LEVOTREN

Composition

active substance: levofloxacin;
1 ml of solution contains levofloxacin (in the form of hemihydrate) 5 mg;
excipients: sodium chloride, concentrated hydrochloric acid, sodium hydroxide, water for injections.

Pharmaceutical form

Solution for infusion.
Main physical and chemical properties: clear solution.

Pharmacotherapeutic group

Antibacterial agents for systemic use. Antibacterial agents of the quinolone group. Fluoroquinolones. ATC code J01MA12.

Pharmacological properties

Pharmacodynamics.
Levofloxacin is a synthetic antibacterial agent of the fluoroquinolone group, the S-enantiomer of the racemic mixture of the medicine ofloxacin.
Mechanism of action. As a fluoroquinolone antibacterial agent, levofloxacin acts on the DNA-gyrase complex and topoisomerase IV.
Pharmacokinetics/pharmacodynamics ratio. The degree of bacterial activity of levofloxacin depends on the ratio of the maximum serum concentration (C_max) or area under the «concentration-time» curve (AUC) and the minimum inhibitory (suppressive) concentration [MIC (MSC)].
Mechanism of resistance. Resistance to levofloxacin is acquired through a stepwise process by target site mutations in both type II topoisomerases, DNA-gyrase and topoisomerase IV. Other resistance mechanisms such as permeation barriers (common in Pseudomonas aeruginosa) and efflux mechanisms may also affect susceptibility to levofloxacin.
Cross-resistance between levofloxacin and other fluoroquinolones is observed.
Due to the mechanism of action, there is generally no cross-resistance between levofloxacin and other classes of antibacterial agents.
Breakpoints. The recommended EUCAST (European Committee on Antimicrobial Susceptibility Testing) MIC breakpoints for levofloxacin, which separate susceptible microorganisms from moderately susceptible (moderately resistant) organisms and moderately susceptible from resistant organisms, are presented in the table below (mg/l).

EUCAST clinical MIC breakpoints for levofloxacin (version 2.0, 2012-01-01):

The prevalence of resistance in individual species may vary geographically and it is advisable to obtain local information on resistance over time, especially in the treatment of severe infections. Specialist advice should be sought if necessary when the local prevalence of resistance is such that the usefulness of the agent in at least some types of infection is questionable.

Commonly susceptible species
Aerobic gram-positive bacteria: Bacillus anthracis, Staphylococcus aureus methicillin-susceptible, Staphylococcus saprophyticus, Streptococci, group C and G, Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes.
Aerobic gram-negative bacteria: Eikenella corrodens, Haemophilus influenzae, Haemophilus para-influenzae, Klebsiella oxytoca, Moraxella catarrhalis, Pasteurella multocida, Proteus vulgaris, Providencia rettgeri.
Anaerobic bacteria: Peptostreptococcus.
Other: Chlamydophila pneumoniae, Chlamydophila psittaci, Chlamydia trachomatis, Legionella pneumophila, Mycoplasma pneumoniae, Mycoplasma hominis, Ureaplasma urealyticum.
Species that may acquire resistance
Aerobic gram-positive bacteria: Enterococcus faecalis, Staphylococcus aureus methicillin-resistant*, Coagulase negative Staphylococcus spp.
Aerobic gram-negative bacteria: Acinetobacter baumannii, Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Morganella morganii, Proteus mirabilis, Providencia stuartii, Pseudomonas aeruginosa, Serratia marcescens.
Anaerobic bacteria: Bacteroides fragilis.
Resistant strains
Aerobic gram-positive strains: Enterococcus faecium
* Methicillin-resistant S. Aureus may be co-resistant to fluoroquinolones, including levofloxacin.
Pharmacokinetics.
Absorption
Orally administered levofloxacin is rapidly and almost completely absorbed with peak plasma concentrations being obtained within 1-2 hours. The absolute bioavailability is approximately 99- 100%.
Food has little effect on the absorption of levofloxacin.
Steady-state conditions are achieved after one or two doses of 500 mg according to the medicine regimen within 48 hours.
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 body tissues and fluids
Levofloxacin penetrates well into bronchial mucosa, epithelial lining fluid, alveolar macrophages, lung tissue, skin (blister fluid), prostate tissue and urine. However, levofloxacin penetrates poorly into cerebrospinal fluid (CSF).
Biotransformation
Levofloxacin is metabolised to a very small extent, the metabolites being desmethyl-levofloxacin and levofloxacin N-oxide. These metabolites account for < 5% of the dose excreted in urine. Levofloxacin is stereochemically stable and does not undergo chiral inversion.
Elimination
After oral and intravenous administration, levofloxacin is excreted from the blood plasma relatively slowly (half-life is 6-8 hours). Excretion is primarily by the renal route (more than 85% of the administered dose). The mean expressed total clearance of levofloxacin after administration of 1 dose of 500 mg was 175 ± 29.2 ml/min. There is no significant difference in the pharmacokinetics of levofloxacin after intravenous and oral administration, indicating that the oral and intravenous routes of administration are interchangeable.
Linearity
Levofloxacin has linear pharmacokinetics in the dose range of 50 – 1000 mg.
Subjects with renal impairment
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 the Table 1 below:

Table 1

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.

Therapeutic indications

Levotren, solution for infusion is indicated in adults for the treatment of the following infections:

• Community-acquired pneumonia;
• Complicated skin and soft tissue infections;
  (for the above infectious diseases, levofloxacin should be prescribed only in cases of insufficient effectiveness of other antibacterial agents that are mainly used for the initial treatment of these infections);
• Acute pyelonephritis and complicated urinary tract infections;
• Chronic bacterial prostatitis;
• Inhalation Anthrax: post exposure prophylaxis and curative treatment.

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

Contraindications

• Hypersensitivity to levofloxacin, other quinolones or any of the excipients.
• Epilepsy.
• History of tendon disorders related to fluoroquinolone administration.
• Children’s age (up to 18 years).
• Pregnancy.
• Lactation period.

Interaction with other medicinal products and other forms of interaction

Effect of other medicinal products on Levotren.
Theophylline, fenbufen or similar non-steroidal anti-inflammatory medicinal products. No pharmacokinetic interactions of levofloxacin were found with theophylline in a clinical study. However a pronounced lowering of the cerebral seizure threshold may occur when quinolones are given concurrently with theophylline, non-steroidal anti-inflammatory drugs, or other agents which lower the seizure threshold.
Levofloxacin concentrations were about 13% higher in the presence of fenbufen than when administered alone.
Probenecid and cimetidine. Probenecid and cimetidine had a statistically significant effect on the elimination of levofloxacin. The renal clearance of levofloxacin was reduced by cimetidine (24%) and probenecid (34%). This is because both drugs are capable of blocking the renal tubular secretion of levofloxacin. However, at the tested doses in the study, the statistically significant kinetic differences are unlikely to be of clinical relevance.
Caution should be exercised when levofloxacin is coadministered with drugs that effect the tubular renal secretion such as probenecid and cimetidine, especially in renally impaired patients.
Other medicinal products. Clinical pharmacology studies have shown that the pharmacokinetics of levofloxacin were not affected to any clinically relevant extent when levofloxacin was administered together with the following drugs: calcium carbonate, digoxin, glibenclamide, ranitidine.
Effect of Levotren on other medicinal products.
Ciclosporin. The half-life of ciclosprorin was increased by 33% when coadministered with levofloxacin.
Vitamin K antagonists. Increased coagulation tests (PT/INR) and / or bleeding, which may be severe, have been reported in patients treated with levofloxacin in combination with a vitamin K antagonist (e.g. warfarin). Coagulation tests, therefore, should be monitored in patients treated with vitamin K antagonists (see section «Special warnings and precautions for use»).
Medicines 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) (see section «Special warnings and precautions for use» QT interval prolongation).
Theophylline. In a pharmacokinetic interaction study, levofloxacin did not affect the pharmacokinetics of theophylline (which is a probe substrate for CYP1A2), indicating that levofloxacin is not a CYP1A2 inhibitor.

Special warnings and precautions for use

The use of levofloxacin should be avoided in patients who have experienced serious adverse reactions in the past when using quinolone or fluoroquinolone containing products (see section «Undesirable effects»).
Treatment of these patients with levofloxacin should be initiated only in the absence of alternative treatment options and after a thorough benefit/risk assessment (see section «Contraindications»).

Prolonged, disabling and potentially irreversible serious adverse drug reactions.
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.

Methicillin-resistant S. aureus (MRSA) may be resistant to fluoroquinolones, including levofloxacin. Therefore, levofloxacin is not recommended for the treatment of known or suspected MRSA infections, unless laboratory results confirm that the microorganisms are susceptible to levofloxacin (and the recommended antibacterial drugs for the treatment of MRSA infections are considered unsuitable).
Patients with severe cerebral atherosclerosis and cerebrovascular disease should be careful when using the drug.
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 in E. coli to fluoroquinolones.
Inhalation Anthrax: use in humans 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.
Infusion time. The recommended duration of administration of Levotren infusion solution should be observed, which is at least 60 minutes for 500 mg. It is known that tachycardia and a temporary decrease in blood pressure may occur during infusion of ofloxacin. In rare cases, a sharp drop in blood pressure and circulatory collapse may occur as a consequence. If a marked decrease in blood pressure is observed during the administration of levofloxacin (L-isomer of ofloxacin), the administration of the medicine must be halted immediately.
Sodium content. This medicinal product contains 15.8 mmol (or 363 mg) of sodium per 100 ml of solution. Caution should be exercised in patients on a sodium-controlled diet.
Tendinitis and tendon rupture. Tendonitis and tendon ruptures (including but not limited to Achilles tendon) are sometimes bilateral and may develop within 48 hours after starting treatment with levofloxacin, but there are cases when up to several months after discontinuation of treatment have been reported. The risk of tendonitis and tendon rupture increases in patients over 60 years of age, patients with impaired renal function, patients receiving a daily dose of 1000 mg, patients undergoing transplantation, and patients taking corticosteroids. Thus, concomitant use of levofloxacin and corticosteroids must be avoided.
At the first signs of tedinitis (inflammation, painful swelling), treatment should be discontinued and alternative methods of treatment should be considered.
Appropriate treatment of the affected tendon (e.g. immobilisation) should be initiated (see sections «Contraindications» and «Undesirable effects»).
Corticosteroids should not be used if signs of tendinopathy occur.
Clostridium difficile-associated disease. Diarrhoea, especially in severe cases, persistent and/or haemorrhagic, during or after treatment with levofloxacin (including several weeks after treatment) may be a symptom of a disease caused by Clostridium difficile (CD-AD, Clostridium difficile-associated diarrhoea). CD-AD can vary in severity from mild to life-threatening, with the most severe form being pseudomembranous colitis (see section «Undesirable effects»). Therefore, it is important to consider this diagnosis in patients who develop severe diarrhoea during or after treatment with levofloxacin. If CD-AD is suspected, levofloxacin must be discontinued and appropriate treatment must be initiated immediately. Products inhibiting the peristalsis are contraindicated in this clinical situation.
Patients predisposed to seizures. Quinolones may lower the seizure threshold and cause seizures. Levofloxacin is contraindicated in patients with epilepsy (see section «Contraindications») and, like other quinolones, levofloxacin should be used with extreme caution in patients prone to seizures or in concomitant therapy with active substances that lower the cerebral convulsive threshold, such as theophylline (see section «Special warnings and precautions for use»). In case of a convulsive seizure (see section «Undesirable effects») treatment with levofloxacin should be discontinued.
Patients with G-6-phosphate dehydrogenase deficiency. Patients with latent or actual defects in glucose-6-phospahte 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 of Levofloxacin should be adjusted in patients with impaired renal function (see section «Posology and method of administration»).
Hypersensitivity reactions. Levofloxacin can cause serious hypersensitivity reactions (e.g. angioedema up to anaphylactic shock) after the initial dose (see section «Undesirable effects»). In this case, patients should discontinue treatment immediately and consult a doctor.
Severe bullous reactions. Cases of severe bullous skin reactions such as Stevens-Johnson syndrome or toxic epidermal necrolysis have been reported with levofloxacin (see section «Undesirable effects»). Patients should be advised to contact their doctor immediately prior to continuing treatment if skin and/or mucosal reactions occur.
Changes in blood glucose levels. Changes in the level of glucose in the blood. Changes in blood glucose levels (hyperglycemia and hypoglycemia) have been reported when using quinolones, especially in patients with diabetes who were simultaneously taking oral hypoglycemic agents (including glibenclamide) or insulin. There have been cases of hypoglycemic coma. Patients with diabetes mellitus should monitor their blood sugar levels (see section «Undesirable effects».
Prevention of photosensitivity reactions. Photosensitivity reactions have been reported during treatment with levofloxacin (see section «Undesirable effects»). Patients are advised to avoid sun exposure and UV rays (e.g., artificial UV lamps, tanning beds) while taking levofloxacin and for 48 hours after discontinuation to prevent photosensitization.
Patients treated with Vitamin K antagonists. Due to the possibility of an increase in coagulation tests (PT/international normalised ratio) and/or bleeding in patients taking levofloxacin in combination with a vitamin K antagonist (e.g. warfarin), the coagulation tests should be monitored (see section «Interaction with other medicinal products and other forms of interaction»).
Psychotic reactions. Psychotic reactions have been reported in patients taking quinolones, including levofloxacin. In very rare cases, such reactions have progressed to suicidal thoughts and self-destructive behavior, sometimes after only a single dose of levofloxacin (see section «Undesirable effects»). If the patient experiences these reactions, levofloxacin should be discontinued and appropriate measures taken. Levofloxacin should be used with caution in patients with psychotic disorders and patients with a history of psychiatric disease.
Aortic aneurysm and dissection. Epidemiological studies indicate an increased risk of aneurysm and dissection after taking fluoroquinolones, especially in elderly patients.
Therefore, fluoroquinolones should be used only after a careful benefit-risk assessment and after consideration of other treatment options in patients with a positive family history of aneurysm, or in patients diagnosed with aortic aneurysm and/or aortic dissection, or in the presence of other risk factors or conditions leading to development of aneurysm and dissection of the aorta (for example, Marfan syndrome, Ehlers-Danlos vascular syndrome, Takayasu arteritis, giant cell arteritis, Behcet’s disease, hypertension, existing atherosclerosis).
In the event of sudden abdominal, chest, or back pain, patients should seek immediate medical attention in the emergency department.
QT interval prolongation. Fluoroquinolones, including levofloxacin, should be used with caution in patients with risk factors for QT prolongation, such as:
– congenital QT prolongation syndrome;
– concomitant use of drugs known to prolong the QT interval (e.g. antiarrhythmic drugs of classes IA and III, tricyclic antidepressants, macrolides, antipsychotic drugs);
– uncorrected electrolyte imbalance (e.g. hypokalemia, hypomagnesemia);
– cardiac disease (e.g. heart failure, myocardial infarction, bradycardia).
Elderly patients and women may be more sensitive to drugs that prolong the QT interval. Therefore, fluoroquinolones, including levofloxacin, should be used with caution in this group of patients (see sections «Posology and method of administration», «Interaction with other medicinal products and other forms of interaction», «Undesirable effects», «Overdose»).
Peripheral neuropathy. Cases of sensory or sensorimotor peripheral neuropathy have been reported in patients resulting in paresthesia, hypoesthesia, dysesthesia in patients receiving fluoroquinolones, including levofloxacin. Patients treated with levofloxacin should be advised to inform their doctor if they develop symptoms of neuropathy such as pain, burning, tingling, numbness, or weakness, and levofloxacin should be discontinued to prevent an irreversible condition (see section «Undesirable effects»).
Hepatobiliary disorders. Cases of necrotizing hepatitis, up to life-threatening liver failure, have been reported with levofloxacin, mainly in patients with severe underlying diseases such as sepsis (see 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.
Exacerbation of pseudoparalytic myasthenia (myasthenia gravis). Fluoroquinolones, including levofloxacin, have neuromuscular blocking activity and may exacerbate muscle weakness in patients with myasthenia gravis. In the post-marketing period, serious adverse reactions, including deaths and the need for mechanical ventilation, have been observed with levofloxacin in patients with myasthenia gravis associated with the use of fluoroquinolones. Levofloxacin is not recommended for patients with a history of myasthenia gravis.
Vision disorders. You should immediately contact an ophthalmologist if any visual disturbances develop (see sections «Effects on ability to drive and use machines» and «Undesirable effects»).
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.
Opiates. In patients treated with levofloxacin, determination of opiates in urine may give false-positive results. It may be necessary to confirm positive opiate screens using more specific methods.
Levofloxacin may inhibit the growth of Mycobacterium tuberculosis and, therefore, may give false-negative results in the bacteriological diagnosis of tuberculosis.

Fertility, pregnancy and lactation.
Pregnancy. There are limited data on the use of levofloxacin in pregnant women. Animal studies do not indicate direct or indirect reproductive toxicity. However, in the absence of data on human use and in the presence of experimental data indicating the risk of damage to the cartilage of the growing organism due to the action of fluoroquinolones, levofloxacin is contraindicated in pregnant women (see section «Contraindications»).
Breast-feeding. Levofloxacin is contraindicated in women who are breastfeeding. There is insufficient information on the excretion of levofloxacin in breast milk. However, other fluoroquinolones pass into breast milk. In the absence of human data and in the presence of experimental data indicating the risk of damage to the cartilage of the growing organism due to the action of fluoroquinolones, levofloxacin is contraindicated in women who are breast-feeding (see section «Contraindications»).
Fertility. Levofloxacin does not cause fertility or reproductive disorders in animals.
Effects on ability to drive and use machines.
Some undesirable effects, such as dizziness, drowsiness, visual disturbances, may impair patients’ ability to concentrate and react and pose a risk in situations where such ability is very important (e.g. driving or operating machinery).

Posology and method of administration

The medicinal product is administered intravenously 1-2 times per day.
The dosage depends on the type and severity of the infection. Dosage in patients with normal renal function with creatinine clearance > 50 ml/min, are described in Table 2.

Table 2

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

Since levofloxacin is mainly excreted by the kidneys, the dose should be reduced in patients with impaired renal function.
Dosage in patients with impaired renal function, with creatinine clearance ≤ 50ml/min, are described in Table 3.

Table 3

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

Dosage for patients with hepatic impairment. No dose adjustment is required, since levofloxacin is metabolized to a small extent in the liver.
Dosage for elderly patients. If renal function is not impaired, there is no need for dose adjustment.
The medicine should be administered slowly intravenously by drip infusion.
The infusion time must be at least 30 minutes for a 250 mg dose or 60 minutes for a 500 mg dose.
Depending on the patient’s condition, it is possible to switch from intravenous administration to oral administration of levofloxacin with the same dosage in a few days.
The therapy duration depends on the progression of the disease. As with other antibacterial agents, it is recommended to continue treatment with the medicine for at least 48-72 hours after normalization of body temperature or microbiological tests confirmation of pathogen eradication.
Preparation for intravenous administration:
– hold the plastic bag with the connection ports uppermost;
– twist off the protection cap from the connection port;
– insert the piercing pin of the intravenous set into the connection port with a twisting motion;
– place the bag on the stand for infusion solutions.
No protection from light is necessary during infusion.
From a microbiological point of view, the solution for infusion should be used immediately. If it is not used, the user is responsible for the operational stability time and the conditions preceding the use.
Unused solution or wastes should be disposed of in accordance with local requirements.
Mixture with other solutions for infusion.
The medicinal product is compatible with the following solutions for infusion: 0.9% sodium chloride solution, 5% glucose monohydrate, 2.5% glucose in Lactated Ringer’s solution, multicomponent solutions for parenteral nutrition (amino acids, carbohydrates, electrolytes).

Paediatric population.
Levofloxacin is contraindicated in children, as destruction of the immature joint cartilage is not excluded.

Overdose

Symptoms of an overdose are related to the central nervous system (CNS): confusion, dizziness, impaired consciousness, and seizures. CNS effects including confusional state, convulsion, hallucination, and tremor have been observed in post marketing experience.
In the event of overdose, symptomatic treatment should be implemented. The functioning of the heart should be monitored with an ECG, because of the possibility of QT interval prolongation. Haemodialysis, including peritoneal dialysis and CAPD, are not effective in removing levofloxacin from the body. No specific antidote exists.

Undesirable effects

The adverse reactions are described according to the MedDRA system organ class and are defined by frequency:
very common (≥ 1/10);
common (≥ 1/100, < 1/10);
uncommon (≥ 1/1000, ≤ 1/100);
rare (≥ 1/10000, ≤ 1/1000);
very rare (≤ 1/10000);
not known (cannot be estimated from the available data).
Infections and infestations. Uncommon: fungal infection including Candida infection, reproduction of other resistant microorganisms.
Blood and lymphatic system disorders. Uncommon: eosinophilia, leukopenia. Rare: thrombocytopenia, neutropenia. Not known: pancytopenia, agranulocytosis, haemolytic anaemia.
Immune system disorders. Rare: angioedema, hypersensitivity (see section «Special warnings and precautions for use»). Not known: anaphylactic shock, anaphylactoid shock, which can sometimes occur even after the first dose (see section «Special warnings and precautions for use»).
Metabolism and nutritional disorders. Uncommon: anorexia. Rare: hypoglycaemia particularly in diabetic patients (see section «Special warnings and precautions for use»). Not known: hyperglycaemia, hypoglycaemic coma (see section «Special warnings and precautions for use»).
Psychiatric disorders.* Common: insomnia. Uncommon: anxiety, confusional state, nervousness. Rare: psychotic reactions (including hallucinations, paranoia), depression, agitation, nightmares. Not known: psychotic disorders with self-destructive behavior, including suicidal thinking or actions (see section «Special warnings and precautions for use»).
Central nervous system disorders. Common: headache, dizziness. Uncommon: somnolence, tremor, dysgeusia. Rare: convulsions (see sections «Contraindications» and «Special warnings and precautions for use»), paresthesia. Unknown: peripheral sensory neuropathy (see section «Special warnings and precautions for use»), peripheral sensory motor neuropathy (see section «Special warnings and precautions for use»), parosmia, including anosmia, dyskinesia, extrapyramidal disorders, ageusia, syncope, benign intracranial hypertension.
Eye disorders.* Rare: visual disturbances such as blurred vision (see section «Special warnings and precautions for use»). Not known: transient vision loss (see section «Special warnings and precautions for use»).
Ear and Labyrinth disorders.* Uncommon: vertigo. Rare: tinnitus. Not known: hearing loss, hearing impaired.
Cardiac disorders. Rare: tachycardia, palpitations. Unknown: ventricular tachycardia, which can lead to cardiac arrest, ventricular arrhythmia and torsade de pointes arrhythmia (mainly in patients with risk factors for QT prolongation), QT prolongation on the electrocardiogram.
Vascular disorders. Common (applies only to the form of the medicine for intravenous administration): phlebiti. Rare: arterial hypotension.
Respiratory, thoracic and mediastinal disorders. Uncommon: dyspnea, bronchospasm, allergic pneumonitis.
Gastrointestinal disorders. Common: diarrhoea, vomiting, nausea. Uncommon: abdominal pain, dyspepsia, bloating, constipation. Unknown: haemorrhagic diarrhoea, which can rarely be a sign of enterocolitis, including pseudomembranous colitis (see section «Special warnings and precautions for use»), pancreatitis.
Hepatobiliary disorders. Common: increased hepatic enzymes (ALT/AST, alkaline phosphatase, GGT). Uncommon: increased bilirubin levels. Not known: jaundice and severe liver damage, including acute fatal liver failure, primarily in patients with severe underlying diseases (see section «Special warnings and precautions for use»). Hepatitis.
Skin and subcutaneous tissue disorders. Uncommon: rash, pruritus, urticaria, hyperhidrosis. Not known: toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, photosensitisation reactions (see section «Special warnings and precautions for use»), leukocytoclastic vasculitis, stomatitis. Skin and mucosal reactions may sometimes occur even after the first dose.
Musculoskeletal system disorders.* Uncommon: arthralgia, myalgia. Rare: tendon disorders (see sections «Contraindications» and «Special warnings and precautions for use»), including tendonitis (e.g. Achilles tendon), muscle weakness, especially in patients with myasthenia gravis (see section «Special warnings and precautions for use»). Not known: rhabdomyolysis, tendon rupture (e.g. Achilles tendon, see sections «Contraindications» and «Special warnings and precautions for use»), ligament rupture, muscle rupture, arthritis.
Renal and urinary disorders. Uncommon: blood creatinine increased. Rare: acute renal failure (e.g. due to interstitial nephritis).
General disorders and reactions at the injection site.* Common (applies only to the form of the medicine for intravenous administration): infusion site reaction (pain, redness). Uncommon: asthenia. Rare: pyrexia. Not known: pain (including pain in the back, chest, extremities).
Other undesirable effects which have been associated with fluoroquinolone administration include porphyria attacks in patients with porphyria.

*Very rare cases have been reported, lasting for several months or years, leading to disability and potentially irreversible severe reactions to the drug, affecting various, sometimes several, organ and sensory systems (reactions such as tendonitis, tendon rupture, limb pain, arthralgia, gait disturbance, neuropathy associated with paresthesia, depression, fatigue, memory, sleep, hearing, vision and smell disturbances), and were associated in some cases with the use of quinolones and fluoroquinolones (see section «Special warnings and precautions for use»).

A) Anaphylactic and anaphylactoid reactions are sometimes possible even after the first dose.
В) Skin and mucous membrane reactions are sometimes possible even after the first dose.
Other undesirable side effects associated with taking fluoroquinolone include:

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

Shelf life

2 years.
The shelf life is 24 hours after removing the protective bag.

Storage conditions

Do not freeze. Store in the original packaging. This medicinal product does not require any special temperature storage conditions. Keep out of the reach of children.

Incompatibilities

The medicine should not be mixed simultaneously with heparin, alkaline solutions (e.g. sodium bicarbonate), with other medicinal products, except those indicated in the section “Posology and method of administration”.

Packaging

100 ml of the medicine in an infusion pack, in a protective bag. 10 packs in a cardboard box.

Prescription status

Available on prescription.

Manufacturer

INFOMED FLUIDS S.R.L.

Manufacturer’s location and address of the place of operation
Str. Theodor Pallady nr. 50, sector 3, Bucuresti, cod 032266, Romania.

Applicant

TEKHNOPAK MANUFACTURE LIMITED.

Applicant ‘s location
Office 4, Unit 1, North Park, Finglas, Dublin, D11 E6C3, Ireland.