Levocin-N

LEVOCIN-N

Solution for infusion 100 ml of the solution contains 500 mg of levofloxacin.100 and 150 ml in the bottle; 1 bottle per folding box.

The product demonstraters a wide anti-bacterial effect.

Marketing Authorization No. UA/12842/01/01

Composition

Active ingredient: levofloxacin;

100 ml of the solution contains 500 mg of levofloxacin;

Excipients: sodium chloride, hydrochloric acid dilute or sodium hydroxide, water for injections.

Pharmaceutical form

Solution for infusion.

Pharmacotherapeutic group

Anti-bacterial products of quinolone group.Fluroquinolones.

ATC code J01M А12.

Indications

Levocin-N for intravenous administration is prescribed for adult patients in order to treat bacterial inflammation processes caused by levofloxacin-sensitive bacteria: pneumonia, complicated infections of urinary tracts (including pyelonephritis), skin and soft tissue infections, chronical bacterial prostatitis.

Contraindications

Hypersensitivity to levofloxacin or other quinolones, epilepsy, complaints about tendon adverse reactions after usage of quinolones.

Pharmacological properties

Pharmacodynamics.

The product demonstraters a wide anti-bacterial effect. It is highly-active towards anaerobic gram-negative and gram-positive bacteria, including nonenzymatic bacteria, atypical microorganisms and anaerobic organisms.

The following organisms are sensitive to Levocin-N.

Strains which are usually sensitive to the product:

Aerobic gram-positive bacteria

Staphylococcuss aureus* methicillinsensitive, Staphylococcus saprophyticus, Streptococci, С and G groups, Streptococcus agalactiae, Streptococcus pneumoniae*, Streptococcus pyogenes*;

Aerobic gram-negative bacteria

Burkholderia cepacia**, Eikenella corrodens, Haemophilus influenzae*, Haemophilus para- influenzae*, Klebsiella oxytoca, Klebsiella pneumoniae*, Moraxella catarrhalis*, Pasteurella multocida, Proteus vulgaris, Providencia rettgeri;

Anaerobic bacteria

Peptostreptococcus;

Other

Chlamydophila pneumoniae*, Chlamydophila psittaci, Chlamidia trachomatis, Legionella pneumophila*, Mycoplasma pneumoniae*, Mycoplasma hominis, Ureaplasma urealyticum.

Strains which can have problematic acquired (secondary) resistance:

Aerobic gram-positive bacteria

Enterococcus faecalis*, Staphylococcus aureus метицилінрезистентний, Staphylococcus coagulase spp.;

Aerobic gram-negative bacteria

Acinetobacter baumannii*, Citrobacter freundii*, Enterobacter aerogenes, Enterobacter agglomerans, Enterobacter cloacae*, Escherichia coli*, Morganella morganii*, Proteus mirabilis*, Providencia stuartii, Pseudomonas aeruginosa*, Serratia marcescens*;

Anaerobic bacteria

Bacteroides fragilis, Bacteroides ovatus**, Bacteroides thetaiotamicron**, Bacteroides vulgatus,**

Clostridium difficile**.

* Clinical efficiency was demonstrated for sensitive isolates in the approved clinical data.

** Natural intermediate sensitivity.

Other data

Hospital infections caused by P. Aeruginosa may require  a combined therapy.

Like other fluroquinolones, levofloxacin has zero activity towards spirochaetales.

The product activity is determined by inhibition of bacteria DNA-gyrase (inhibition of cell division) which leads to its death.

Pharmacokynetics.

There is no significant difference between intravenous and peroral application of levofloxacin in terms of its pharmacokinetic characteristics.

When administered peorally, the product is accumulated in bronchial mucosa and bronchial mucus in pulmonary tissue (concentration in lungs is higher that in plasma) and urea. Levofloxacin hardly penetrates into spinal fluid.

Distribution. Almost 30-40 % of levofloxacin binds with serum protein. When used in therapeutic doses, cumulative effect is almost absent.

Metabolism. Levofloxacin is very slightly metabolized.  Dismethyl-levofloxacin and levofloxacin N-oxide act as the metabolites. These metabolites make less than 5%of the product being cleared with urea.

Clearance. Upon intravenous administration, levofloxacin is slowly cleared from plasma (half-life period is 6 - 8 hours), mainly through kidneys (over 85 %of the dose injected).

Special group of patients

Patients having renal failure

Levofloxacin pharmacokinetics can be affected by kidney failure. When kidney functions are decreased, renal excretion and clearance are decreased as well. Half-life periods are increased, as shown in the table below.

Creatinine clearance (ml/min) < 20 20-40 50-80
Renal clearance (ml/min) 13 26 57
Half-life period (hours) 35 27 9

Elderly patients

There is no significant difference between elderly and young patients in terms of levofloxacin pharmacokinetic characteristics, except for the differences related to creatinine clearance.

Gender

A separate analysis among male and female patients demonstrates slight differences in terms of levofloxacin pharmacokinetics. There is no evidence that these gender differences have any clinical significance.

Interaction with other medicinal products and other forms of interaction

Impact of other medicines on levofloxacin.

Theophylline, fenbufen or similar non-steroid anti-inflammation medicines

No pharmacokinetic interaction between levofloxacin and theophylline was found. However, there may be significant decrease of convulsive threshold during simultaneous intake of quinolones with theophylline, non-steroid and anti-inflammatory medicines and other agents that can lower convulsive threshold. Levofloxacin concentration in presence of fenbufen was 13% higher than during the intake of levofloxacin only.

Probenecid and cimetidine

Probenecid and cimetidine have statistically significant influence on levofloxacin clearance. Renal clearance is reduced in presence of cimetidine by 24% and in presence of probenecid by 34%. This is because both products can inhibit tubular secretion of levofloxacin. However, at the doses tested during the trials it is not probable that statistically significant kinetic differences have clinical importance. Care should be exercised in simultaneous intake of levofloxacin with the medicines which influence on tubular secretion, such as probenecid and cimetidine, especially among the patients having renal failure.

Other

Pharmacological clinical trials show that there is no significant influence on levofloxacin pharmacokinetics during the intake of levofloxacin along with the following products: calcium carbonate, digoxin, glibenclamidum and ranitidine.

Impact of levofloxacin on other medicinal products

Cyclosporin

Half-life of cyclosporin increases by  33 % during simultaneous intake with levofloxacin.

Vitamin K antagonists

During simultaneous intake of levofloxacin with vitamin K antagonists (for example, warfarin), it was reported about increase of coagulation tests (IF/INR) and/or haemorrhages, which may be apparent. Taking the above fact into account, the patients who intake vitamin K antagonist at the same time, should have their coagulation data momnitored (see “Precautions for use”).

Medicinal products which extend QT interval

As other quinolones, levofloxacin should be administered with due care among the patiens who are also treated with the medicines which can extend QT interval (for example, antiarrhythmic products IA and II class, tricyclic antidepressants and macrolides) (see section “Precautions for use”) (QT interval extension). The product is compatible with 0.9% sodium chloride solution, 5 % glucose solution, 2.5% Ringer and glucose solution, combined solutions for parenteral use (amino-acids, carbohydrates, electrolytes).

Precautions for use

Levofloxacin may not demonstrate its optimal therapeutic effect if patient suffers from severe pneumonia caused by Streptococcus pneumoniae.

There is no need in dose adjustment for the patients having liver dysfunction, since levofloxacin metabolizes in liver in a minor way.

If elderly patient has no renal dysfunction, the product dose may not be adjusted.

Hospital infections caused by P. Aeruginosa may require a combined therapy.

Administration time

Recommended administration time should be not less than 60 minutes for 500 mg of levofloxacin solution for infusion.

Regarding ofloxacin, it is known that tachycardia and temporary hypertension may occur during infusion procedure. In rare cases sudden low pressure and circulatory collapse may happen. If apparent low pressure is present during levofloxacin administration (ofloxacin l-isomer), discontinue the use of the product.

Tendinitis and tendon rupture

Sometimes tendinitis is likely to happen. Mostly is affects achilles tendon and may lead to tendon rupture. Elderly patients and patients who take corticosteroids have increased risk of tendinitis and tendon rupture. Hence, their condition should be carefully monitored, when levofloxacin is prescribed. If tendinitis symptoms appear, consult with your physician. When tendinitis is suspected, discontinue the use of levofloxacin and start the relevant therapy (for example, tendon immobilization).

Diseases caused by Clostridium difficile

Diarrhea, especially severe one, persistent and/or  hemorrhagic, which was caused either during or after treatment with levofloxacin, can be a symptom of the disease caused by Clostridium difficile, where the most severe form is pseudomembranous colitis. If pseudomembranous colitis is suspected, immediately discontinue the infusion of levofloxacin and obtain the treatment with the relevant supportive medicines ± specific therapy (for example, oral administration of vancomycin). Medicines which decrease the gastric motility are not indicated for use in this clinical situation.

Patients prone to convulsions

Levofloxacin is contraindicated for the patients having epilepsy in their medical history, since as any other quinolones the product should be administered with due care among the patients which are prone to convulsions, such as the patients having nervous system impairment, during simultaneous therapy with fenbufen and other similar anti-inflammation producs or products which can increase convulsive readiness (reduce convulsion threshold), for example, theophyllin (see section “Interaction with other medicinal products and other forms of interaction”). Should convulsions appear, discontinue the use of levofloxacin.

Patients having glucose-6-phosphate dehydrogenase deficit

Patients having latent or apparent defects of glucose-6-phosphate dehydrogenase activity may be prone to hemolytic reactions during their treatment with quinolone antibacterial medicines. Hence, levofloxacin should be administered with due attention among this group of patients.

Patients having renal diseases

Since levofloxacin is cleared mostly renally, the dose for the patients having decreased renal function (renal failure) must be adjusted accordingly (see section “Posology and method of administration”).

Hypersensitivity reactions

Upon initial dose, levofloxacin may cause from time to time the serious potential fatal hypersentivity reactions (for example, angioedema which may lead to anaphylactic shock ) (see section “Adverse reactions”). In this case, discontinue the use of levofloxacin and obtain an immediate medical treatment.

Hypoglycemia

As for any other quinolones, it was reported about hypoglycemia, especially among the patients who suffer from diabetes and who had  concomitant treatment with oral hypoglycemic medicines (for example, glibenclamide) or insulin. Patients having diabetes should be carefully monitored regarding their glucose level in blood (see section “Adverse reactions”).

Photoallergy  prevention

Although photoallergy is rarely to occur during levofloxacin intake, for its prevention patients should avoid exposure to the strong sunlight or UV-light (for example, UV-lamps, indoor tanning).

Patients who took vitamin K antagonists

Due to the possible increase of coagulation index (IF/INR) and/or haemorrhages, the patients who intake vitamin K antagonist at the same time with levofloxacin should have their coagulation data monitored (see “Interaction with other medicinal products and other forms of interaction”).

Psychotic reactions

It was reported about psychotic reactions among the patients who took quinolones, including levofloxacin. In some very rare cases it led to suicidal ideation and self-harm, sometimes even after the first dose of levofloxacin (see section “Adverse reactions”). Should patient have the above reactions, discontinue the usage of levofloxacin and take the relevant measures. Levofloxacin should be administered with due care among the patients having psychotic disorders or mental disturbance in their past medical history.

QT interval extension

Fluorquinolones, including levofloxacin, should be administered with due attention among the patients having well-known risk factors of QT interval extension, for example, congenital  long QT interval syndrome;

– concomitant intake of medicines which are known to extend QT interval (for example, antiarrhythmic products of IA and III class, tricyclic antidepressants, macrolides);

– non-adjusted electrolytic disbalance (for example, hypokalemia, hypomagnesaemia);

– elderly patients;

– cardiac diseases (for example, cardiac failure, myocardial infarction, bradycardia) (see sections “Posology and method of administration”, “Interaction with other medicinal products and other forms of interaction”, “Adverse reactions”, “Overdose”).

Peripheric neuropathy

It was reported about sensory and sensomotor neuropathy, which can occur fast, among the patients who took fluorquinolones, including levofloxacin. If patient has neuropathy symptoms, discontinue the use of levofloxacin in order to avoid irreversible state.

Opiates

The patients who took levofloxacin may have fake positive opiate test. There may be a need to confirm the opiate test with the help of  more specific methods.

Hepatobiliary disorders

It was reported about hepatic necrosis during levofloxacin intake, even to life-threatening hepatic failure, among the patients having severe main diseases, for example, sepsis (see section Adverse reactions”). If such hepatic diseases, as anorexia, jaundice, black urea, itching or stomachache occur, patients should discontinue the usage of levofloxacin and consult with their physician.

Preganncy and lactation.

Since there is no studies and due to the possible damage of the developing articular cartilage by quinolones, levofloxacin is not recommended for pregnant or lactating women. If pregnancy is diagnosed in the course of treatment with levofloxacin, a physician must be informed accordingly.

Effects on ability to drive and use machines.

Patients who drive vehicles, work with machines and mechanisms must take into account all nervous system adverse reactions (dizziness, numbing, drowsiness, convoluted thinking, vision defects and impaired hearing, movement disorder, including difficulties with walking).

Posology and method of administration

Skin tolerance test should be performed before use of the product.

Levocin-N for infusion should be used immediately after perforation of rubber seal in the bottle (within 3 hours) in order to avoid any kind of bacterial contamination. No light protection is required during infusion.

The dose is determined by infection type and its degree of severity and sensitivity of a microorganism to the product as well. Internal administration in the same dosage  is possible several days after.

For treatment of adult patients with the normal renal function, whose creatinine clearance is 50 ml/minute, the following doses are usually recommended:

Indications Daily dose Number of administrations per day
Non-hospital pneumonia 500 mg 1-2
Complicated urinary tract infections, including  pyelonephritis 250 mg* 1
Chronical bacterial prostatitis 500 mg** 1
Skin and soft tissue infections 500 mg 1-2

* In case of severe infection, the feasibility of dose increase should be taken into account (only for infusion solutions)

** Based on patient’s condition, intravenous injection may be replaced with peroral administration with the same dose several days after.

Since levofloxacin is cleared mostly in renal way, the patients having weak renal function should receive a decreased product dose.

Dosage for adult patients having renal dysfunction whose creatinine clearance is less than 50 ml/minute:

Creatinine clearance Dosage (depends on infection severity and nosological entity)
50-20  ml/minute 250 mg/24 h 500 mg/24 h 500 mg/12 h
First dose - 250 mg,

next doses -

125 mg/24 h

First dose - 500 mg,

next doses -

250 mg/24 h

First dose - 500 mg,

next doses -

250 mg/12 h

19-10  ml/minute First dose - 250 mg,

next doses -

125 mg/48 h

First dose - 500 mg,

next doses -

125 mg/24 h

First dose - 500 mg,

next doses -

125 mg/12 h

<10 ml/minute(also during hemodialysis and CAPD1)

 

First dose - 250 mg,

next doses -

125 mg/48 h

First dose - 500 mg,

next doses -

125 mg/24 h

First dose - 500 mg,

next doses-

125 mg/24 h

1 no additional  doses are required after hemodialysis and CAPD.

Dosage for the patients having liver dysfunction. No dose adjustment is required, since levofloxacin  metabolizes in liver in a minor way.

Dosage for elderly patients. If patient has no liver dysfunction, no dose adjustment is required.

Solution is administered intravenously and slowly by dropwise infusion. Administration time for one bottle (100 ml of the solution for intravenous administration having 500 mg of levofloxacin) should be not less than 60 minutes.

Treatment duration depends on patient’s clinical state and should not be more than 14 days..

Children.

The product is not for pediatric use.

Overdose

Symptoms

The most critical unforeseen overdose symptoms deal with the central nervous system. It  was reported about long QT interval caused by product overdose.

Treatment

Apply symptomatic treatment. If overdose occurs, the patient’s state  should be carefully monitored (including ECG). Hemodialysis, including peritoneal dialysis or APP, is not efficient for levofloxacin clearance. No specific antidotes are known.

Adverse reactions

The following adverse reactions are classified according to MedDRA:

Infections and invasions

Mycoses (and proliferation of other resistant microorganisms).

Blood and lymphatic system

Leucopenia, eosinophilia, thrombocytopenia, neutropenia, agranulocytosis, pancytopenia, hemolytic anemia

Immune system disorders

Anaphylaxis reactions, including anaphylactic shock (see section “Precautions for use”), may occur even after the first dose; hypersensitivity (see section “Precautions for use”).

Metabolic disorders

Anorexia, hypoglycemia, especially among the patients suffering from diabetes (see section “Precautions for use”).

Mental disorders

Insomnia, nervousness, psychotic disorders, depression, convoluted thinking, anxiety, agitation, frustration, psychotic reactions accompanied by destructive behavior which includes sucidial thinking or actions (see section “Precautions for use”), hallucinations.

Neurological disorders

Dizziness, headache, drowsiness, convulsions, tremor, paresthesia, sensor or sensor-motor peripheric neuropathy, dysgeusia (subjective hypogeusia), including ageusia (taste-blindness), parosmia (smell defects), including anosmia (smell-blindness).

Visions disorders

Vision defects

Hearing and vestibular apparatus

Hearing impairment, vertigo, tingling.

Cardiac and vascular disorders

Tachycardia, arterial hypotension, QT interval extension on the ECG (see section “Precautions for use” (QT interval extension) and “Overdose”).

Vascular disorders

Arterial hypotension.

Respiratory, thoracic and mediastinum disorders

Bronchial spasm, dyspnea, allergic pneumonitis.

Gastro-intestinal disorders

Nausea, vomit, stomachache, dyspepsia, bloating, constipation, diarrhea (including hemorrhagic, which sometimes may be a symptom of enterocolitis, including pseudomembranous one).

Hepatobiliary system disorders

Increase of liver enzymes index (ALT/AST, alkaline phosphatase, GGT), increase of bilirubin level in blood, hepatitis. It was reported about jaundice and severe hepatic injury during levofloxacin intake, including acute hepatic failure mostly among the patients having severe primary diseases (see section “Precautions for use”).

Skin and subcutaneous tissue

Rash, itching, urticarial, angioedema, hypersensitivity to sun- and UV light, toxic epidermal necrolysis (Lyell's syndrome), Stevens-Johnson syndrome, exudative erythema multiforme, hyperhidrosis, possible dermal and mucosa reactions even after the first dose.

Muscular and skeletal system disorders, connective tissue disorders

Tendon damage (see section “Precautions for use”), including inflammation (tendinitis) (for example, Achilles tendon), arthralgia,  myalgia, tendon rupture (see section “Precautions for use”). This adverse reaction may occur within 48 hours from the beginning of treatment and affect Achilles tendom on both legs. Possible muscle weakness which can be critical for patients having severe myasthenia, muscle disorders (rhabdomyolysis).

Urinary system disorders

Increased creatinine index in blood serum, acute renal failure, for example, increased creatinine in blood serum, acute renal failure (for example, resulting from interstitial nephritis).

General disorders

Asthenia, pyrexia, ache  (including backache, chest pain, melalgia).

Among the other adverse reactions associated with fluorquinolone, are seen the following ones:

- extrapyramidal symptoms and other motor dysfunction;

- hypersensitive vasculitis;

- porphyria attacks among the patients suffering from porphyria.

In case of improper use, administration or storage, vein irritation may occur, which in its turn may result in phlebitis, venous thrombosis in the area of administration.

Shelf life

2 years.

Shelf life after the first opening of a bottle

Levocin-N for infusion should be used immediately after perforation of rubber seal in the bottle (within 3 hours) in order to avoid any kind of bacterial contamination. No light protection is required during infusion.

Unused bottle content should be disposed, it shall not be stored for its further use.

Storage conditions

Store in original package at the temperature not above 25 °С. Do not freeze. Keep away from children.

Incompatibility

When administered, the product should not be mixed with other injection solutions.

Packaging

100 and 150 ml in the bottle; 1 bottle per folding box.

Prescription category

Following the doctor’s prescription.

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Materials on the medicine

No materials available.

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