APPROVED BY

Order of the Ministry of Health of Ukraine

   18.05.2016    №  453

Registration certificate

№ UA/13203/01/01

INSTRUCTION

for medical use of the preparation

LEVASEPT

Composition:

Active substance: levofloxacin;

100 ml of solution contains 500 mg of levofloxacin as levofloxacin hemihydrate;

Excipients: anhydrous glucose, concentrated hydrochloric acid, sodium hydroxide, water for Injections.

Pharmaceutical form. Solution for infusion.

Basic physical and chemical properties: clear solution greenish-yellow color.

Pharmacotherapeutic group.

Quinolone antibacterials – Fluoroquinolones.       

ATC Code: J01MA12.

Pharmacological properties.

Pharmacodynamics.

Levofloxacin is a broad-spectrum antibiotic from the group of quinolone. Levofloxacin, like other fluorinated quinolones, blocks bacterial DNA gyrase, due to that bacterial DNA function is damaged. Levofloxacin is active against gram-positive and gram-negative microorganisms, including strains resistant to penicillins, cephalosporins, and / or aminoglycosides. The development of resistance may significantly effect on the drug sensitivity of the local strains; therefore, this information should be considered when the drug is prescribed, especially in treating severe infections. Levofloxacin has a broad-spectrum against microorganisms both in vitro, and in vivo: Enterococcus faecalis, Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Viridans group streptococci, Enterobacter cloacae, Enterobacter aerogenes, Enterobacter agglomerans, Enterobacter sakazakii, Escherichia coli, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Klebsiella oxytoca, Legionella pneumonia, Moraxella catarrhalis, Proteus mirabilis, Pseudomonas aeruginosa, Pseudomonas fluorescens, Chlamydophila pneumoniae, Mycoplasma pneumoniae, Acinetobacter anitratus, Acinetobacter baumannii, Acinetobacter calcoaceticus, Bordetella pertussis, Citrobacter diversus, Citrobacter freundii, Morganella morganii, Proteus vulgaris, Providencia rettgeri et stuartii, Serratia marcescens, Clostridium perfringens.

Like other fluoroquinolones, levofloxacin is inactive for spirochetes.

Pharmacokinetics.

There is no significant difference in the pharmacokinetics of levofloxacin following intravenous and oral administration.

Absorption. Orally administered levofloxacin is rapidly and almost completely absorbed. A peak plasma concentration is observed in 1 hour after intake. The absolute bioavailability is almost 100%. Levofloxacin is subject to linear pharmacokinetics in the range of 50-600 mg. Food has little effect on the absorption of levofloxacin.

Distribution.

Approximately 30 - 40 % of levofloxacin is bound to serum protein. Cumulative effect of levofloxacin is almost absent in the dose of 500 mg once a day. There is a little but predictable cumulation in the dose of 500 mg twice a day. Stable indicators of distribution are reached within 3 days.

- Distribution into tissues and body fluids. Distribution into bronchial mucosa and secretions of the bronchial epithelium. In the dose above 500 mg per os the maximum levofloxacin concentrations in bronchial mucosa and secretions bronchial epithelium were 8.3 and 10.8 mg / ml, respectively.

- Distribution into lung tissue. In the dose above 500 mg per os the maximum levofloxacin concentrations in lung tissue was approximately 11.3 mg/ml and it is achieved within 4-6 hours after administration. Concentration in the lungs exceeded concentration in plasma, consistently.

- Distribution into cerebrospinal fluid. Levofloxacin gets bad into the cerebrospinal fluid.

- Distribution into prostatic tissue. After oral levofloxacin 500 mg once a day for 3 days, the average concentrations in prostatic tissue were 8.7 mg/g, 8.2 mg/g and 2 mg/g after 2, 6 and 24 hours respectively; the average ratio of concentrations in the prostate/plasma - 1.84.

Concentrations in urine. After a single dose of 150 mg, 300 mg or 500 mg per os the average concentrations of levofloxacin for 8-12 hours were 44 mg/mL, 91 mg/mL and 200 mg/mL, respectively.

Metabolism. Levofloxacin is metabolized in a very low degree. The metabolites are dysmetyl-levofloxacin and levofloxacin N-oxide. These metabolites make less than 5% of the amount of drug excreted in the urine.

Elimination. Following oral and intravenous administration, levofloxacin is eliminated relatively slowly from the plasma (partial ejection is 6-8 hours). Excretion is primarily by the renal route (> 85 % of the administered dose).

Clinical particulars.

Indications.

Bacterial inflammations caused by bacteria sensitive to drug:

1) Pneumonia;

2) Pyelonephritis and complicated urinary tract infections;

3) Complicated skin and soft tissue infections;

4) Chronic bacterial prostatitis.

Contraindications.

Hypersensitive to levofloxacin, to any other fluoroquinolones or to any of the excipients.

Epilepsy. Patients with history of tendon disorders related to quinolones administration.

Interaction with other medicinal products and other forms of interaction.

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 had a statistically significant effect on the elimination of levofloxacin. The renal clearance of levofloxacin was reduced by cimetidine (24%) and probenecid (34%). Caution should be exercised when levofloxacin is coadministered with drugs that effect the tubular renal secretion such as probenecid and cimetidine, especially in renally impaired patients.

Ciclosporin: The half-life of ciclosporin was increased by 33% when coadministered with levofloxacin.

Vitamin K antagonists: as a result of the possible occurrence of bleeding in patients treated with levofloxacin in combination with any of the vitamin K antagonist (e.g. warfarin), coagulation indicators of tests should be monitored when these drugs are used simultaneously.

as a result of the possible occurrence of bleeding in patients taking levofloxacin in combination with any of the vitamin K antagonist (e.g. warfarin), coagulation indicators of tests should be monitored when these drugs are used simultaneously.

Levofloxacin pharmacokinetics has not changed during the concomitant introduction along with such drugs: calcium carbonate, digoxin, glibenclamide, ranitidine and warfarin.

Drugs known to prolong QT interval

Levofloxacin, like other fluoroquinolones, should be used with caution in patients receiving drugs known to prolong the QT interval (e.g. Class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics).

Theophylline.

Levofloxacin does not effect on the pharmacokinetics of theophylline, which is predominantly metabolized by means of CYP1A2, so we can assume that levofloxacin is not CYP1A2 inhibitor.

Glucocorticoids.

Concomitant administration of glucocorticoids increases the risk of tendon rupture.

Other.

There is no clinically significant effect on the pharmacokinetics of levofloxacin when it used along with drugs: calcium carbonate, digoxin, glibenclamide and ranitidine.

Levofloxacin is not recommended with alcohol.

Excipients.

The drug contains 5 g of glucose per dose (vial 100 ml). Therefore, the drug should be used with caution in patients with diabetes.

Precautions for use.

Patients with severe cerebral atherosclerosis, cerebrovascular accident should be careful when using the drug. In the case of side effects, especially the adverse reaction of the central nervous system and allergic reactions that may occur after the first administration of the drug, the use of levofloxacin should be discontinued.

Regarding ofloxacin it is known that during infusion tachycardia and a temporary increase in blood pressure may occur. As a result, in rare cases, the sudden decrease in blood pressure and circulatory collapse may occur. If a pronounced decrease in blood pressure is observed during the administration of levofloxacin (ofloxacin S-isomer), administration should be stopped immediately.

In patients treated with vitamin K antagonists, the coagulation parameters in concomitant use of levofloxacin and vitamin K antagonists (warfarin) should be monitored due to increase of the risk of blood coagulation (prothrombin time / INR) and/or bleeding.

Patients with severe renal failure, as well as severe cerebral atherosclerosis and stroke should be careful when using the drug.

Throughout the course of treatment the function of kidney and liver should be monitored.

During the course of treatment you should refrain from drinking alcohol.

In very severe pneumonia caused by pneumococcus, levofloxacin cannot give an optimal therapeutic effect.

In nosocomial infections caused by Ps. Aeruginosa, and in severe cases of pneumococcal pneumonia, a combination therapy may be required.

Tendinitis and tendon rupture.

Tendinitis may rarely occur. It most frequently involves the Achilles tendon and may lead to tendon rupture. The risk of tendinitis and tendon rupture is increased in elderly patients and in patients using corticosteroids. Close monitoring of these patients is therefore necessary if they are prescribed levofloxacin. All patients should consult their physician if they experience symptoms of tendinitis. If tendinitis is suspected, treatment with levofloxacin must be discontinued 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 levofloxacin, (including several weeks after treatment) may be symptomatic of Clostridium difficile-associated disease (CDAD). CDAD may range in severity from mild to life threatening, the most severe form of which is pseudomembranous colitis. If CDAD is suspected or confirmed, levofloxacin should be stopped immediately and appropriate treatment initiated without delay.Anti-peristaltic medicinal products are contraindicated in this clinical situation.

Patients predisposed to seizures.

Levofloxacin is contraindicated in patients with a history of epilepsy and, as with other quinolones, should be used with extreme caution in patients predisposed to seizures.

Concomitant treatment with fenbufen and similar nonsteroidal anti-inflammatory drugs (NSAIDs) or drugs that decrease cerebral convulsive threshold, such as theophylline, also requires caution. 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. In such cases Levofloxacin should be used with caution.

Prevention of photosensitisation.

Although in the use of levofloxacin, photosensitisation  is very rare, patients should avoid UV exposure to prevent photosensitivity.

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.

In the event that the patient develops these reactions, levofloxacin should be discontinued. Caution is recommended if levofloxacin is to be used in psychotic patients or in patients with history of psychiatric disease.

Patients with renal failure.

Since levofloxacin is excreted mainly by the kidneys, so the dose of medicinal product should be adjusted in patients with renal (see section «Way of administration and dosage»).

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.

Severe bullous reactions.

Cases of severe bullous skin reactions, such as Stevens-Johnson syndrome or toxic epidermal necrolysis have been reported with Levofloxacin. In case of bullous reaction the use of levofloxacin should be discontinued immediately, the patients should contact their physician who will initiate appropriate treatment.

Dysglycaemia.

As with all quinolones, disturbances in blood glucose, including both hypoglycaemia and hyperglycaemia have been reported , usually in diabetic patients receiving concomitant treatment with an oral hypoglycaemic agent (e.g., glibenclamide) or with insulin. Cases of hypoglycaemic coma have been reported. In diabetic patients, careful monitoring of blood glucose is recommended.

QT interval prolongation.

During the use of fluoroquinolones the cases of QT prolongation have been reported. Caution should be taken when using fluoroquinolones, including levofloxacin, in patients with known risk factors for prolongation of the QT interval such as:

 - congenital or acquired 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 and antipsychotics);

 - uncorrected electrolyte imbalance (e.g. hypokalaemia, hypomagnesaemia);

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

- elderly patients and women may be more sensitive to QT-prolonging medications.

Therefore, caution should be taken when using fluoroquiolones, including levofloxacin, in these populations.

Peripheral neuropathy.

Peripheral sensory neuropathy and peripheral motor sensory neuropathy have been reported in patients receiving fluoroquinolones, including levofloxacin. Levofloxacin should be discontinued if the patient experiences symptoms of neuropathy in order to prevent the development of an irreversible condition.

Opiates.

In patients treated with levofloxacin, determination of opiates in urine may give false-positive results. It could be necessary to confirm positive results for opiates by means of more specific methods.

Hepatobiliary disorders.

Cases of hepatic necrosis up to fatal hepatic failure have been reported with levofloxacin, primarily in patients with severe underlying diseases, e.g. sepsis (see section «Adverse reactions»). 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.

Pregnancy and lactation.

In the absence of research data and suggested risk of damage by quinolones to an articular cartilage of the growing organism, levofloxacin is contraindicated during pregnancy and lactation. If a pregnancy has come during the treatment period you should consult your doctor.

Effects on ability to drive and use machines.

In some patients the drug can cause headache, dizziness / vertigo, drowsiness, insomnia, blurred vision, confusion, hearing impairment, movement disorders, so you should refrain from driving or operating complex mechanisms requiring attention and psychomotor reactions.

Way of administration and dosage.

Before starting the treatment, it is necessary to make a sensitivity test.

Levofloxacin solution is administered by slow intravenous infusion once or twice daily. The dosage depends in the type and severity of the infection and the susceptibility of the presumed causative pathogen. Usually after several days of treatment if the patient's condition is good, you can transfer him from original intravenous introduction to oral intake (tablets Levofloxacin 250 mg or 500 mg). The duration of treatment depends on course of disease and should be not more than 14 days. The introduction of the drug should be continued for at least 48-72 hours after the disappearance of clinical signs of disease. Levofloxacin, solution for infusion is designed only for slow intravenous introduction and it should be used 1-2 times a day. The introduction time should be at least 30 minutes for a dose of 250 mg or less than 60 minutes for a dose of 500 mg.

Dosage in patients with normal renal function (i.e. CL_CR ≥ 50 ml/min)

Indication	Daily dose regimen
Community-acquired pneumonia	500 mg, once or twice a day, 7-14 days
Complicated urinary tract infections, including pyelonephritis	500 mg, once a day, 7-10 days
Chronic bacterial prostatitis	500 mg, once a day, 28 days
Complicated skin and soft tissue infections	500 mg, once or twice a day, 7-14 days

 

Since levofloxacin is excreted primarily by the kidneys, in patients with impaired kidney function the dose can be reduced.

Dosage in patients with impaired renal function (creatinine clearance < 50 ml/min)

Creatinine clearance	Dose regimen (depending on the severity of infection)
50-20 ml/min	first dose: 250 mg, then: 125 mg /24 h	first dose: 500 mg, then: 250 mg /24 h	first dose: 500 mg, then: 250 mg /12 h
19-10 ml/min	first dose: 250 mg, then: 125 mg /48 h	first dose: 500 mg, then: 125 mg /24 h	first dose: 500 mg, then: 125 mg /12 h
< 10 ml/min (including haemodialysis and CAPD 1)	first dose: 250 mg, then: 125 mg /48 h	first dose: 500 mg, then: 125 mg /24 h	first dose: 500 mg, then: 125 mg /24 h

¹ No additional doses are required after haemodialysis or continuous ambulatory peritoneal dialysis (CAPD).

No adjustment of dose is required since levofloxacin is not metabolised to any relevant extent by the liver and is mainly excreted by the kidneys.

No adjustment of dose is required in the elderly patients with normal renal function.

Levofloxacin is administered slowly and intravenously by drip infusion. The infusion time of one vial (100 ml solution for i.v. introduction from 500 mg of levofloxacin) should be at least 60 minutes for 250 mg, the recommended rate of introduction for solution for infusion for 250 mg - 30 minutes.

According to the patient’s condition in a few days it is possible to transfer him from intravenous introduction to oral intake of the same dose.

The duration of treatment depends on the disease. As with other antibacterial drugs, drug treatment is recommended to continue for at least 48-72 hours after normalization of body temperature or confirmed microbiological tests regarding the pathogens’ destruction.

Mixing with other infusion solutions:

Levofloxacin is compatible with the following solutions for infusion:

- 0.9% sodium chloride;

- 5% glucose monohydrate;

- 2.5% glucose in Ringer's solution;

- composite solutions for parenteral nutrition (amino acids, carbohydrates, electrolytes).

In sequential infusions of levofloxacin and other drugs, they cannot be introduced into the same vein.

After opening a vial the remained drug must be utilized.

Children.

Do not use because of suggested damage of the articular cartilage.

Overdose.

Symptoms: confusion, dizziness, tremors, impaired consciousness and seizures, QT prolongation or other sings of adverse reactions.

Treatment: symptomatic and supportive.  ECG monitoring should be undertaken, because of the possibility of QT prolongation. Haemodialysis, including peritoneal dialysis and CAPD, are not effective in elimination levofloxacin from the body. No specific antidote exists.

Adverse reactions.

Infections and infestations: Fungal infection including Candida infection, Pathogen resistance.

Allergic reactions: uncommon – redness of the skin, itching, rash; rare – urticaria, bronchospasm / dyspnea; very rare - angioneurotic edema, hypotension, anaphylactic shock, photosensitivity; in rare cases - severe bullous rash, including Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), exudative erythema multiforme, angioedema; hypersensitivity reactions, anaphylactic and anaphylactoid reactions, hyperhidrosis, leukoplakic vasculitis, skin and mucous reactions and stomatitis.

Such reactions may occur after the first dose and within a few minutes or hours after administration.

Gastro-intestinal/metabolism disorders: common - nausea, diarrhea; uncommon - anorexia, vomiting, abdominal pain, dyspepsia, indigestion, bloating; constipation; pancreatitis; rare - diarrhea mixed with blood, which in rare cases may indicate enterocolitis, including pseudomembranous colitis; very rare - hypoglycemia, which is particularly important for patients with diabetes mellitus, hyperglycemia and hypoglycemic coma.

Signs of hypoglycemia may be increased appetite, nervousness, sweating and tremor.

Nervous system disorders: uncommon – headache, dizziness / vertigo, drowsiness, insomnia; rare - paresthesia, tremor, confusion, seizures, anxiety, nervousness, concern, depression, psychotic reactions with self-destructive behavior, including suicidal tendencies; agitation; very rare - hypoesthesia, ageusia, anosmia (disturbances of taste and smell perception), psychotic disorder (including hallucinations and paranoia), anxiety, fear state, benign intracranial hypertension, syncope, dyskinesia, sensory or sensomotor peripheral neuropathy.

Cardiac disorders: rare - tachycardia; ventricular tachycardia, which can lead to heart failure; ventricular fibrillation and torsade de pointes type arrhythmia (predominantly in patients with risk factors for QT prolongation); hypotension; very rare - anaphylactic shock; in rare cases – QT prolongation; collapse; vasculitis; phlebitis and palpitation.

Musculoskeletal and connective tissue disorders: rare - arthralgia, myalgia, tendon injuries including tendonitis (e.g. Achilles tendon); very rare - tendon rupture (e.g. Achilles, the painful reaction can occur within 48 hours of treatment); bilateral muscle weakness, particularly dangerous for patients with malignant myasthenia; in rare cases - rhabdomyolysis (muscle destruction); rupture of ligaments, muscles; arthritis.

Renal and liver disorders: common – increase of liver enzymes (e.g. ALT / AST); rare - increased bilirubin, increased serum creatinine; very rare - liver responses, such as hepatitis; acute renal failure (e.g. due to interstitial nephritis).

Blood and the lymphatic system disorders: uncommon – eosinophilia, leucopenia; rare - neutropenia, thrombocytopenia, which may cause a predisposition to bleeding or hemorrhages; very rare - agranulocytosis; in rare cases - hemolytic anemia and pancytopenia.

Eye disorders: visual disturbances, blurred vision and temporary loss of vision.

Ear and Labyrinth disorders: vertigo, tinnitus, hearing loss, hearing impairment.

Respiratory, thoracic and mediastinal disorders: dyspnea, bronchospasm and allergic pneumonitis.

Other: common – pain, redness at the site’s injection and phlebitis; uncommon - fatigue, candidiasis, excessive multiplication of other resistant organisms; very rare - allergic pneumonitis, fever.

Other adverse reactions which have been associated with fluoroquinolone administration include: extrapyramidal symptoms and other disorders of the musculoskeletal system, allergic vasculitis, porphyria attack in patients with porphyria.

Shelf life.

2 years.

Storage conditions.

Keep out of the reach of children.

Store in the original package at temperature not exceeding 25 °С.

Unused drug should be removed.

Incompatibility.

Levofloxacin should not be mixed with heparin or solutions with an alkaline reaction (e.g. sodium bicarbonate), with other medicines, except medicines listed in the section «Way of administration and Dosage».

Package.

In 100 ml in containers. Each container in PVC film along with the text instruction in a box.

Terms of dispensing. On prescription.

Manufacturer.

Eurolife Healthcare Pvt. Ltd.

Manufacturer’s registered address.

Khasra № 520, Bhagwanpur, Roorkee, Haridwar, India.

Applicant.

Ananta Medicare Ltd.

Applicant’s registered address.

Suite 1, 2 Station Court, Imperial Wharf, Townmead Road, Fulham, SW6 2PY, London, United Kingdom.

Date of last update. 18.05.2016