Levofloxacin-Vertex, 500 mg 10 pcs

Pharmacotherapeutic group

Antimicrobial agent – fluoroquinolone

ATX code

J01MA

Pharmacodynamics:

Levofloxacin is a synthetic broad-spectrum antibacterial agent of the fluoroquinolone group, the left-handed isomer ofloxacin. Levofloxacin blocks DNA-Giase and topoisomerase IV disrupts superspiralization and cross-linking of DNA breaks inhibits DNA synthesis and causes deep morphological changes in cytoplasm of cell wall and bacterial membranes.

Levofloxacin is active against most strains of microorganisms both in vitro and in vivo.

In vitro:

Sensitive microorganisms (minimum suppressive concentration (MDC) ≤ 2 mg/L; zone of inhibition ≥17 mm)

Aerobic Gram-positive microorganisms: Bacillus anthracis Corynebacterium diphtheriae Corynebacterium jeikeium Enterococcus faecalis Enterococcus spp. Listeria monocytogenes Staphylococcus coagulase-negative methi-S(I) (coagulase-negative methicillin-sensitive/moderately sensitive strains) Staphylococcus aureus methi-S (methicillin-sensitive strains) Staphylococcus epidermidis methi-S (methicillin-sensitive strains) Staphylococcus spp. CNS (coagulazonegative); Streptococcus spp. groups C and G Streptococcus agalactiae Streptococcus pneumoniae peni I/S/R (penicillin-sensitive/moderately sensitive/resistant strains) Streptococcus pyogenes Viridans streptococci peni-S/R (penicillin-sensitive/resistant strains).

Aerobic Gram-negative microorganisms: Acinetobacter baumannii Acinetobacter spp. Actinobacillus actinomycetemcomitans Citrobacter freundii Eikenella corrodens Enterobacter aerogenes Enterobacter cloacae Enterobacter spp. Escherichia coli Gardnerella vaginalis Haemophilus ducreyi Haemophilus influenzae ampi-S/R (ampicillin sensitive/resistant strains) Haemophilus parainfluenzae Helicobacter pylori Klebsiella oxytoca Klebsiella pneumoniae Klebsiella spp. Moraxella catarrhalis P+/(3- (beta-lactamase producing and non-producing strains) Morganella morganii Neisseria gonorrhoeae non PPNG/PPNG (penicillinase producing and non-producing strains) Neisseria meningitidis Pasteurella canis Pasteurella dagmatis Pasteurella multocida Pasteurella spp. Proteus mirabilis Proteus vulgaris Providencia rettgeri Providencia stuartii Providencia spp. Pseudomonas aeruginosa (hospital infections caused by Pseudomonas aeruginosa may require combined treatment) Pseudomonas spp. Serratia spp. Serratia marcescens Salmonella spp.

Anaerobic microorganisms: Bacteroides fragilis Bifidobacterium spp. Clostridium perfringens Fusobacterium spp. Peptostreptococcus spp. Propionibacterium spp. Veillonella spp.

Other microorganisms: Bartonella spp. Chlamydia pneumoniae Chlamydia psittaci Chlamydia trachomatis Legionella pneumophila Legionella spp. Mycobacterium spp. Mycobacterium leprae Mycobacterium tuberculosis Mycoplasma hominis Mycoplasma pneumoniae Rickettsia spp. Ureaplasma urealyticum.

Moderately sensitive microorganisms (MPC = 4 mg/L; inhibition zone 16-14 mm)

Aerobic Gram-positive microorganisms: Corynebacterium urealyticum Corynebacterium xerosis Enterococcus faecium Staphylococcus epidermidis methi-R (Methicillin-resistant strains) Staphylococcus haemolyticus methi-R (Methicillin-resistant strains).

Aerobic Gram-negative microorganisms: Campylobacter jejuni Campylobacter coli.

Anaerobic microorganisms: Prevotella spp. Porphyromonas spp.

Resistant microorganisms (MPC ≥8 mg/L; inhibition zone ≤ 13 mm)

Aerobic Gram-positive microorganisms: Staphylococcus aureus methi-R (methicillin-resistant strains) Staphylococcus coagulase-negative methi-R (coagulase-negative methicillin-resistant strains).

Aerobic Gram-negative microorganisms: Alcaligenes xylosoxidans.

Other microorganisms: Mycobacterium avium.

Resistance

Resistance to levofloxacin develops as a result of a stepwise process of mutations in the genes encoding both tin II topoisomerases: DNA-Gyrase and topoisomerase IV. Other mechanisms of resistance such as the mechanism of influence on the penetration barriers of the microbial cell (mechanism typical for Pseudomonas aeruginosa) and mechanism of efflux (active elimination of antimicrobial agent from the microbial cell) can also decrease the sensitivity of microorganisms to levofloxacin.

In view of the specific mechanism of action of levofloxacin there is usually no cross-resistance between levofloxacin and other antimicrobial agents.

Clinical efficacy (effectiveness in clinical studies in the treatment of infections caused by the following microorganisms)

Aerobic gram-positive microorganisms: Enterococcus faecalis Staphylococcus aureus Streptococcus pneumoniae Streptococcus pyogenes.

Aerobic Gram-negative microorganisms: Citrobacter Freundii Enterobacter cloacae Escherichia coli Haemophilus influenzae Haemophilus parainfluenzae Klebsiella pneumoniae Moraxella (Branhamella) catarrhalis Morganella morganii Proteus mirabilis Pseudomonas aeruginosa Serratia marcescens.

Other microorganisms: Chlamydia pneumoniae Legionella pneumophila Mycoplasma pneumoniae.

Pharmacokinetics:

Absorption

Levofloxacin is quickly and almost completely absorbed after oral administration. Food intake has little effect on the speed and completeness of absorption. Bioavailability of levofloxacin after oral administration is 99-100%. After a single dose of 500 mg of levofloxacin maximum concentration in plasma is 52 ± 12 mcg/ml time to reach maximum concentration – 13 h. Pharmacokinetics of levofloxacin is linear in dose range from 50 to 1000 mg. The equilibrium state of plasma concentrations of levofloxacin in administration of 500 mg 1 or 2 times per day is reached within 48 hours.

Distribution

The binding to plasma proteins is 30-40%. It penetrates well into organs and tissues: lungs, mucous membrane of bronchi, sputum, genitourinary system organs, bone tissue, cerebrospinal fluid, prostate gland, polymorphonuclear leukocytes, alveolar macrophages. After a single and repeated administration of 500 mg of levofloxacin, the volume of distribution averages 100 l.

Infiltration into the bronchial mucosa fluid epithelial lining alveolar macrophages

. After a single oral administration of 500 mg of levofloxacin, maximum concentrations of levofloxacin in bronchial mucosa and epithelial lining fluid were reached within 1 h or 4 h and were 83 µg/g and 108 µg/mL, respectively, with penetration rates into bronchial mucosa and epithelial lining fluid compared to plasma concentrations of 11-18 and 08-3, respectively.

After 5 days of oral administration of 500 mg of levofloxacin, mean concentrations of levofloxacin 4 hours after the last administration were 994 μg/mL in the epithelial lining fluid and 979 μg/mL in alveolar macrophages.

Penetration and pulmonary tissue

The maximum concentration in pulmonary tissue after oral administration of 500 mg of levofloxacin was approximately 113 µg/g and was reached 4-6 h after drug administration with penetration coefficients of 2-5 compared to plasma concentrations.

Alveolar fluid penetration

After 3 days of administration of 500 mg of levofloxacin once or twice daily, maximum concentrations of levofloxacin in alveolar fluid were reached 2-4 h after drug administration and were 40 and 67 µg/ml respectively with a penetration factor of 1 compared to the plasma concentration.

Bone penetration

Levofloxacin penetrates well into cortical and cancellous bone tissue in both proximal and distal femur with a penetration coefficient (bone tissue/plasma) of 01-3. Maximum concentration of levofloxacin in cancellous bone tissue of proximal femur after oral administration of 500 mg of the drug was approximately 15.1 mcg/g (2 h after drug administration).

Cerebrospinal fluid penetration

Levofloxacin does not readily penetrate into the cerebrospinal fluid.

Permeability to prostate tissue

After oral administration of 500 mg of levofloxacin once daily for 3 days, the average concentration of levofloxacin in prostate tissue was 87 mcg/g and the average prostate/plasma concentration ratio was 184.

Urinary concentrations

The mean urinary concentrations 8-12 hours after oral doses of 150,300 and 600 mg of levofloxacin were 44 µg/ml 91 µg/ml and 162 µg/ml, respectively.

Metabolism

Levofloxacin is metabolized to a small extent (5% of the dose taken). Its metabolites are demethyllevofloxacin and levofloxacin N-oxide which are excreted by the kidneys. Levofloxacin is stereochemically stable and does not undergo chiral conversions.

Elimation

Extracted mainly by the kidneys through glomerular filtration and tubular secretion. The elimination half-life (T1/2) is 6-8 hours. After oral administration, about 85% of the administered dose is excreted by the kidneys within 48 hours. A small part is excreted by the intestine (less than 4% of the taken dose is excreted within 72 hours). Total clearance of levofloxacin after a single dose of 500 mg is 175 ± 292 ml/minute.

There are no significant differences in pharmacokinetics of levofloxacin when administered intravenously and when administered orally, which confirms that intravenous and oral administration are interchangeable.

Pharmacokinetics in selected patient groups

The pharmacokinetics of levofloxacin do not differ in men and women.

Pharmacokinetics in elderly patients does not differ from that in younger patients except for differences in pharmacokinetics associated with differences in creatinine clearance (CK).

In renal failure the pharmacokinetics of levofloxacin changes. As renal function decreases, renal excretion and renal clearance (CIR) decreases and T1/2 increases.

Indications

Inflammation of the female reproductive organs, tonsillitis, skin infections, prostatitis, bronchitis, urinary tract infections, respiratory tract infections, Lung inflammation (pneumonia), Sinusitis

Infectious and inflammatory diseases caused by microorganisms sensitive to levofloxacin:

– acute sinusitis;

– exacerbation of chronic bronchitis;

– community-acquired pneumonia;

– complicated urinary tract infections (including pyelonephritis);

– uncomplicated urinary tract infections;

– Chronic bacterial prostatitis;

– skin and soft tissue infections;

– anthrax with airborne infection (prevention and treatment);

– tuberculosis (complex treatment of drug-resistant forms).

When using the drug Levofloxacin the official national guidelines for the appropriate use of antibacterial agents as well as the sensitivity of the pathogenic microorganisms must be taken into account (see section “Cautions”).

Active ingredient

Levofloxacin

Composition

One film-coated tablet contains:

the active ingredient:

levofloxacin 500 mg (in terms of levofloxacin hemihydrate – 512.46 mg);

excipients: microcrystalline cellulose, 61.66 mg; hypromellose, 17.98 mg; croscarmellose sodium, 18.60 mg; polysorbate 80, 3.10 mg; calcium stearate, 6.20 mg.

The composition of the shell: [hypromellose – 15.00 mg, hyprolose (hydroxypropyl cellulose) – 5.82 mg, talc – 5.78 mg, titanium dioxide – 3.26 mg, iron oxide yellow (iron oxide) – 0.14 mg] or [dry blend for film coating, containing hypromellose – 50.0%, hyprolose (hydroxypropylcellulose) – 19.4%, talc – 19.26%, titanium dioxide – 10.87%, iron oxide yellow (iron oxide) – 0.47%] – 30.0 mg.

How to take, the dosage

The drug is taken orally once or twice a day. Tablets should not be chewed and laced with enough liquid (05 to 1 cup) can be taken before meals or between meals. Doses are determined by the nature and severity of the infection as well as the sensitivity of the suspected pathogen. Taking into account that bioavailability of levofloxacin tablets is 99-100 % if a patient is transferred from intravenous infusion to administration of tablets, the treatment should be continued in the same dose which was used for intravenous infusion (see section “Pharmacological properties”).

Patients with normal or moderately reduced nocicular function (CK more than 50 ml/min) are recommended the following dosing regimen of the drug:

Acute sinusitis: 500 mg once daily for 10-14 days.

The exacerbation of chronic bronchitis: 500 mg once a day – 7-10 days.

Out-of-hospital pneumonia: 500 mg 1 or 2 times a day – 7-14 days.

Uncomplicated urinary tract infections: 250 mg once daily for 3 days. Chronic bacterial prostatitis: 500 mg once a day – 28 days.

Complicated urinary tract infections: 500 mg once daily – 7-14 days. Pyelonephritis: 500 mg once a day – 7-10 days.

Infections of the skin and soft tissues: 500 mg 1-2 times a day for 7-14 days.

Tuberculosis (complex treatment of drug-resistant forms): 500 mg 1 -2 times a day for up to 3 months.

Prevention and treatment of anthrax in case of airborne route of infection: 500 mg once a day for 8 weeks.

Patients with impaired renal function (with CKR less than 50 ml/min) require correction of the dosage regimen.

To maintain the dosing regimen of the drug in a dose of 125 mg it is recommended to use levofloxacin in another dosage form: tablets 250 mg with a rib.

Patients with hepatic impairment

In patients with hepatic impairment no special dosage adjustment is required because levofloxacin is only metabolized to a very minor extent in the liver.

Patients in the elderly

In elderly patients no dosing adjustments are required unless the CK falls to 50 ml/min or lower.

As with other antimicrobials, treatment with Levofloxacin is recommended to continue for at least 48-78 hours after normalization of body temperature or after laboratory-confirmed recovery.

Interaction

Medications containing magnesium aluminum iron and zinc didanosine

Drugs containing bivalent or trivalent cations such as zinc or iron salts (drugs to treat anemia) Drugs containing bivalent or trivalent cations such as zinc or iron salts (drugs to treat anemia) magnesium- and/or aluminum-containing drugs (such as antacids) didanosine (only pharmaceutical forms containing aluminum or magnesium as a buffer) should be taken at least 2 hours before or 2 hours after taking Levofloxacin.

Calcium salts

Calcium salts have minimal effect on the absorption of levofloxacin when taken orally.

Sucralfate

The effect of levofloxacin is significantly impaired when sucralfate (a gastric mucosal protection agent) is used at the same time. It is recommended to take sucralfate 2 hours after taking Levofloxacin.

Theophylline phenbufen or similar drugs from the group of non-steroidal anti-inflammatory drugs (NSAIDs) that lower the seizure threshold of the brain.

Pharmacokinetic interaction of levofloxacin with theophylline has not been identified. However, with concomitant use of quinolones and theophylline NSAIDs and other drugs which decrease cerebral seizure threshold, there may be a marked decrease in cerebral seizure threshold.

The concentration of levofloxacin is increased by only 13% when concomitant administration of phenbufen.

Indirect anticoagulants (vitamin K antagonists)

In patients treated with levofloxacin in combination with indirect anticoagulants (e.g. warfarin) an increase in prothrombin time/international normalized ratio and/or development of bleeding including severe bleeding was observed. Therefore, regular monitoring of blood clotting parameters is necessary when concomitant use of indirect anticoagulants and levofloxacin.

Probenecid and cimetidine

Caution should be exercised when concomitant use of drugs that impair renal tubular secretion such as probenecid and cimetidine and levofloxacin especially in patients with renal insufficiency.

Elevation (renal clearance) of levofloxacin is slowed by 24% by cimetidine and 34% by probenecid. This is unlikely to be clinically relevant in normal renal function.

Cyclosporine

Levofloxacin increased the T1/2 of cyclosporine by 33%. Since this increase is clinically insignificant, no dose adjustment of cyclosporine is required when used concomitantly with levofloxacin.

Glucocorticosteroids

The concomitant use of glucocorticosteroids increases the risk of tendon rupture.

Drugs that prolong the OT interval

Levofloxacin as well as other fluoroquinolones should be used with caution in patients treated with drugs prolonging the QT interval (antiarrhythmic drugs of class IA and III tricyclic and tetracyclic antidepressants neuroleptics macrolides antifungal imidazole derivatives some antihistamines including astemizole terfenadine ebastine).

Other

The clinical and pharmacological studies conducted to investigate possible pharmacokinetic interactions of levofloxacin with digoxin glibenclamide ranitidine and warfarin have shown that the pharmacokinetics of levofloxacin with these drugs does not change enough to be of clinical significance.

Special Instructions

Hospital infections caused by Pseudomonas aeruginosa may require combined treatment.

The prevalence of acquired resistance of bacterial strains can vary by geographic region and over time. Therefore, information on levofloxacin resistance in a particular country is required. For therapy of severe infections or in case of ineffective treatment, a microbiological diagnosis with isolation of the pathogen and determination of its sensitivity to levofloxacin should be established. Staphylococcus aureus (methicillin-resistant strains). There is a high probability that methicillin-resistant Staphylococcus aureus will be resistant to fluoroquinolones including levofloxacin. Therefore, levofloxacin is not recommended for the treatment of established or suspected infections caused by methicillin-resistant Staphylococcus aureus unless laboratory testing has confirmed sensitivity of this microorganism to levofloxacin.

Patients who are predisposed to the development of seizures. Like other quinolones, levofloxacin should be used with great caution in patients with a predisposition to seizures. This includes patients with previous central nervous system injuries such as stroke or severe traumatic brain injury; patients receiving concomitant medications decreasing cerebral threshold of seizures such as phenbufen and other similar NSAIDs or other drugs decreasing seizure threshold such as theophylline (see “Interaction with other medicines”).

Pseudomembranous colitis. Diarrhea developing during or after treatment with levofloxacin especially severe persistent and/or with blood may be a symptom of pseudomembranous colitis caused by Clostridium difficile. If pseudomembranous colitis is suspected, treatment with Levofloxacin should be stopped immediately and specific antibiotic therapy (oral vancomycin teicoplanin or metronidazole) started immediately. Drugs that inhibit intestinal peristalsis are contraindicated.

Tendinitis. Rarely observed tendinitis with quinolones including levofloxacin can lead to tendon rupture including Achilles tendon. This side effect can occur within 48 hours of starting treatment and can be bilateral. Elderly patients are more prone to develop tendonitis. The risk of tendon rupture may increase with concomitant administration of glucocorticosteroids. If tendinitis is suspected, treatment with Levofloxacin should be stopped immediately and appropriate treatment of the affected tendon should be initiated, for example, by providing sufficient immobilization (see “Contraindications” and “Side effects”).

Hypersensitivity reactions. Levofloxacin may cause serious potentially fatal hypersensitivity reactions (angioedema anaphylactic shock) even when using initial doses (see section “Side effects”). Patients should immediately stop taking the drug and consult a physician.

Serious bullous reactions. Cases of severe bullous skin reactions such as Stevens-Johnson syndrome or toxic epidermal necrolysis have been observed while taking levofloxacin (see section “Adverse effects”). In case of any reactions of the skin or mucous membranes, the patient should immediately consult a physician and do not continue treatment until he or she has been consulted.

Liver and biliary tract disorders. Cases of hepatic necrosis have been reported, including the development of fatal hepatic failure when using levofloxacin mainly in patients with severe underlying diseases such as sepsis (see section “Adverse effects”). Patients should be advised to discontinue treatment and seek prompt medical attention if signs and symptoms of liver damage occur, such as anorexia, jaundice, darkened urine, itching and abdominal pain.

Patients with renal insufficiency. Because levofloxacin is excreted mainly through kidneys in patients with impaired renal function it is required obligatory control of renal function as well as adjustment of dosage regimen (see section “Dosage and administration”). When treating elderly patients it should be taken into account that patients of this group often have impaired renal function (see section “Dosage and administration”).

Prevent photosensitization reactions. Although photosensitization by levofloxacin is very rare to prevent its development patients are not recommended during the treatment and within 48 hours after treatment with levofloxacin to be exposed to strong sunlight or artificial ultraviolet radiation without any special need (e.g. to visit a solarium).

Superinfection. As with other antibiotics the use of levofloxacin, especially over a prolonged period of time, may lead to increased proliferation of microorganisms (bacteria and fungi) which are not sensitive to it and which may cause changes in the microflora which is normally present in humans. This can result in superinfection. Therefore it is imperative that the patient’s condition is reevaluated during treatment and appropriate measures are taken if superinfection develops during treatment.

Long QT interval. Very rare cases of QT interval prolongation have been reported in patients taking fluoroquinolones including levofloxacin. Caution should be exercised when using fluoroquinolones including levofloxacin in patients with known risk factors for QT interval prolongation: In patients with uncorrected electrolyte abnormalities (with hypokalemia hypomagnesemia); with congenital QT interval prolongation syndrome; with heart disease (heart failure myocardial infarction bradycardia); concomitant use of drugs that can prolong the QT interval, such as antiarrhythmic drugs of classes IA and III tricyclic and tetracyclic antidepressants neuroleptics macrolides antifungal imidazole derivatives some antihistamines including astemizole terfenadine ebastine. Elderly patients and female patients may be more sensitive to drugs prolonging the QT interval. Therefore, fluoroquinolones including levofloxacin should be used with caution in them (see sections “Caution”, “Side effects” “Interaction with other medicinal products).

Patients with glucose-6-phosphate dehydrogease deficiency. Patients with latent or manifest glucose-6-phosphate dehydrogenase deficiency have a predisposition to hemolytic reactions when treated with quinolones which should be taken into account when treating with levofloxacin.

Hypo- and hyperglycemia (dysglycemia). As with other quinolones during levofloxacin use there have been cases of hyperglycemia and hypoglycemia usually in patients with diabetes mellitus concomitantly treated with oral hypoglycemic agents (for example, glibenclamide) or insulin drugs. Cases of hypoglycemic coma have been reported. In patients with diabetes mellitus, monitoring of blood glucose concentrations is required (see “Side effects”).

Peripheral neuropathy. Patients taking fluoroquinolones including levofloxacin. have reported sensory and sensory-motor peripheral neuropathy, the onset of which may be rapid. If the patient develops symptoms of neuropathy the use of Levofloxacin should be discontinued. This minimizes the possible risk of developing irreversible changes.

The exacerbation of pseudoparalytic myasthenia gravis (myastheniagravis). Fluoroquinolones including levofloxacin are characterized by neuromuscular conduction blocking activity and may exacerbate muscle weakness in patients with pseudoparalytic myasthenia gravis. Adverse reactions, including pulmonary failure requiring artificial ventilation and death, have been observed associated with fluoroquinolone use in patients with pseudoparalytic myasthenia gravis. The use of levofloxacin in patients diagnosed with pseudoparalytic myasthenia gravis is not recommended (see section “Side effects”).

The use in the airborne route of anthrax infection. Levofloxacin usage in humans for this indication is based on the data on Bacillus anthracis sensitivity to it obtained in vitro studies and in experimental studies performed on animals as well as on limited data on levofloxacin usage in humans. Treating physicians should refer to national and/or international documents that represent the consensus view of anthrax treatment.

Psychotic reactions. When using quinolones including levofloxacin the development of psychotic reactions has been reported, which in very rare cases have progressed to the development of suicidal thoughts and self-harm behavior disorders (sometimes after a single dose of levofloxacin) (see section “Adverse effects”). If such reactions develop, treatment with Levofloxacin should be stopped and appropriate therapy should be prescribed. Caution should be exercised when prescribing the drug in patients with psychosis or patients with a history of mental illness.

VIight impairment. If any visual disturbances develop, immediate consultation with an ophthalmologist is necessary (see section “Side effects”).

The effect on laboratory tests. In patients taking levofloxacin, urinary opioid determination may lead to false-positive results which should be confirmed by more specific methods. Levofloxacin may inhibit the growth of Mycobacterium tuberculosis and further lead to false-negative results of bacteriological diagnosis of tuberculosis.

Influence on the ability to drive vehicles and vehicles:

With therapy with levofloxacin it is necessary to refrain from driving vehicles and potentially dangerous activities requiring increased concentration and rapid psychomotor reactions as dizziness, drowsiness and visual disturbances may occur (see section “Adverse effects”).

Contraindications

– Hypersensitivity to levofloxacin or other quinolones as well as to any of the components of the drug;

– epilepsy;

– tendon lesions from previous quinolone treatment;

– pseudoparalytic myasthenia gravis;

– Children and adolescents under 18 years of age (because of incomplete skeletal growth, as the risk of cartilage growth points cannot be completely ruled out);

Pregnancy (we cannot completely rule out the risk of fetal cartilage growth points);

Breastfeeding (we cannot completely rule out the risk of cartilage growth points in the baby).

With caution:

– Predisposition to seizure reactions (cerebral vascular atherosclerosis cerebral circulatory disorders (history) organic diseases of the central nervous system simultaneous use of drugs that reduce the threshold of seizure readiness of the brain such as phenbufen theophylline);

– glucose-6-phosphate dehydrogenase deficiency (increased risk of hemolytic reactions when treated with quinolones);

– renal function disorder (mandatory monitoring of renal function is required and dosage regimen correction see “Dosage method”.

– known risk factors for QT interval prolongation: elderly patients female patients unadjusted electrolyte abnormalities (e.g. hypokalemia hypomagnesemia) congenital QT interval prolongation syndrome heart disease (heart failure myocardial infarction bradycardia) concurrent administration concomitant use of QT prolonging agents (antiarrhythmic agents of class IA and III tricyclic and tetracyclic antidepressants neuroleptics macrolides antifungal imidazole derivatives some antihistamines including astemizole terfenadine ebastine);

– In patients with diabetes receiving oral hypoglycemic medications such as glibenclamide or insulin preparations (increased risk of hypoglycemia);

– Severe adverse reactions to other fluoroquinolones such as severe neurological reactions (increased risk of similar adverse reactions with levofloxacin);

– history of psychosis or other psychiatric disorders;

– hepatic porphyria.

Side effects

Classification of the frequency of side effects according to the recommendations of the World Health Organization (WHO):

very often >1/10;

often from >1/100 to <1/10;

infrequent from > 1/1000 to < 1/100;

rarely from > 1/10000 to < 1/1000;

very rarely < 1/10000 including individual reports;

frequency is unknown – it is not possible to determine the frequency of occurrence from the available data.

Chronic disorders:

rarely – sinus tachycardia palpitations;

frequency unknown – prolonged QT interval ventricular rhythm disturbances ventricular tachycardia pirouette type which can lead to cardiac arrest (See sections “Overdose Sections “Overdose” and “Precautions”).

Disorders of the blood and lymphatic system:

infrequent – leukopenia eosinophilia; rare – neutropenia thrombocytopenia;

frequency unknown – pancytopenia agranulocytosis hemolytic anemia.

Nervous system disorders:

often – headache dizziness;

infrequent – somnolence tremor dysgeusia (perversion of taste);

rarely – paresthesia seizures (see

frequency unknown – peripheral sensory neuropathy peripheral sensorimotor neuropathy dyskinesia extrapyramidal disorders aguesia (loss of taste sensation) parosmia (disorder of smell sensation especially subjective sense of smell objectively absent) including loss of smell fainting benign intracranial hypertension.

Visual disturbances:

very rare – visual disturbances such as blurred visible images;

frequency unknown – transient loss of vision.

Hearing and labyrinth disorders:

infrequent – vertigo (feeling of deviation or spinning or of own body or surrounding objects);

rare – ringing in the ears;

frequency unknown – hearing loss hearing loss.

Respiratory system disorders of the thorax and mediastinum:

infrequent – shortness of breath;

incidence unknown – bronchospasm allergic pneumonitis.

Gastrointestinal disorders:

often – diarrhea vomiting nausea;

infrequent – abdominal pain dyspepsia flatulence constipation;

frequency unknown – hemorrhagic diarrhea which in very rare cases may be a sign of enterocolitis including pseudomembranous colitis) (see section “Special Indications”) pancreatitis.

Repnal and urinary tract disorders:

frequent – increase of creatinine concentration in plasma;

seldom – acute renal failure (for example, due to development of interstitial nephritis).

Skin and subcutaneous tissue disorders:

frequent – rash itching urticaria hyperhidrosis;

frequency unknown – toxic epidermal necrolysis Stevens-Johnson syndrome erythema exudative multiforme photosensitization reactions (see sect. section “Special indications”) leukocytoclastic vasculitis stomatitis.

Some skin and mucous membrane adverse reactions may sometimes develop even after the first dose of the drug.

Muscular and connective tissue disorders:

infrequent – arthralgia myalgia;

rarely – tendon involvement including tendinitis muscle weakness which can be especially dangerous in patients with pseudoparalytic myasthenia gravis (see

Prevalence unknown – rhabdomyolysis tendon rupture (this side effect may occur within 48 hours of treatment start and may be bilateral) ligament tears muscle tears arthritis.

Disorders of metabolism and nutrition:

infrequent – anorexia;

rarely – hypoglycemia especially in patients with diabetes (possible signs of hypoglycemia: “wolf” appetite nervousness sweating shivering);

frequency unknown – hyperglycemia hypoglycemic coma (see See section “Special Indications”).

Infectious and parasitic diseases:

infrequent – fungal infections development of resistance of pathogens.

Vascular disorders:

rarely – decreased blood pressure;

General disorders:

infrequent – asthenia; rare – pyrexia;

frequency unknown – pain (including back pain in the chest and extremities).

Disorders of the immune system:

rarely – angioedema;

incidence unknown – anaphylactic shock anaphylactoid shock.

Anaphylactic and anaphylactoid reactions can sometimes develop even after the first dose of the drug.

Liver and biliary tract disorders:

often – increased activity of “hepatic” enzymes increased activity

alkaline phosphatase and gamma-glutamyltransferase;

infrequent – increased plasma bilirubin concentration;

frequency unknown – severe liver failure including cases of acute liver failure sometimes with fatal outcome especially in patients with severe underlying disease (e.g., patients with sepsis) hepatitis jaundice.

Mental disorders:

often – insomnia;

infrequent – anxiety anxiety confusion;

rarely – mental disorders (e.g. hallucinations paranoia) depression agitation (agitation) sleep disorders nightmares;

frequency unknown- mental disorders with conduct disorder with self-harm including suicidal thoughts and suicide attempts.

Other possible side effects apply to all fluoroquinolones:

very rarely, exacerbation of porphyria.

Overdose

Symptoms

The symptoms of levofloxacin overdose are manifested at the central nervous system level (confusion, dizziness, impaired consciousness and seizure-like epilepsy). Gastrointestinal complaints (e.g., nausea) and mucosal erosions can also occur with prolongation of the QT interval.

Treatment

In case of overdose, close monitoring of the patient is required, including monitoring of the electrocardiogram.

The treatment should be symptomatic. In case of acute overdose gastric lavage and administration of antacids to protect the gastric mucosa are indicated. Levofloxacin is not excreted by dialysis (hemodialysis peritoneal dialysis and continuous peritoneal dialysis). There is no specific antidote.

Similarities

Signicef, Tavanic, Oftavix, Flexid, Levolet R, Levofloxacin-Teva, Glevo, Haileflox, Leflobakt, L-Optik Rompharm, Levofloxacin, Korfecin