovatus, Bacteroides thetaiotaomicron, Bacteroides vulgatus, Clostridium difficile.

PHARMACOKINETICS:

Absorption

Orally administered levofloxacin is rapidly and almost completely absorbed with peak plasma concentrations being obtained within 1h. The absolute bioavailability is approximately 100%. Food has little effect on the absorption of levofloxacin.

Distribution

Approximately 30-40% of levofloxacin is bound to serum protein. 500 mg once daily multiple dosing with levofloxacin showed negligible accumulation. There is modest but predictable accumulation of levofloxacin after doses of 500 mg twice daily. Steady-state is achieved within 3 days.

Penetration into Bronchial Mucosa, Epithelial Lining Fluid (ELF)

Maximum levofloxacin concentrations in bronchial mucosa and epithelial lining fluid after 500 mg p.o. were 8.3 μg/g and 10.8 μg/ml respectively. These were reached approximately one hour after administration.

Penetration into Lung Tissue

Maximum levofloxacin concentrations in lung tissue after 500 mg p.o. were approximately 11.3 μg/g and were reached between 4 and 6 hours after administration. The concentrations in the lungs consistently exceeded those in plasma.

Penetration into Cerebro-Spinal Fluid

Levofloxacin has poor penetration into cerebro-spinal fluid.

Penetration into prostatic tissue

After administration of oral 500mg levofloxacin once a day for three days, the mean concentrations in prostatic tissue were 8.7 µg/g, 8.2 µg/g and 2.0 µg/g respectively after 2 hours, 6 hours and 24 hours; the mean prostate/plasma concentration ratio was 1.84.

Biotransformation

Levofloxacin is metabolised to a very small extent, the metabolites being desmethyl-levofloxacin and levofloxacin N-oxide. These metabolites account for < 5% of the dose excreted in urine. Levofloxacin is stereochemically stable and does not undergo chiral inversion.

Elimination

Following oral and intravenous administration of levofloxacin, it is eliminated relatively slowly from the plasma (t½: 6 – 8 h). Excretion is primarily by the renal route (> 85 % of the administered dose).

There are no major differences in the pharmacokinetics of levofloxacin following intravenous and oral administration, suggesting that the oral and intravenous routes are interchangeable.

STORAGE CONDITION:

Store below 30°C.

Keep all medicines out of reach of children.

SHELF-LIFE:

36 months

DOSAGE FORMS AND PACKAGING AVAILABLE:

5 tablets are in a PVC/PVDC/Alu blister, 1 or 10 blisters are in a carton box. 10 tablets are in a PVC/PVDC/Alu blister, 10 blisters are in a carton box.

NAME AND ADDRESS OF MANUFACTURER:

Kusum Healthcare Pvt. Ltd.

SP 289(A), RIICO Indl. Area,

Chopanki, Bhiwadi (Rajasthan), India

DATE OF REVISION OF PACKAGE INSERT: Not Applicable

Tigeron 250 mg- MM Reg. No.: 1804AA 6065

Tigeron 500 mg- MM Reg. No.: 1709AA 4703

Tigeron 750 mg- MM Reg. No.: 1709AA 4702