Levofloxacin-Darnitsa

Composition:

active substance: levofloxacin;

Each mL of solution contains levofloxacin hemihydrate as 5 mg of levofloxacin;

excipients: sodium chloride, hydrochloric acid, diluted, sodium hydroxide, water for injection.

Pharmaceutical form. Solution for infusion.

Main physicochemical properties: a clear greenish-yellow liquid practically free from particles.

Pharmacotherapeutic group.

Antibacterial agents for systemic use. Quinolone antibacterials. Fluoroquinolones. Levofloxacin. ATC code J01M A12.

Pharmacological properties.

Pharmacodynamic properties.

Levofloxacin is a synthetic antibacterial agent of the fluoroquinolone class and is the S (-) enantiomer of the racemic active substance ofloxacin. As a fluoroquinolone antibacterial agent, levofloxacin acts on the DNA-/DNA-gyrase complex and topoisomerase IV. The main mechanism of resistance is due to mutations in gyr-A genes.

In vitro cross-resistance between levofloxacin and other fluoroquinolones is observed.

Breakpoints.

The EUCAST recommended MIC breakpoints for levofloxacin, separating susceptible from intermediately susceptible organisms and intermediately susceptible from resistant organisms are presented in table 1 below for MIC testing (mg/L).

EUCAST clinical MIC breakpoints for levofloxacin:

Table 1

1  The breakpoints for levofloxacin relate to high dose therapy.

2 Low-level fluoroquinolone resistance (ciprofloxacin MICs of 0.12-0.5 mg/l) may occur but there is no evidence that this resistance is of clinical importance in respiratory tract infections with Haemophilus influenzae.

3 Strains with MIC values above the susceptible breakpoint are very rare or not yet reported. The identification and antimicrobial susceptibility tests on any such isolate must be repeated and if the result is confirmed the isolate must be sent to a reference laboratory. Until there is evidence regarding clinical response for confirmed isolates with MIC above the current resistant breakpoint they should be reported resistant.

4 Breakpoints apply to an oral dose of 500 mg x 1 to 500 mg x 2 and an intravenous dose of 500 mg x 1 to 500 mg x 2.

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.

Commonly susceptible microorganisms.

Aerobic Gram-positive bacteria: Bacillus anthracis, Staphylococcus aureus methicillin-susceptible, Staphylococcus saprophyticus, Streptococci − groups С and G, Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes.

Aerobic Gram-negative bacteria: 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.

Species for which acquired (secondary) 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 aerogenes, Enterobacter cloacae, Escherichia coli, Morganella morganii, Proteus mirabilis, Providencia stuartii, Pseudomonas aeruginosa, Serratia marcescens.

Anaerobic bacteria: Bacteroides fragilis.

Inherently Resistant Strains.

Areobic Gram-positive bacteria: Enterococcus faecium.

* Methicillin-resistant S. aureus are very likely to possess co-resistance to fluoroquinolones, including levofloxacin.

Pharmacokinetic properties.

Absorption

Orally administered levofloxacin is rapidly and almost completely absorbed with peak plasma concentrations Сmax being obtained within 1-2 h. The absolute bioavailability is 99-100 %. Food has little effect on the absorption of levofloxacin. Steady state conditions are reached within 48 hours following a 500 mg once or twice daily dosage regimen.

Distribution

Approximately 30-40 % of levofloxacin is bound to serum protein. The mean volume of distribution of levofloxacin is approximately 100 L after single and repeated 500 mg doses, indicating widespread distribution into body tissues.

Penetration into tissues and body fluids

Levofloxacin has been shown to penetrate bronchial mucosa, epithelial lining fluid, alveolar macrophages, lung tissue, skin (blister fluid), prostatic tissue and urine. However, levofloxacin has poor penetration into cerebro-spinal fluid.

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 and are 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).

The mean apparent total body clearance of levofloxacin following a 500 mg single dose was 175 ± 29.2 mL/min.

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

Linearity

Levofloxacin obeys linear pharmacokinetics over a range of 50 to 1000 mg.

Subjects with renal insufficiency

The pharmacokinetics of levofloxacin are affected by renal impairment. With decreasing renal function renal elimination and clearance are decreased, and elimination half-lives increased as shown in table 2:

Table 2

Elderly subjects

There are no significant differences in levofloxacin kinetics between young and elderly subjects, except those associated with differences in creatinine clearance.

Gender differences

Separate analysis for male and female subjects showed small to marginal gender differences in levofloxacin pharmacokinetics. There is no evidence that these gender differences are of clinical relevance.

Clinical particulars.

Therapeutic indications.

Levofloxacin-Darnitsa is indicated in adults for the treatment of the following infections caused by levofloxacin-sensitive microorganisms:

− community-acquired pneumonia *;

− complicated skin and soft tissue infections *;

− acute pyelonephritis and complicated urinary tract infections;

− chronic bacterial prostatitis;

− inhalation anthrax: postexposure prophylaxis and curative treatment.

* Concerning these infections levofloxacin should be used only when it is considered inappropriate to use other antibacterial agents that are commonly recommended for the treatment of these infections.

Consideration should be given to official guidance on the appropriate use of anti-bacterial agents.

Contraindications.

− Hypersensitivity to levofloxacin or any other quinolone and any of the excipients

− History of tendon disorders related to fluoroquinolone administration

− Epilepsy

− Children (below 18)

− Pregnancy or breast-feeding.

Interaction with other medicinal products and other forms of interaction.

Theophylline, fenbufen or similar non-steroidal anti-inflammatory drugs (NSAIDs)

A pronounced lowering of the cerebral seizure threshold may occur when quinolones are given concurrently with theophylline, NSAIDs, 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 34% by probenecid and 24% by cimetidine. This is because both drugs are capable of blocking the renal tubular secretion of levofloxacin. Caution should be exercised when levofloxacin is co-administered with drugs that effect the tubular renal secretion (probenecid and cimetidine), especially in renally impaired patients.

Ciclosporin

The half-life of ciclosporin was increased by 33% when co-administered with levofloxacin.

Vitamin K antagonists.

Increased coagulation tests (PT/INR) have been reported in patients treated with levofloxacin in combination with a vitamin K antagonist (e.g. warfarin). There may be severe bleeding. Coagulation tests, therefore, should be monitored in patients treated with vitamin K antagonists

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 affect the pharmacokinetics of theophylline, which is predominantly metabolised by CYP1A2, and therefore levofloxacin cannot be considered a CYP1A2 inhibitor.

Glucocorticoids.

Concomitant use with glucocorticoids increases the risk of tendon rupture.

Other information.

There is no clinically significant effect on the pharmacokinetics of levofloxacin when used in combination with the following drugs: calcium carbonate, digoxin, glibenclamide, ranitidine.

It is not recommended to drink alcohol when taking levofloxacin

Special warnings and precautions for use.

The use of the medicinal product should be avoided in patients who have experienced serious adverse reactions in the past when using quinolone or fluoroquinolone containing products. Treatment of these patients with levofloxacin should only be initiated in the absence of alternative treatment options and after careful benefit/risk assessment.

Patients with severe renal impairment, as well as with severe cerebral atherosclerosis, cerebrovascular disorders should be careful when using the medicinal product.

Renal and hepatic function should be monitored throughout the course of treatment.

Alcohol should be avoided when using the medicinal product.

In severe pneumococcal pneumonia, levofloxacin may not give the optimal therapeutic effect.

Nosocomial infections caused by P. aeruginosa may require combination therapy.

Methicillin-resistant S. aureus (MRSA)

Methicillin-resistant S. aureus are very likely to possess co-resistance to fluoroquinolones, including levofloxacin. Therefore, levofloxacin is not recommended for the treatment of known or suspected MRSA infections unless laboratory results have confirmed susceptibility of the organism to levofloxacin.

Resistance of E. coli.

Resistance to fluoroquinolones of E. coli -– the most common pathogen involved in urinary tract infections – varies across the European Union. Prescribers are advised to take into account the local prevalence of resistance of E. coli to fluoroquinolones.

Inhalation anthrax.

Clinical use is based on in vitro Bacillus anthracis susceptibility data and on animal experimental data together with limited human data. Treating physicians should refer to national and/or international consensus documents regarding the treatment of anthrax.

Long-term, disabling and potentially irreversible serious side effects.

Very rare cases of prolonged (continuing months or years), disabling and potentially irreversible serious adverse drug reactions affecting different, sometimes multiple, body systems (musculoskeletal, nervous, psychiatric and senses) have been reported in patients receiving quinolones and fluoroquinolones irrespective of their age and pre-existing risk factors. Levofloxacin should be discontinued immediately at the first signs or symptoms of any serious adverse reaction and patients should be advised to contact their prescriber for advice.

Infusion time.

The recommended infusion time of at least 60 minutes for 500 mg solution for infusion should be observed. It is known for ofloxacin that during infusion tachycardia and a temporary decrease in blood pressure may develop. In rare cases, as a consequence of a profound drop in blood pressure, circulatory collapse may occur. Should a conspicuous drop in blood pressure occur during infusion of levofloxacin, (L-isomer of ofloxacin) the infusion must be halted immediately.

Aortic aneurysm and dissection, and heart valve regurgitation/incompetence

Epidemiologic studies report an increased risk of aortic aneurysm and dissection, particularly in elderly patients, and of aortic and mitral valve regurgitation after intake of fluoroquinolones. Cases of aortic aneurysm and dissection, sometimes complicated by rupture (including fatal ones), and of regurgitation/incompetence of any of the heart valves have been reported in patients receiving fluoroquinolones (see the section “Undesirable effects”).

Therefore, fluoroquinolones should only be used after a careful benefit-risk assessment and after consideration of other therapeutic options in patients with positive family history of aneurysm disease or congenital heart valve disease, or in patients diagnosed with pre-existing aortic aneurysm and/or dissection or heart valve disease, or in presence of other risk factors or conditions predisposing:

- for both aortic aneurysm and dissection and heart valve regurgitation/incompetence: connective tissue disorders such as Marfan syndrome or vascular Ehlers-Danlos syndrome, Turner syndrome, Behçet´s disease, hypertension, rheumatoid arthritis;

- for aortic aneurysm and dissection: vascular disorders such as Takayasu arteritis or giant cell arteritis, or known atherosclerosis, or Sjögren’s syndrome;

- for heart valve regurgitation/incompetence: infective endocarditis.

The risk of aortic aneurysm and dissection, and their rupture may also be increased in patients treated concurrently with systemic corticosteroids.

In case of sudden abdominal, chest or back pain, patients should be advised to immediately consult a physician in an emergency department.

Patients should be advised to seek immediate medical attention in case of acute dyspnoea, new onset of heart palpitations, or development of oedema of the abdomen or lower extremities.

Tendinitis and tendon rupture.

Tendinitis may rarely occur. Tendinitis and tendon rupture (especially but not limited to Achilles tendon), sometimes bilateral, may occur as early as within 48 hours of starting treatment with quinolones and fluoroquinolones and have been reported to occur even up to several months after discontinuation of treatment with the medicinal product. The risk of tendinitis and tendon rupture is increased in older patients, patients with renal impairment, patients with solid organ transplants, in patients receiving a daily dose of 1 000 mg of levofloxacin, as well as in patients receiving concomitant treatment with corticosteroids. Therefore, concomitant use of corticosteroids should be avoided.

At the first sign of tendinitis (e.g. painful swelling, inflammation) the treatment with levofloxacin should be discontinued and alternative treatment should be considered. The affected limb(s) should be appropriately treated (e.g., immobilisation). Corticosteroids should not be used if signs of tendinopathy occur.

Clostridium difficile-associated disease.

Diarrhoea, particularly if severe, persistent and/or bloody, during or after treatment with levofloxacin may be symptomatic of Clostridium difficile-associated disease (CDAD), the most severe form of which is pseudomembranous colitis. If pseudomembranous colitis is suspected or confirmed, levofloxacin must be stopped immediately and appropriate treatment initiated without delay (e.g. with vancomycin). Anti-peristaltic medicinal products are contraindicated in this clinical situation.

Patients predisposed to seizures.

Quinolones may lower the seizure threshold and may trigger seizures. Levofloxacin is contraindicated in patients with a history of epilepsy.

As with other quinolones, the medicinal product should be used with extreme caution in patients predisposed to seizures, such as patients with central nervous system disorders, with concomitant therapy with fenbufen and similar drugs or agents increasing convulsive readiness (lower the seizure threshold), such as theophylline (see the section “Interaction with other medicinal products and other forms of interaction”). 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. Therefore, if levofloxacin has to be used in these patients, potential occurrence of haemolysis should be monitored.

Patients with renal impairment.

Since levofloxacin is excreted mainly by the kidneys, the dose should be adjusted in patients with renal impairment (see the section “Posology and method of administration”).

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 doctor or an emergency doctor, who will initiate appropriate emergency measures.

Severe bullous reactions.

Severe bullous adverse reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis (also known as Lyell’s syndrome) and drug reaction with eosinophilia and systemic symptoms (DRESS), which could be life-threatening or fatal, have been reported with levofloxacin. At the time of prescription, patients should be advised of the signs and symptoms of severe skin reactions, and be closely monitored. If signs and symptoms suggestive of these reactions appear, levofloxacin should be discontinued immediately and an alternative treatment should be considered. If the patient has developed a serious reaction such as toxic epidermal necrolysis, Stevens-Johnson syndrome or DRESS-syndrome with the use of levofloxacin, treatment with levofloxacin must not be restarted in this patient.

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.

Prevention of photosensitisation.

Photosensitisation has been reported with levofloxacin. It is recommended that patients should not expose themselves unnecessarily to strong sunlight or to artificial UV rays (e.g. sunray lamp, solarium), during treatment and for 48 hours following treatment discontinuation in order to prevent photosensitisation.

In patients treated with vitamin K antagonists, due to possible increase in coagulation tests (prothrombin time / international normalized ratio (INR)) and/or bleeding in patients treated with levofloxacin in combination with a vitamin K antagonist (e.g. warfarin), coagulation tests should be monitored when these drugs are given concomitantly.

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 and appropriate measures instituted. Caution is recommended if levofloxacin is to be used in psychotic patients or in patients with history of psychiatric disease.

QT interval prolongation.

Cases of QT prolongation have been reported with fluoroquinolones. 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:

- syndrome of congenital or acquired prolonged QT interval

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

- electrolyte imbalance (e.g. hypokalaemia, hypomagnesemia)

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

Elderly patients and women may be more sensitive to QTc-prolonging medications. Therefore, caution should be taken when using fluoroquinolones, including levofloxacin in these populations.

Peripheral neuropathy.

Cases of sensory or sensorimotor polyneuropathy resulting in paraesthesia, hypaesthesia, dysesthesia, or weakness have been reported in patients taking fluoroquinolones, including levofloxacin. Levofloxacin should be discontinued if symptoms of neuropathy such as pain, burning, tingling, numbness, or weakness develop in order to prevent the development of potentially irreversible condition.

Exacerbation of myasthenia gravis.

Fluoroquinolones, including levofloxacin, have neuromuscular blocking activity and may exacerbate muscle weakness in patients with myasthenia gravis. Postmarketing serious adverse reactions, including deaths and the requirement for respiratory support, have been associated with fluoroquinolone use in patients with myasthenia gravis. Levofloxacin is not recommended in patients with a known history of myasthenia gravis.

Vision disorders.

If vision becomes impaired or any effects on the eyes are experienced, an eye specialist should be consulted immediately.

Superinfection.

The use of levofloxacin, especially if prolonged, may result in overgrowth of non-susceptible organisms. If superinfection occurs during therapy, appropriate measures should be taken.

Interference with laboratory tests.

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 methods.

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

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 (see the section “Undesirable effects”). 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.

Important information about excipients.

This medicine contains 860 mg/dose of sodium. Caution should be exercised when using in patients on a controlled sodium diet.

Fertility, pregnancy and lactation.

In the absence of studies and possible damage by fluoroquinolones to the weight-bearing cartilage of the growing organism, levofloxacin must not be used in pregnant and breast-feeding women. If pregnancy occurs during the use of the product, consult the doctor.

Levofloxacin caused no impairment of fertility or reproductive performance in animals.

Effects on ability to drive and use machines.

When using the medicinal product it is necessary to refrain from driving and from potentially dangerous activities that require increased attention and speed of reaction, due to the possibility of nervous system disorders (dizziness, bloating, drowsiness, confusion, visual and hearing disorders, movement disorders, including while walking).

Posology and method of administration.

A sensitivity test must be performed before use.

The solution should be used within 3 hours after perforation of the vial.

The medicinal product is administered intravenously 1-2 times a day.

The dosage depends on the type and severity of the infection. Dosage recommendations should be followed for patients with normal renal function (see Table 3) with creatinine clearance greater than 50 mL/min.

Table 3

1Treatment duration includes intravenous plus oral treatment. The time to switch from intravenous levofloxacine to oral treatment with the same dosage depends on the patient’s condition but is normally 2 to 4 days from the onset of treatment.

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

Dosage for patients with impaired renal function (see Table 4) with creatinine clearance less than 50 mL/min.

Table 4

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

Dosage in patients with impaired liver function. No adjustment of dose is required since levofloxacin is not metabolised to any relevant extent by the liver.

Dosage in elderly population. If renal function is not impaired, no dose adjustment is required.

The medicinal product is only intended for slow intravenous drip infusion. The infusion time must be at least 30 minutes for 250 mg dose or at least 60 minutes for 500 mg dose.

Based on the patient’s condition, it is possible to switch from intravenous to oral levofloxacin with the same dosage in a few days.

The duration of treatment depends on the course of the disease. As with other antibacterial agents, it is recommended to continue treatment with levofloxacin for at least 48-72 hours after normalization of body temperature or confirmed by microbiological tests of elimination of pathogens.

Mixing with solutions for infusions.

The medicinal product is compatible with the following solutions for infusion:

0.9% sodium chloride solution, 5% glucose monohydrate, 2.5% dextrose in Ringer’s solution, multicomponent solutions for parenteral nutrition (amino acids, carbohydrates, electrolytes).

Paediatric population.

The medicinal product is contraindicated for use in children, as damage to articular cartilage is not excluded.

Overdose.

Symptoms: dizziness, disturbance/ confusional state, seizures, hallucinations, tremor, prolongation of the QT interval or increased manifestations of other adverse reactions.

Treatment –symptomatic, according to clinical manifestations. In case of overdose, the patient should be closely monitored, including ECG. Haemodialysis, including peritoneal dialysis and CAPD, are not effective in removing levofloxacin from the body. No specific antidote exists.

Undesirable effects.

All undesirable effects are classified by system organ class and ordered by frequency: very common (≥ 1/10), common (≥ 1/100 – < 1/10), uncommon (≥ 1/1 000 – < 1/100), rare (≥ 1/10000 – < 1/1000), very rare (< 1/10 000), and not known (frequency cannot be estimated from the available data).

Eye disorders*: rare – visual disturbances such as blurred vision; not known – transient vision loss, uveitis.

Ear and labyrinth disorders *: uncommon – vertigo; rare – tinnitus; not known – hearing loss, hearing impaired.

Respiratory, thoracic and mediastinal disorders: uncommon – dyspnoea; not known – bronchospasm, pneumonitis allergic.

Gastro-intestinal disorders: common – diarrhoea, vomiting, nausea; uncommon – abdominal pain, dyspepsia, flatulence, constipation; not known – Diarrhoea – haemorhagic which in very rare cases may be indicative of enterocolitis including pseudomembranous colitis; pancreatitis.

Hepatobiliary disorders: common – hepatic enzyme increased (alanine aminotransferase (ALT) / aspartate aminotransferase (AST), alkaline phosphatase, gamma-glutamine transpeptidase (GGTP)); uncommon – blood bilirubin increased; not known – jaundice and severe liver injury, including cases with fatal acute liver failure, primarily in patients with severe underlying diseases; hepatitis.

Renal and urinary disorders: uncommon – blood creatinine increased; rare – renal failure acute (e.g. due to interstitial nephritis).

Endocrine disorders: rare – syndrome of inappropriate secretion of antidiuretic hormone (SIADH).

Metabolism and nutrition disorders: uncommon – anorexia; rare – Hypoglycaemia, particularly in diabetic patients, hypoglycaemic coma; not known  – hyperglycaemia. Signs of hypoglycaemia may be increased appetite, nervousness, sweating, trembling limbs.

Nervous system disorders*: common – headache, dizziness; uncommon – somnolence, tremor, dysgeusia; rare – convulsion, paraesthesia; not known – peripheral sensory neuropathy, peripheral sensory motor neuropathy, parsomia including ansomia, dyskinesia, extrapyramidal disorder, other disorders of coordination of movements, in particular when walking, torpor, ageusia, syncope, benign intracranial hypertension.

Psychiatric disorders*: common – insomnia; uncommon – anxiety, confusional state, nervousness, unrest; rare – psychotic reactions (with e.g. hallucination paranoia), depression, agitation, abnormal dreams, nightmares, anxiousness; not known – psychotic disorders with self-endangering behaviour including suicidal ideation or suicide attempt (see the section “Special warnings and precautions for use”).

Cardiac disorders**: common – phlebitis; rare – tachycardia, palpitation, arterial hypotension; not known – ventricular tachycardia which may result in cardiac arrest; Ventricular arrhythmia and torsade de pointes (reported predominantly in patients with risk factors of QT prolongation), electrocardiogram QT prolonged, collapse, vasculitis.

Blood and lymphatic system disorders: uncommon – leukopenia, eosinophilia; rare – neutropenia, thrombocytopenia, which causes an increased tendency to haemorrhage or bleeding; not known – pancytopenia, agranulocytosis, haemolytic anaemia.

Immune system disorders: rare – hypersensitivity reactions, angioedema; not known – anaphylactic shock, anaphylactoid shock. Anaphylactic and anaphylactoid reactions may sometimes occur even after the first dose.

Skin and subcutaneous tissue disorders: uncommon – rash, pruritus, urticaria, hyperhidrosis; rare − drug reaction with eosinophilia and systemic symptoms (DRESS-syndrome), local drug rashes; not known – toxic epidermal necrolysis (Lyell’s syndrome), Stevens-Johnson syndrome, exudative erythema multiforme, photosensitivity reaction, leukocytoclasic vasculitis, stomatitis. Occasionally, skin and mucosal reactions may occur even after the first dose.

Infections and infestations: uncommon – fungal infection including Candida infection, reproduction of other resistant microorganisms.

Musculoskeletal and connective tissue disorders *: uncommon – arthralgia, myalgia; rare – tendon disorders (see the section “Special warnings and precautions for use”), including tendinitis (e.g. Achilles tendon), muscular weakness which may be of special importance in patients with myasthenia gravis; not known – Rhabdomyolysis, tendon rupture, ligament and muscle rupture, arthritis.

General disorders and administration site conditions *: common – infusion site reaction including pain, reddening; uncommon – asthenia, general weakness; rare – pyrexia; not known – pain (including pain in back, chest and extremities), as with other fluoroquinolones, there may be attacks of porphyria in patients with porphyria.

Other undesirable side effects associated with the use of fluoroquinolones include:

• extrapyramidal symptoms and other disorders of coordination;
• hypersensitive vasculitis;
• attacks of porphyria in patients with porphyria.

*Very rare cases of prolonged (up to months or years), disabling and potentially irreversible serious drug reactions affecting several, sometimes multiple, system organ classes and senses (including reactions such as tendonitis, tendon rupture, arthralgia, pain in extremities, gait disturbance, neuropathies associated with paraesthesia, depression, fatigue, memory impairment, sleep disorders, and impairment of hearing, vision, taste and smell) have been reported in association with the use of quinolones and fluoroquinolones in some cases irrespective of pre-existing risk factors.

** Cases of aortic aneurysm and dissection, sometimes complicated by rupture (including fatal ones), and of regurgitation/incompetence of any of the heart valves have been reported in patients receiving fluoroquinolones (see the section “Special warnings and precautions for use”).

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the state pharmacovigilance system.

Shelf life. 3 years.

Storage conditions.

Store in the original package below 25 ºC. Do not freeze.

Keep out of reach of children.

Incompatibilities.

This medicinal product should not be mixed with heparin or alkaline solutions (e.g. sodium bicarbonate), with other medicinal products except those mentioned in the section “Posology and method of administration”.

Nature and contents of container.

100 ml in a vial; 1 vial in a pack.

Prescription status. Upon prescription.

Manufacturer. PRJSC Pharmaceutical company Darnitsa.

Manufacturer’s location and place of business.

13 Boryspilska Street, 02093, City of Kyiv, Ukraine.

Date of the last revision. 09.12.2021