Lebel

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT LEBEL (LEBEL)

Composition:

Active substance: levofloxacin;

1 tablet contains levofloxacin 500 mg (as levofloxacin hemihydrate);

Excipients: microcrystalline cellulose, hypromellose, crospovidone, sodium stearyl fumarate; coating Opadry Y1 7000 White: hypromellose, titanium dioxide (E 171), polyethylene glycol 400.

Pharmaceutical form. Film-coated tablets.

Main physical and chemical properties: elongated, film-coated tablets, white in colour, with a break line on one side.

Pharmacotherapeutic group.

Antibacterial agents of the quinolone group. Fluoroquinolones. ATC code J01M A12.

Pharmacological properties.

Pharmacodynamics.

Levofloxacin is a synthetic antibacterial agent from the group of fluoroquinolones and is the S(-) enantiomer of the racemic mixture of the drug ofloxacin.

Mechanism of action. As an antibacterial agent from the fluoroquinolone group, levofloxacin acts on the DNA gyrase and topoisomerase IV complex.

Pharmacokinetic/pharmacodynamic relationship. The degree of antibacterial activity of levofloxacin depends on the ratio of maximum serum concentration (Cmax) or area under the pharmacokinetic curve (AUC) to minimum inhibitory concentration (MIC).

Mechanism of resistance. Resistance to levofloxacin develops through a stepwise process due to mutations in the target site in both type II topoisomerases, DNA gyrase and topoisomerase IV. Other resistance mechanisms, such as impermeable barrier (common in Pseudomonas aeruginosa) and efflux mechanisms, may also affect sensitivity to levofloxacin.

Due to its mechanism of action, cross-resistance between levofloxacin and other classes of antibacterial agents is usually not observed.

Clinical breakpoints. The recommended European Committee on Antimicrobial Susceptibility Testing (EUCAST) clinical breakpoints for levofloxacin MIC values, which differentiate susceptible microorganisms from those with intermediate susceptibility and intermediate from resistant microorganisms, are presented in the table below for MIC testing (mg/L).

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

Antibacterial spectrum

Resistance prevalence may vary geographically and over time for selected species; it is advisable to obtain local resistance information, especially when treating severe infections. Advice from a specialist should be sought when local resistance prevalence renders the utility of the agent at least questionable for certain types of infections.

*Methicillin-resistant Staphylococcus aureus is highly likely to exhibit cross-resistance to fluoroquinolones, including levofloxacin.

Pharmacokinetics.

Absorption

Levofloxacin is rapidly and almost completely absorbed after oral administration, with peak plasma concentrations reached within 1 hour. Absolute bioavailability is approximately 99–100%.

Food has almost no effect on the absorption of levofloxacin.

Steady-state concentrations are achieved within 48 hours with a dosing regimen of 500 mg once or twice daily.

Distribution

Approximately 30–40% of levofloxacin is protein-bound in plasma. The mean volume of distribution of levofloxacin is approximately 100 L after single and repeated 500 mg doses, indicating good tissue penetration throughout the body.

Penetration into tissues and body fluids

Levofloxacin has the ability to penetrate into bronchial mucosa, bronchoalveolar fluid, alveolar macrophages, lung tissue, skin (blister fluid), prostate tissue, and urine. Levofloxacin penetrates poorly into cerebrospinal fluid.

Biotransformation

Levofloxacin undergoes minimal metabolism. The metabolites are desmethyl-levofloxacin and levofloxacin N-oxide. These metabolites account for less than 5% of the total drug excreted in urine. Levofloxacin is stereochemically stable and does not undergo chiral inversion.

Elimination

After both oral and intravenous administration, levofloxacin is eliminated from plasma relatively slowly (elimination half-life is 6–8 hours). Total clearance of levofloxacin after a single 500 mg dose was 175 ± 29.2 mL/min. There is no significant difference in the pharmacokinetics of levofloxacin between intravenous and oral administration, indicating interchangeability of these routes.

Linearity

Levofloxacin exhibits linear pharmacokinetics over the range of 50–1000 mg.

Patients with renal impairment

Renal impairment affects the pharmacokinetics of levofloxacin. With reduced renal function, renal excretion and creatinine clearance decrease, and elimination half-life increases, as shown in the table below:

Pharmacokinetics in renal impairment after a single 500 mg oral dose.

Geriatric patients

There are no significant differences in the pharmacokinetics of levofloxacin between younger patients and elderly patients, except for differences related to creatinine clearance.

Gender differences

Separate analysis of female and male patients demonstrated minor differences in the pharmacokinetics of levofloxacin depending on gender. There is no evidence that these gender differences are clinically significant.

Clinical characteristics.

Indications.

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

• acute bacterial sinusitis;
• exacerbation of chronic obstructive pulmonary disease, including bronchitis;
• community-acquired pneumonia;
• complicated skin and soft tissue infections;
• uncomplicated cystitis

(when treating the above-mentioned infections, the drug should be used only if other antibacterial agents typically prescribed for initial treatment of these infections cannot be used);

• acute pyelonephritis and complicated urinary tract infections;
• chronic bacterial prostatitis;
• pulmonary form of anthrax: post-exposure prophylaxis and treatment.

Levofloxacin in this pharmaceutical form (tablets) may be used to complete the course of therapy in patients who have shown clinical improvement during initial treatment with levofloxacin intravenous solution.

Official recommendations regarding appropriate use of antibacterial agents should be taken into account.

Contraindications.

Hypersensitivity to levofloxacin, other fluoroquinolones, or to any component of the drug; epilepsy; tendon damage following previous use of fluoroquinolones; childhood age; pregnancy or breastfeeding.

Interaction with other medicinal products and other forms of interaction.

Antacids containing magnesium and aluminium: medicinal products containing iron or zinc salts, didanosine.

Absorption of levofloxacin is significantly reduced when administered concomitantly with antacids containing magnesium and aluminium, medicinal products containing iron salts, or with didanosine (didanosine in a buffered tablet containing aluminium or magnesium). Concurrent administration of fluoroquinolones with multivitamins containing zinc leads to reduced absorption.

The recommended interval between administration of levofloxacin and the above-mentioned medicinal products should be at least 2 hours.

Calcium salts have minimal effect on levofloxacin absorption.

Sucralfate

The bioavailability of levofloxacin tablets is significantly reduced when administered concomitantly with sucralfate. If a patient needs to receive both sucralfate and levofloxacin, it is preferable to take sucralfate 2 hours after administration of levofloxacin (see section "Dosage and administration").

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

No pharmacokinetic interaction between levofloxacin and theophylline has been observed. However, a significant reduction in seizure threshold may occur when quinolones are administered concomitantly with theophylline, NSAIDs, or other medicinal products that lower the seizure threshold. It is known that levofloxacin concentrations are approximately 13% higher when co-administered with fenbufen compared to levofloxacin alone.

Probenecid and cimetidine

Probenecid and cimetidine have a statistically significant effect on the elimination of levofloxacin.

Renal clearance of levofloxacin is reduced by 24% with concomitant administration of cimetidine and by 34% with probenecid. This is explained by the fact that both drugs can block tubular secretion of levofloxacin. Levofloxacin should be used with caution when administered concomitantly with medicinal products affecting tubular secretion, such as probenecid and cimetidine, especially in patients with renal impairment.

Other medicinal products

Calcium carbonate, digoxin, glyburide, and ranitidine do not exhibit clinically significant effects on the pharmacokinetics of levofloxacin when administered concomitantly.

Effect of the drug on other medicinal products

Cyclosporine

The elimination half-life of cyclosporine increases by 33% when administered concomitantly with levofloxacin.

Vitamin K antagonists

When administered concomitantly with vitamin K antagonists (e.g., warfarin), coagulation test parameters (INR/international normalized ratio) may increase and/or bleeding may occur, which can be severe. Therefore, in patients receiving concomitant vitamin K antagonists, coagulation parameters should be monitored (see section "Special precautions for use").

MEDICINAL PRODUCTS THAT PROLONG THE QT INTERVAL

Levofloxacin, like other fluoroquinolones, should be used with caution in patients receiving medicinal products known to prolong the QT interval, such as class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, and antipsychotic agents (see section "Special precautions for use" ("QT interval prolongation")).

Levofloxacin does not affect the pharmacokinetics of theophylline, which is primarily metabolized via CYP1A2; therefore, levofloxacin is not considered an inhibitor of CYP1A2.

Other forms of interaction

Food intake

No clinically significant interaction between the drug and food has been observed; therefore, levofloxacin tablets may be taken regardless of food intake.

Special precautions for use

The use of the drug should be avoided in patients who have previously experienced serious adverse reactions to quinolones or fluoroquinolones. Treatment of these patients with levofloxacin should only be initiated if there are no alternative treatment options and after careful benefit-risk assessment.

Resistance

Levofloxacin may not provide optimal therapeutic effect in very severe pneumonia caused by pneumococci.

Hospital-acquired infections caused by P. aeruginosa may require combination therapy.

Methicillin-resistant S. aureus (MRSA)

Methicillin-resistant Staphylococcus aureus (MRSA) is resistant to fluoroquinolones, including levofloxacin. Therefore, levofloxacin is not recommended for treatment of MRSA infections, except in cases where susceptibility of the microorganism to levofloxacin has been confirmed.

Levofloxacin may be prescribed for the treatment of acute bacterial sinusitis and acute exacerbation of chronic bronchitis when these conditions have been adequately diagnosed.

Escherichia coli resistant to levofloxacin may be the most common pathogen causing urinary tract infections, and this should be taken into account when prescribing levofloxacin to patients with urinary tract diseases. When prescribing fluoroquinolones, local prevalence of fluoroquinolone resistance in Escherichia coli should be considered.

For the pulmonary form of anthrax, use is based on in vitro susceptibility data of Bacillus anthracis, experimental animal data, and limited human use. Physicians should refer to national and/or international consensus guidelines for the treatment of anthrax.

Long-term, disabling, and potentially irreversible serious adverse reactions

Very rarely, in patients receiving quinolones or fluoroquinolones regardless of age or risk factors, long-term (lasting months or years), disabling, and potentially irreversible serious adverse reactions affecting various systems of the body—sometimes multiple systems simultaneously (e.g., musculoskeletal, nervous, psychiatric, and sensory organs)—have been reported. The drug should be discontinued immediately at the first signs or symptoms of any serious adverse reaction, and medical advice should be sought.

Tendinitis and tendon rupture

Tendinitis and tendon rupture (not limited to the Achilles tendon), sometimes bilateral, may occur within 48 hours after initiation of treatment with quinolones or fluoroquinolones, and even several months after discontinuation of treatment in patients receiving daily doses of 1000 mg levofloxacin. The risk of tendinitis and tendon rupture is increased in elderly patients, patients with impaired renal function, patients with solid organ transplants, and patients receiving concomitant corticosteroid therapy. Therefore, concomitant use of corticosteroids should be avoided.

If early signs of tendinitis (e.g., painful swelling, inflammation) occur, treatment with the drug should be discontinued, and alternative therapy should be considered. The affected limb(s) should be appropriately managed (e.g., immobilization). Corticosteroids should not be used if signs of tendinopathy occur.

Clostridium difficile-associated disease

Diarrhea, particularly severe, persistent, or with blood, occurring during or after treatment (including several weeks after treatment) with levofloxacin, may be symptoms of Clostridium difficile-associated disease (CDAD). CDAD may range in severity from mild to life-threatening; the most severe form being pseudomembranous colitis. If pseudomembranous colitis is suspected, the drug should be discontinued immediately, and patients should be urgently treated with supportive measures. Specific therapy may also be required (e.g., oral vancomycin). Antiperistaltic agents are contraindicated in this clinical situation.

Patients predisposed to seizures

The drug is contraindicated in patients with a history of epilepsy. As with other quinolones, levofloxacin should be used with extreme caution in patients predisposed to seizures, particularly those with prior central nervous system disorders, those receiving concomitant therapy with phenylbutazone or similar NSAIDs, or drugs that increase seizure susceptibility (lower the seizure threshold), such as theophylline (see section "Interaction with other medicinal products and other types of interactions"). If seizures occur, levofloxacin therapy should be discontinued.

Patients with glucose-6-phosphate dehydrogenase deficiency

Patients with latent or overt glucose-6-phosphate dehydrogenase (G6PD) deficiency are prone to hemolytic reactions when treated with quinolone-class antibacterial agents; therefore, levofloxacin should be used with caution in such patients.

Patients with renal impairment

Since levofloxacin is primarily excreted by the kidneys, dose adjustment is required in patients with impaired renal function (renal insufficiency) (see section "Dosage and administration").

Hypersensitivity reactions

Levofloxacin may occasionally cause serious, potentially fatal hypersensitivity reactions (e.g., angioedema up to anaphylactic shock) after administration of the initial dose (see section "Adverse reactions"). In such cases, patients should discontinue treatment immediately and seek medical advice.

Severe skin reactions

Severe skin reactions, including toxic epidermal necrolysis (TEN, also known as Lyell's syndrome), Stevens-Johnson syndrome, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), have been reported with levofloxacin use, which may be life-threatening or fatal (see section "Adverse reactions"). Patients should be informed of the signs and symptoms of these severe skin reactions, and close monitoring is required during treatment. If signs or symptoms suggestive of these reactions occur, levofloxacin should be discontinued immediately and alternative therapy considered. Re-administration of levofloxacin is contraindicated in patients who have experienced a serious reaction such as Stevens-Johnson syndrome, TEN, or DRESS syndrome during prior treatment.

Blood glucose alterations

As with all quinolones, changes in blood glucose levels—including both hypoglycemia and hyperglycemia—have been reported, usually in diabetic patients receiving concomitant therapy with oral hypoglycemic agents (e.g., glyburide) or insulin. Cases of hypoglycemic coma have been reported. Close monitoring of blood glucose levels is recommended in diabetic patients (see section "Adverse reactions").

Phototoxicity prevention

Although phototoxicity is very rare with levofloxacin, patients should avoid unnecessary exposure to strong sunlight or artificial UV radiation (e.g., UV lamps, sunbeds) during treatment and for 48 hours after discontinuation of levofloxacin due to the potential for photosensitization.

Patients receiving vitamin K antagonists

Due to the potential for increased coagulation test parameters (PT/INR) and/or bleeding in patients taking levofloxacin concomitantly with vitamin K antagonists (e.g., warfarin), coagulation parameters should be monitored (see section "Interaction with other medicinal products and other types of interactions").

Psychotic reactions

Psychotic reactions have been reported in patients receiving quinolones, including levofloxacin. In rare cases, these reactions have progressed to suicidal ideation and self-destructive behavior, sometimes even after a single dose of levofloxacin (see section "Adverse reactions"). If such reactions occur, levofloxacin should be discontinued and appropriate measures taken. Levofloxacin should be used with caution in patients with psychiatric disorders or a history of psychiatric illness.

QT interval prolongation

Fluoroquinolones, including levofloxacin, should be used with caution in patients with known risk factors for QT interval prolongation, such as:

• congenital long QT syndrome;
• concomitant use of drugs known to prolong the QT interval (e.g., class IA and III antiarrhythmics, tricyclic antidepressants, macrolides);
• uncorrected electrolyte imbalances (e.g., hypokalemia, hypomagnesemia);
• advanced age;
• cardiac disease (e.g., heart failure, myocardial infarction, bradycardia);
• concomitant use of drugs that prolong the QT interval (including class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics); elderly patients and women are more sensitive to drugs that prolong the QT interval, so caution is required when using fluoroquinolones, including levofloxacin, in these patient groups (see sections "Interaction with other medicinal products and other types of interactions", "Dosage and administration" ("Elderly patients"), "Overdose", "Adverse reactions").

Peripheral neuropathy

Cases of sensory or sensorimotor polyneuropathy, leading to paresthesia, hyposthesia, dysesthesia, 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 immediately to prevent potentially irreversible damage.

Hepatobiliary disorders

Cases of necrotizing hepatitis, progressing to life-threatening liver failure, have been reported with levofloxacin use, primarily in patients with severe underlying conditions such as sepsis (see section "Adverse reactions"). Patients should be advised to discontinue treatment and consult a physician if symptoms of liver disease occur, 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. In the post-marketing period, serious adverse reactions, including fatal cases and conditions requiring respiratory support, have been associated with fluoroquinolone use in patients with myasthenia gravis. Levofloxacin is not recommended for use in patients with a history of myasthenia gravis.

Visual disturbances

If any visual disturbances or adverse reactions affecting the eyes occur during levofloxacin treatment, patients should seek immediate ophthalmological consultation (see sections "Ability to influence reaction speed when driving or operating machinery" and "Adverse reactions").

Superinfection

With the use of levofloxacin, particularly prolonged use, opportunistic infections and overgrowth of resistant microorganisms may occur. Appropriate measures should be taken if secondary infection develops.

Laboratory tests

In patients receiving levofloxacin, urine opiate screening may yield false-positive results. Confirmation of positive opiate results by specific methods may be necessary.

Levofloxacin may inhibit the growth of Mycobacterium tuberculosis, potentially leading to false-negative results in bacteriological diagnosis of tuberculosis.

Aortic aneurysm/dissection

Epidemiological data suggest an increased risk of aortic aneurysm or dissection with fluoroquinolone use, particularly in elderly patients. Therefore, fluoroquinolone antibiotics should only be used after careful benefit-risk assessment and consideration of alternative treatment options in patients with aortic aneurysm/dissection, those with a family history of aortic aneurysm, or those with risk factors or conditions that may predispose to aortic aneurysm/dissection (e.g., Marfan syndrome, vascular Ehlers-Danlos syndrome, Takayasu arteritis, giant cell arteritis, Behçet’s disease, hypertension, and atherosclerosis).

If sudden abdominal, chest, or back pain occurs, patients should seek immediate emergency medical attention.

Use during pregnancy or breastfeeding

Pregnancy. Data on the use of levofloxacin in pregnant women are limited.

Due to the lack of human studies and the potential for quinolones to damage developing joint cartilage, levofloxacin is contraindicated in pregnant and breastfeeding women. If pregnancy occurs during treatment, the physician should be informed immediately.

Breastfeeding period. Levofloxacin is contraindicated during breastfeeding. Information on the excretion of levofloxacin into breast milk is insufficient, although other fluoroquinolones are known to be excreted into breast milk. Due to the lack of human studies and the potential for fluoroquinolones to damage developing joint cartilage, levofloxacin should not be administered to breastfeeding women.

Fertility. Levofloxacin did not cause fertility or reproductive function disorders in animal studies.

Ability to influence reaction speed when driving or operating machinery

Patients who drive vehicles or operate machinery should be aware of possible adverse reactions affecting the nervous system (e.g., dizziness, somnolence, confusion, visual and hearing disturbances, motor disturbances, including gait disturbances), which may impair concentration or reaction speed.

Dosage and Administration.

Take tablets once or twice daily. The dose depends on the type and severity of the infection. The duration of treatment depends on the course of the disease. It is recommended to continue treatment with the drug for at least 48–72 hours after normalization of body temperature or until microbiological tests have confirmed eradication of the causative pathogens.

The tablets should be swallowed whole without chewing, with an adequate amount of liquid. For convenience in dosing, the tablet may be divided using the score line. Tablets may be taken either with food or at any other time.

The drug should be administered at least 2 hours before or after administration of iron salts, zinc salts, antacids containing magnesium or aluminum, didanosine (only for formulations containing aluminum or magnesium in buffering agents), and sucralfate (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

Tablets may be used to complete the treatment course in patients who have shown improvement during initial therapy with levofloxacin in the form of an infusion solution, using the same dosage regimen.

For adult patients with normal renal function (creatinine clearance over 50 mL/min), the following recommendations should be followed:

Dosing for patients with renal impairment in whom creatinine clearance is less than 50 ml/min:

*Administer in appropriate dosage.

1Additional doses are not required after hemodialysis or chronic ambulatory peritoneal dialysis (CAPD).

Dosing in patients with hepatic impairment. Dose adjustment is not necessary, since levofloxacin is minimally metabolized in the liver and is primarily excreted via the kidneys.

Dosing in elderly patients. If renal function is normal, dose adjustment is not required (see section "Special precautions" ("Tendinitis and tendon rupture", "QT interval prolongation")).

Children.

The use of the drug is contraindicated in children, as damage to joint cartilage cannot be excluded.

Overdose.

According to toxicity studies in animals and clinical pharmacological studies conducted with doses higher than therapeutic ones, the most important signs expected after acute levofloxacin overdose are symptoms related to the central nervous system, such as confusion, dizziness, disturbances of consciousness, and seizures, QT interval prolongation, as well as gastrointestinal reactions such as nausea and mucosal erosions.

During post-marketing use of levofloxacin, effects on the central nervous system have been observed, including confusion, convulsions, hallucinations, and tremor.

In case of overdose, symptomatic treatment should be administered. ECG monitoring is necessary due to the potential for QT interval prolongation. Antacids may be used to protect the gastric mucosa. Hemodialysis, including peritoneal dialysis and CAPD, is not effective in removing levofloxacin from the body. There are no specific antidotes.

Adverse reactions.

The frequency of adverse effects was determined using the following criteria: very common (>1/10), common (from >1/100 to <1/10), uncommon (from >1/1000 to <1/100), rare (from >1/10,000 to <1/1000), very rare (>1/10,000), frequency not known (cannot be estimated from available data).

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

Infections and infestations: uncommon – fungal infections, including Candida species, overgrowth of other resistant microorganisms, disruption of normal intestinal flora, and development of secondary infections.

Blood and lymphatic system disorders: uncommon – leukopenia, eosinophilia; rare – thrombocytopenia, neutropenia; frequency not known – pancytopenia, agranulocytosis, hemolytic anemia.

Immune system disorders: rare – angioneurotic edema, hypersensitivity (see section "Special precautions"); frequency not known – anaphylactic/anaphylactoid shock (see section "Special precautions").

Metabolism and nutrition disorders: uncommon – anorexia; rare – hypoglycemia, mainly in diabetic patients, hypoglycemic coma (see section "Special precautions"); frequency not known – hyperglycemia (see section "Special precautions").

Psychiatric disorders*: common – insomnia; uncommon – anxiety, restlessness, fear, confusion, nervousness; rare – psychotic reactions (including hallucinations, paranoia), depression, agitation, abnormal dreams, night terrors, delirium; frequency not known – psychotic reactions with self-destructive behavior, including suicidal ideation or actions (see section "Special precautions").

Nervous system disorders*: common – headache, dizziness; uncommon – somnolence, tremor, dysgeusia (subjective taste disturbance); rare – seizures (see sections "Contraindications" and "Special precautions"), paresthesia; frequency not known – peripheral sensory or sensorimotor neuropathy (see section "Special precautions"), olfactory disturbances (parosmia), including anosmia (loss of smell), dyskinesia (impaired movement coordination), extrapyramidal disorders, ageusia, syncope (fainting), benign intracranial hypertension.

Eye disorders*: rare – visual disturbances such as blurred vision, visual blurring (see section "Special precautions"); frequency not known – transient loss of vision, uveitis (see section "Special precautions").

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

Cardiac disorders: rare – tachycardia, palpitations, arterial hypotension; frequency not known – ventricular tachycardia, which may lead to cardiac arrest; ventricular arrhythmia of the torsade de pointes type (mainly in patients with risk factors for QT interval prolongation); QT interval prolongation on ECG (see sections "Special precautions" ("QT interval prolongation") and "Overdose").

Respiratory system disorders: uncommon – dyspnea (shortness of breath); frequency not known – bronchospasm, allergic pneumonia.

Gastrointestinal disorders: common – diarrhea, vomiting, nausea; uncommon – abdominal pain, dyspepsia, flatulence/distension of the abdomen, constipation; frequency not known – hemorrhagic diarrhea, which may indicate enterocolitis, including pseudomembranous colitis (see section "Special precautions"); pancreatitis.

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

Hepatobiliary disorders: common – increased liver enzyme levels (ALT/AST, alkaline phosphatase, GGT); uncommon – increased blood bilirubin levels; frequency not known – jaundice and severe hepatic injury, including cases of acute liver failure (sometimes fatal), mainly in patients with severe underlying diseases (see section "Special precautions"); hepatitis.

Skin and subcutaneous tissue disorders: uncommon – rash, pruritus, urticaria, hyperhidrosis; rare – drug rash with eosinophilia and systemic symptoms (DRESS syndrome), localized skin reactions due to drugs; frequency not known – toxic epidermal necrolysis (Lyell's syndrome), Stevens-Johnson syndrome, erythema multiforme, photosensitivity reactions (see section "Special precautions"); leukocytoclastic vasculitis, stomatitis.

Musculoskeletal and connective tissue disorders*: uncommon – arthralgia, myalgia; rare – tendon disorders (see section "Special precautions"), including tendon inflammation (tendinitis) (e.g., Achilles tendon); muscle weakness, which may be particularly significant in patients with myasthenia gravis (see section "Special precautions"); frequency not known – rhabdomyolysis, tendon rupture (e.g., Achilles tendon: see section "Special precautions"), ligament rupture, muscle rupture, arthritis.

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

General disorders*: uncommon – asthenia; rare – increased body temperature (pyrexia); frequency not known – pain (including back, chest, and limb pain).

a Anaphylactic and anaphylactoid reactions may sometimes occur even after administration of the first dose.

b Skin and mucous membrane reactions may sometimes occur even after administration of the first dose.

Other adverse effects associated with fluoroquinolone administration include:

• Acute attacks of porphyria in patients with porphyria.

*In very rare cases, patients receiving quinolones and fluoroquinolones, regardless of existing risk factors, have reported prolonged (lasting months or years), disabling, and potentially irreversible serious adverse reactions affecting various, and sometimes multiple simultaneously, body systems and sensory organs (including reactions such as tendinitis, tendon rupture, arthralgia, limb pain, gait disturbances, neuropathies associated with paresthesia, depression, fatigue, memory impairment, sleep disturbances, hearing impairment, visual disturbances, taste and smell disturbances).

Shelf life.

4 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in the original packaging.

Keep out of reach and sight of children.

Packaging.

7 tablets in a blister pack, 1 blister pack in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

NOBEL ILAC SANAYI VE TICARET A.S.

Manufacturer's address and place of business.

Sankaklar Quarter, Eskikarakodja Avenue, No. 299, 81100 Duzce, Turkey.