INSTRUCTION

for medical use of the medicinal product

 

LEVOFLOXACIN

 

Composition:

active substance: levofloxacin;

100 ml of solution contains levofloxacin hemihydrate equivalent to levofloxacin 500 mg;

excipients: anhydrous glucose, concentrated hydrochloric acid, sodium hydroxide, water for injection.

 

Pharmaceutical form. Solution for infusion.

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

 

Pharmacotherapeutic group.

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

 

Pharmacological properties.

Pharmacodynamics.

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

Like other fluoroquinolones, levofloxacin is inactive for spirochetes.

Pharmacokinetics.

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

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

Distribution.

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

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

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

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

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

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

Biotransformation. Levofloxacin is poorly metabolised. Dysmetyl-levofloxacin and levofloxacin N-oxide are metabolites. These metabolites are less than 5% of the amount of the drug excreted in the urine.

Elimination. Following oral and intravenous administration, levofloxacin is slowly eliminated from the plasma (partial ejection is 6-8 hours). It is mainly excreted by the kidneys (> 85 % of the administered dose).

 

Clinical particulars.

Indications.

Bacterial inflammations caused by levofloxacin-susceptible bacteria:

1) community-acquired pneumonia*;

2) complicated urinary tract infections including acute pyelonephritis;

3) complicated skin and soft tissue infections*;

4) chronic bacterial prostatitis;

5) pulmonary anthrax: post-exposure prophylaxis and radical treatment.

*For the above-mentioned infectious diseases, levofloxacin should only be prescribed in cases where other antibacterial drugs, which are primarily used for the initial treatment of these infections, are not sufficiently effective.

Official recommendations for the appropriate use of antibacterial agents must be considered.

 

Contraindications.

Hypersensitivity to levofloxacin, other fluoroquinolones or any component of the drug. Epilepsy. Patients with complaints of tendon side effects after previous use of quinolones. Children (under 18 years of age). Pregnancy or breastfeeding.

 

Interaction with other medicinal products and other forms of interaction.

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

No pharmacokinetic interactions of levofloxacin were found with theophylline in a clinical study. However a pronounced lowering of the seizure threshold may occur when quinolones are given concurrently with theophylline and non-steroidal anti-inflammatory drugs as well as other agents lowering the seizure threshold. Levofloxacin concentrations were about 13% higher in the presence of fenbufen than when administered alone.

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

Cyclosporine

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

Vitamin K antagonists

Due to the possibility of bleeding in patients taking levofloxacin in combination with any vitamin K antagonist (e.g. warfarin), coagulation tests should be monitored if these drugs are used concomitantly.

The pharmacokinetics of levofloxacin was not changed when administered concomitantly with the following drugs: calcium carbonate, digoxin, glibenclamide, ranitidine, warfarin.

Drugs known to prolong QT interval

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

Theophylline

Levofloxacin does not effect on the pharmacokinetics of theophylline, which is predominantly metabolised by means of CYP1A2. Therefore it can be assumed that levofloxacin is not CYP1A2 inhibitor.

Glucocorticoids

The concomitant administration of glucocorticoids increases the risk of tendon rupture.

Other

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

It is not recommended to use levofloxacin simultaneously with alcohol.

 

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 (see section “Adverse reactions”). Treatment of these patients with levofloxacin should only be initiated in the absence of alternative treatment options and after careful benefit/risk assessment (see section “Contraindications”).

Prolonged, debilitating and potentially irreversible serious adverse reactions

In very rare cases, the prolonged (months or years), debilitating and potentially irreversible serious adverse reactions affecting different body systems (musculoskeletal, nervous, psyche systems and sensory organs) have been reported in patients receiving quinolones and fluoroquinolones, regardless of age and risk factors.  The use of drug should be discontinued immediately after the first signs or symptoms of any serious adverse reaction and seek medical advice and consult a doctor.

Patients with severe renal impairment, as well as those with severe atherosclerosis of the cerebral vessels and cerebral circulation disorders, should exercise caution when using this drug. In case of side effects, especially reactions from the central nervous system (CNS) and allergic reactions, which may occur after the first dose of the drug, the use of levofloxacin should be discontinued.

Duration of administration

The recommended duration of administration of the medicinal product is at least 60 minutes for 500 mg of infusion solution. It is known that ofloxacin may cause tachycardia and a temporary increase in blood pressure during infusion. In rare cases, this may result in a sudden drop in blood pressure and circulatory collapse. If a marked drop in blood pressure is observed during the administration of levofloxacin (the S-isomer of ofloxacin), the infusion should be discontinued immediately.

For methicillin-resistant S. aureus (MRSA), there is a very high probability of 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 microorganism to levofloxacin (antibacterial agents usually recommended for the treatment of MRSA infections cannot be used).

Infections caused by Escherichia coli

Resistance of E. coli – the most common pathogen in urinary tract infections – to fluoroquinolones varies across different countries of the European Union. Physicians prescribing therapy are advised to consider local prevalence of E. coli resistance to fluoroquinolones.

Pulmonary anthrax

Recommendations for use in humans are based on in vitro susceptibility data of Bacillus anthracis, experimental data obtained from animal studies, and limited human data. Physicians should refer to national and/or international consensus documents on the treatment of anthrax.

Patients receiving vitamin K antagonists

Due to the potential increase in coagulation test values (prothrombin time/international normalized ratio (INR)) and/or bleeding in patients treated with fluoroquinolones, including levofloxacin, in combination with vitamin K antagonists (e.g. warfarin), monitoring of coagulation test results is recommended when these medicinal products are used concomitantly (see section “Interaction with other medicinal products and other forms of interaction”).

Patients with severe renal impairment, as well as those with severe atherosclerosis of the cerebral vessels and cerebral circulation disorders, should exercise caution when using this drug.

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

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

In very severe pneumonia caused by pneumococcus, levofloxacin cannot give an optimal therapeutic effect. In nosocomial infections caused by Ps. Aeruginosa, and in severe cases of pneumococcal pneumonia, a combination therapy may be required.

Tendinitis and tendon rupture

Tendinitis 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 in patients receiving levofloxacin at the daily dose of 1000 mg . The risk of tendinitis and tendon rupture is increased in elderly patients, patients with renal impairment, patients with solid organ transplants, and those treated concurrently 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, occurring during or after treatment with the medicinal product (including several weeks after treatment), may be indicative of Clostridium difficile-associated disease, the most severe form of which is pseudomembranous colitis. The severity of Clostridium difficile-associated diseases may range from mild to life-threatening, with pseudomembranous colitis being the most severe form (see section “Adverse reactions”). Therefore, it is important to consider this diagnosis in patients who develop severe diarrhoea during or after treatment with levofloxacin. If pseudomembranous colitis is suspected, treatment with the medicinal product should be discontinued immediately and appropriate symptomatic and specific therapy initiated without delay. Anti-peristaltic medicinal products are contraindicated in this clinical situation.

Patients predisposed to seizures

Quinolones may lower the seizure threshold and provoke seizures. Levofloxacin is contraindicated in patients with a history of epilepsy (see section “Contraindications”). As with other quinolones, it should be used with extreme caution in patients predisposed to seizures and in those receiving concomitant treatment with active substances that lower the seizure threshold, such as theophylline (see section “Interaction with other medicinal products and other forms of interaction”). If seizures occur, treatment with levofloxacin must be discontinued.

Glucose-6-phosphate dehydrogenase deficiency

Patients with latent or diagnosed glucose-6-phosphate dehydrogenase deficiency may be prone to haemolytic reactions when treated with quinolone antibacterial agents. Therefore, levofloxacin should be used with caution in such patients, with monitoring for possible haemolysis.

Prevention of photosensitivity reactions

Photosensitivity reactions have been reported with the use of levofloxacin (see section “Adverse reactions”). Patients taking levofloxacin should avoid exposure to strong sunlight and artificial ultraviolet radiation (UV lamps, sunbeds) during treatment and for 48 hours after stopping the medicine in order to prevent photosensitivity reactions.

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-injurious behaviour – sometimes after only a single dose of levofloxacin.

In the event of psychotic reactions, levofloxacin must be discontinued. Caution is advised when using levofloxacin in patients with existing or a history of psychiatric disorders.

Renal impairment

As levofloxacin is primarily excreted by the kidneys, dose adjustment is required in patients with renal impairment (see section “Method of administration and dosage”).

Hypersensitivity reactions

Levofloxacin may occasionally cause serious, potentially fatal hypersensitivity reactions (including angioedema and anaphylactic shock), sometimes even after the first dose. In case of hypersensitivity reactions, treatment with levofloxacin must be discontinued, medical advice should be sought, and appropriate therapy initiated.

Severe skin reactions

Severe skin reactions have been reported with levofloxacin, including toxic epidermal necrolysis (also known as Lyell’s syndrome), Stevens-Johnson syndrome, and drug reaction with eosinophilia and systemic symptoms (DRESS), which may be life-threatening or fatal. Patients should be informed of the signs and symptoms of these serious skin reactions and monitored closely. If symptoms suggestive of such reactions appear, treatment with levofloxacin should be discontinued immediately and alternative therapy considered. Patients who have experienced Stevens-Johnson syndrome, toxic epidermal necrolysis or DRESS with the use of levofloxacin must not be re-exposed to levofloxacin.

Dysglycaemia

Alterations in blood glucose levels (hyperglycaemia and hypoglycaemia) have been reported during treatment with quinolones, particularly in diabetic patients receiving concomitant oral hypoglycaemic agents (including glibenclamide) or insulin. Cases of hypoglycaemic coma have been reported. Diabetic patients should be carefully monitored for blood glucose levels.

QT interval prolongation

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

  - congenital or acquired syndrome of QT interval prolongation;

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

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

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

Elderly patients and women may be more sensitive to QT interval prolongation. Therefore, caution should be taken when using fluoroquiolones, including levofloxacin, in these populations.

Aortic aneurysm and dissection, and heart valve regurgitation/insufficiency

Epidemiological studies indicate an increased risk of aortic aneurysm and dissection, particularly in elderly patients, as well as aortic and mitral valve regurgitation following fluoroquinolone use. Cases of aortic aneurysm and dissection, sometimes complicated by rupture (including fatal cases), and regurgitation/insufficiency of any heart valve have been reported in patients receiving fluoroquinolones (see section “Adverse reactions”).

Therefore, fluoroquinolones should only be used after a careful assessment of the benefit/risk balance and consideration of alternative treatment options in patients with a positive family history of aneurysmal disease or congenital heart valve disease, or in patients diagnosed with aortic aneurysm and/or aortic dissection or heart valve disease, or in the presence of risk factors or conditions that predispose to:

- both aortic aneurysm and dissection and valve regurgitation/incompetence (e.g. connective tissue disorders such as Marfan syndrome or Ehlers-Danlos syndrome, Turner syndrome, Behçet’s disease, arterial hypertension, rheumatoid arthritis); or additionally:

- aortic aneurysm and dissection (e.g. vascular disorders such as Takayasu arteritis or giant cell arteritis, known atherosclerosis, or Sjögren’s syndrome); or additionally:

- heart valve regurgitation/insufficiency (e.g. infectious endocarditis).

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

In the event of sudden abdominal pain, chest pain, or back pain, patients should be advised to seek immediate medical attention in an emergency department.

Patients should also be advised to promptly consult a physician if they experience acute shortness of breath, a new onset of rapid heartbeat, or swelling of the abdomen or lower limbs.

Peripheral neuropathy

Cases of sensory or sensorimotor polyneuropathy resulting in paraesthesia, hypaesthesia, dysaesthesia, or weakness have been reported in patients receiving quinolones and fluoroquinolones. If symptoms of neuropathy such as pain, burning, tingling, numbness, or weakness occur, patients should inform their physician in order to prevent the development of a potentially irreversible condition (see section “Adverse reactions”).

Hepatobiliary disorders

Cases of hepatic necrosis up to life-threatening hepatic failure have been reported with the use of levofloxacin, primarily in patients with severe underlying conditions such as sepsis (see section “Adverse reactions”). Patients should be advised to stop treatment and consult a physician if signs and symptoms of liver disease develop, such as anorexia, jaundice, dark urine, pruritus, or abdominal pain.

Exacerbation of myasthenia gravis

Fluoroquinolones, including levofloxacin, have neuromuscular blocking activity and may exacerbate muscle weakness in patients with myasthenia gravis. Serious adverse reactions, including fatalities and respiratory support–requiring events, have been associated with fluoroquinolone use in patients with myasthenia gravis during the post-marketing period. Levofloxacin is not recommended in patients with a history of myasthenia gravis.

Visual disturbances

If vision is impaired or any effects on the eyes are experienced, an ophthalmologist should be consulted immediately (see sections “Effects on ability to drive and use machines” and “Adverse reactions”).

Superinfection

The use of levofloxacin, particularly over prolonged periods, may result in overgrowth of non-susceptible microorganisms. If superinfection occurs during treatment, appropriate measures should be taken.

Interference with laboratory tests

In patients treated with levofloxacin, urine opiate screening tests may give false-positive results. Confirmation of positive opiate test results may be required using more specific methods.

Excipients

This medicinal product contains 5 g of glucose per dose (100 mL vial) and should therefore be used with caution in patients with diabetes mellitus.

 

Pregnancy and lactation.

Pregnancy

There is limited data on the use of levofloxacin in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. However, in the absence of human data and based on experimental data suggesting a risk of damage to developing cartilage associated with fluoroquinolones, levofloxacin is contraindicated during pregnancy (see section “Contraindications”).

Breastfeeding

Levofloxacin is contraindicated in breastfeeding women. There is insufficient information on the excretion of levofloxacin in human breast milk. However, other fluoroquinolones are known to be excreted in human milk. In the absence of human data and due to the potential risk of cartilage damage in the growing organism observed in experimental studies with fluoroquinolones, levofloxacin is contraindicated during breastfeeding (see section “Contraindications”).

Fertility

Levofloxacin did not impair fertility or reproductive function in animal studies.

 

Effects on ability to drive and use machines.

Some adverse reactions (e.g. dizziness/vertigo, drowsiness, visual disturbances) may impair the patient’s ability to concentrate and react, and therefore may pose a risk in situations where these abilities are of special importance (e.g. when driving or operating machinery).

 

Method of administration and dosage.

A skin test for sensitivity must be performed prior to administration.

Levofloxacin solution should be administered by slow intravenous infusion once or twice daily. The dose depends on the type and severity of the infection and the susceptibility of the suspected pathogen(s). After a few days of treatment, if the patient's condition allows, a switch from initial intravenous administration to oral administration (levofloxacin tablets 250 mg or 500 mg) may be made. The duration of treatment depends on the course of the disease. Administration should be continued for at least 48-72 hours after the disappearance of clinical symptoms. Levofloxacin solution for infusion is intended for slow intravenous administration only and should be administered once or twice daily. The infusion duration should be no less than 30 minutes for a 250 mg dose or no less than 60 minutes for a 500 mg dose.

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

Indication	Daily dosage regimen, duration of treatment*
Community-acquired pneumonia	500 mg, once or twice a day, 7-14 days
Complicated urinary tract infections	500 mg, once a day, 7-14 days
Acute pyelonephritis	500 mg, once a day, 7-10 days
Chronic bacterial prostatitis	500 mg, once a day, 28 days
Complicated skin and soft tissue infections	500 mg, once or twice a day, 7-14 days
Pulmonary anthrax	500 mg, once a day, 8 weeks

* Depending on the patient's clinical condition, a switch from initial intravenous to oral administration with the same dosage may be possible after a few days (usually after 2-4 days).

 

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

 

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

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

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

 

Dose adjustment is not necessary in patients with hepatic impairment, as levofloxacin is only minimally metabolised by the liver and is primarily excreted by the kidneys.

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

When levofloxacin is to be infused sequentially with other medicinal products, the solutions must not be administered simultaneously via the same intravenous line.

After opening the vial, any remaining solution should be discarded.

Levofloxacin should be administered by slow intravenous drip infusion. The duration of administration for one vial (100 mL of infusion solution containing 500 mg of levofloxacin) must be no less than 60 minutes. The recommended infusion time for a 250 mg dose is 30 minutes.

Depending on the patient’s clinical condition, a switch from intravenous to oral administration with an equivalent dose may be possible after a few days.

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

Mixing with other infusion solutions

Levofloxacin is compatible with the following infusion solutions:

0.9% sodium chloride solution;

5% glucose monohydrate solution;

2.5% glucose in Ringer’s solution;

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

When administering sequential infusions of levofloxacin and other drugs, they should not be administered into the same vein.

After opening the vial, any remaining drug should be disposed of.

 

Children.

This medicinal product is contraindicated in children, as damage to the articular cartilage cannot be excluded.

 

Overdose.

Symptoms: confusion, dizziness, tremor, impaired consciousness and convulsive seizures, QT interval prolongation, or exacerbation of other adverse reactions. Post-marketing experience with levofloxacin has reported central nervous system effects including confusion, seizures, hallucinations, and tremor.

Treatment: symptomatic and supportive. ECG monitoring should be considered due to the possibility of QT interval prolongation. Levofloxacin is not effectively removed by haemodialysis, peritoneal dialysis, or continuous ambulatory peritoneal dialysis (CAPD); there is no specific antidote.

 

Adverse reactions.

Adverse reactions listed below are classified according to organ systems and frequency. Frequency categories are defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), and frequency not known (cannot be estimated from the available data).

In each group, adverse reactions are listed in order of decreasing severity.

Infections and infestations: uncommon – fungal infections, including Candida, overgrowth of other resistant microorganisms.

Blood and lymphatic system disorders: uncommon – eosinophilia, leukopenia; rare – neutropenia, thrombocytopenia which may lead to increased bleeding tendency; frequency not known – agranulocytosis, haemolytic anaemia, pancytopenia.

Immune system disorders: rare – angioedema, hypersensitivity (see section “Precautions for use”); frequency not known – anaphylactic shock, anaphylactoid shock, which may occur even after the first dose (see section “Precautions for use”).

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

Metabolism and nutrition disorders: uncommon – anorexia; rare – hypoglycaemia, especially in diabetic patients; frequency not known – hyperglycaemia, hypoglycaemic coma (see section “Precautions for use”).

Psychiatric disorders*: common – insomnia; uncommon – anxiety, confusion, nervousness; rare – psychotic reactions (including hallucinations, paranoia), depression, agitation, abnormal dreams, nightmares; frequency not known – psychotic disorders with self-injurious behaviour including suicidal ideation or acts (see section “Precautions for use”).

Nervous system disorders*: common – headache, dizziness; uncommon – drowsiness, tremor, dysgeusia; rare – seizures (see sections “Contraindications” and “Precautions for use”), paraesthesia;

frequency not known – peripheral sensory neuropathy (see section “Precautions for use”), peripheral sensorimotor neuropathy (see section “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 “Precautions for use”);

frequency not known – transient vision loss (see section “Precautions for use”).

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

Cardiac disorders**: rare – tachycardia, palpitations; frequency not known – ventricular tachycardia which may lead to cardiac arrest, ventricular arrhythmia and torsade de pointes (predominantly in patients with risk factors for QT prolongation), hypotension, QT interval prolongation, collapse, vasculitis, phlebitis.

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

Gastrointestinal disorders: common – diarrhoea, vomiting, nausea; uncommon – abdominal pain, dyspepsia, flatulence, constipation; frequency not known – haemorrhagic diarrhoea, which may be indicative of enterocolitis including pseudomembranous colitis (see section “Precautions for use”), pancreatitis.

Hepatobiliary disorders: common – elevated liver enzymes (ALT/AST, alkaline phosphatase, GGT);

uncommon – increased blood bilirubin; frequency not known – jaundice and severe liver damage including acute liver failure (mostly in patients with severe underlying diseases, see section “Precautions for use”), hepatitis.

Skin and subcutaneous tissue disorders: uncommon – rash, pruritus, urticaria, skin redness, hyperhidrosis; rare – drug reaction with eosinophilia and systemic symptoms (DRESS), localised drug eruption; frequency not known – toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme exudativum, photosensitivity reactions, increased sensitivity to sunlight and ultraviolet light (see section “Precautions for use”), leukocytoclastic vasculitis, stomatitis.

Musculoskeletal and connective tissue disorders*: uncommon – arthralgia, myalgia; rare – tendon disorders (see sections “Contraindications” and “Precautions for use”), including tendinitis (e.g. Achilles tendon), muscular weakness which may be significant in patients with severe myasthenia gravis; frequency not known – rhabdomyolysis, tendon rupture (see sections “Contraindications” and “Precautions for use”), ligament rupture, muscle rupture, arthritis.

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

General disorders and administration site conditions*: common – infusion site reactions including redness and pain; uncommon – asthenia; rare – pyrexia; frequency not known – general weakness, pain (including back, chest and limb pain); as with other fluoroquinolones, attacks of porphyria may occur in patients with porphyria.

* In very rare cases, patients receiving quinolones and fluoroquinolones have reported long-lasting (up to months or years), disabling and potentially irreversible serious adverse drug reactions affecting multiple systems and senses, regardless of pre-existing risk factors (including reactions such as tendinitis, tendon rupture, arthralgia, limb pain, gait disturbances, neuropathies associated with paraesthesia, depression, fatigue, memory impairment, sleep disturbances, and impairment of hearing, vision, taste and smell).

** In patients treated with fluoroquinolones, cases of aortic aneurysm and dissection (sometimes complicated by rupture, including fatal cases), as well as regurgitation/incompetence of any of the heart valves, have been reported (see section “Precautions for use”).

 

Adverse reactions reporting

Adverse reactions reporting after marketing authorisation is an important procedure. 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 national reporting system.

 

Shelf life.

3 years.

 

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °С. Keep out of reach of children.

Any unused medicinal product must be disposed.

 

Incompatibility.

Levofloxacin should not be mixed with heparin or solutions with an alkaline reaction (e.g. sodium bicarbonate), with other medicines, other than medicines listed in the section “Method of administration and dosage”.

 

Packaging. 100 ml in a container. 1 container in PVC film along with the instruction for medical use in a box.

 

Terms of dispensing. On prescription.

 

 

Date of last update.

23.04.2021