Levomac 750

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LEVOMAC 750 (LEVOMAC 750)

Composition:

Active substance: levofloxacin;

1 tablet contains levofloxacin hemihydrate equivalent to 750 mg of levofloxacin;

Excipients: microcrystalline cellulose, crospovidone, hypromellose, magnesium stearate, titanium dioxide (E 171), polyethylene glycol 400, polysorbate 80, iron oxide red (E 172), iron oxide yellow (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: biconvex, elongated-shaped film-coated tablets, brownish-red in color, with "T" and "64" imprints and a break line on one side, and a break line on the other side.

Pharmacotherapeutic group.

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

Pharmacological properties.

Pharmacodynamics.

Levofloxacin is a synthetic antibacterial agent of the fluoroquinolone group, the S-enantiomer of the racemic mixture of the drug ofloxacin.

Mechanism of action

As a fluoroquinolone antibacterial agent, levofloxacin acts on the DNA-DNA gyrase complex and topoisomerase IV.

Pharmacokinetic/pharmacodynamic relationship

The degree of antibacterial activity of levofloxacin depends on the ratio of maximum serum concentration (Cmax) or area under the pharmacokinetic concentration-time curve (AUC) to minimum inhibitory (suppressive) concentration (MIC).

Mechanism of resistance

The primary mechanism of resistance results from mutations in the gyr-A genes. In vitro, cross-resistance exists between levofloxacin and other fluoroquinolones.

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

Breakpoints

The recommended breakpoints for minimum inhibitory concentration (MIC) of levofloxacin established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST), which differentiate susceptible microorganisms from intermediate (moderately resistant) organisms, and intermediate from resistant organisms, are presented in the table below (Table 1, MIC testing, mg/L).

Table 1

EUCAST clinical breakpoints for levofloxacin (20.06.2006)

The recommended CLSI (Clinical and Laboratory Standards Institute, formerly NCCLS) MIC breakpoints for levofloxacin, which distinguish susceptible from intermediate organisms and intermediate from resistant organisms, are presented in Table 2 for MIC testing (μg/mL) or disk diffusion method (zone diameter [mm] using a 5-μg levofloxacin disk).

Table 2

Recommended CLSI MIC and disk diffusion breakpoints for levofloxacin (M100-S17, 2007)

Antibacterial spectrum

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

*Clinical efficacy has been demonstrated for susceptible isolates in approved clinical indications.

** Natural intermediate susceptibility.

Other data

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

Pharmacokinetics.

Absorption

Levofloxacin is rapidly and almost completely absorbed after oral administration, with Cmax reached within 1 hour. Absolute bioavailability is approximately 100%.

Food has almost no effect on levofloxacin absorption.

Distribution

Approximately 30–40% of levofloxacin is bound to plasma proteins. Cumulative effect after multiple doses of levofloxacin at 500 mg once daily is practically negligible. A slight but predictable accumulation occurs after repeated 500 mg twice daily dosing. Steady state is achieved within 3 days.

Penetration into tissues and body fluids

Penetration into bronchial mucosa, bronchial secretions, and lung tissue (BSLT)

Maximum levofloxacin concentrations in bronchial mucosa and bronchial secretions after a 500 mg oral dose were 8.3 µg/g and 10.8 µg/mL, respectively. These levels were achieved within 1 hour after dosing.

Penetration into lung tissue

Maximum levofloxacin concentration in lung tissue after a 500 mg oral dose was approximately 11.3 µg/g, achieved 4–6 hours after administration. Concentrations in lung tissue exceed those in plasma.

Penetration into bladder contents

Maximum levofloxacin concentrations of 4–6.7 µg/mL in bladder contents were achieved 2–4 hours after dosing, following 3 days of treatment with 500 mg once or twice daily, respectively.

Penetration into cerebrospinal (CSF) fluid

Levofloxacin penetrates poorly into cerebrospinal fluid.

Penetration into prostate tissue

After oral administration of 500 mg levofloxacin once daily for 3 days, mean concentrations in prostate tissue were 8.7 µg/g, 8.2 µg/g, and 2.0 µg/g at 2, 6, and 24 hours, respectively. The mean prostate/plasma concentration ratio was 1.84.

Urine concentrations

Mean urinary concentrations of levofloxacin 8–12 hours after a single oral dose of 150 mg, 300 mg, or 500 mg were 44 mg/L, 91 mg/L, and 200 mg/L, respectively.

Metabolism

Levofloxacin undergoes minimal metabolism, with metabolites being desmethyl-levofloxacin and levofloxacin N-oxide. These metabolites account for less than 5% of the administered dose 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 of 6–8 hours). Elimination occurs primarily via the kidneys (over 85% of the administered dose).

There is no significant difference in the pharmacokinetics of levofloxacin between intravenous and oral administration, indicating that these routes (oral and intravenous) are interchangeable.

Linearity

Levofloxacin exhibits linear pharmacokinetics in the range of 50–600 mg.

Patients with renal impairment

Renal impairment affects the pharmacokinetics of levofloxacin. With reduced renal function, renal excretion and clearance decrease, and elimination half-life increases, as shown in Table 3.

Table 3

Elderly patients

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

Gender differences

Separate analysis has shown minor differences in levofloxacin pharmacokinetics depending on patient gender. There is no evidence that these gender differences are clinically significant.

Clinical characteristics.

Indications.

For adults in the treatment of infections caused by microorganisms sensitive to levofloxacin: acute bacterial sinusitis, complicated and uncomplicated urinary tract infections (including pyelonephritis), complicated skin and soft tissue infections, nosocomial pneumonia, community-acquired pneumonia.

Contraindications.

Hypersensitivity to levofloxacin or to other quinolones, to any component of the drug; epilepsy; history of adverse reactions affecting tendons following prior use of quinolones. Pregnancy or breastfeeding period. Pediatric age.

Interaction with other medicinal products and other forms of interaction.

Effect of other medicinal products on levofloxacin

Iron salts, zinc salts, antacids containing magnesium or aluminium, didanosine
The absorption of levofloxacin is significantly reduced when iron salts, magnesium or aluminium-containing antacids, or didanosine (this applies only to medicinal forms of didanosine containing aluminium- or magnesium-based buffering agents) are administered concomitantly with the drug. Concurrent administration of fluorquinolones and multivitamin preparations containing zinc reduces their oral absorption. It is not recommended to use medicinal products containing divalent or trivalent cations, such as iron salts, zinc salts, magnesium- or aluminium-containing antacids, or didanosine (this applies only to medicinal forms of didanosine containing aluminium- or magnesium-based buffering agents), within 2 hours before or after administration of the drug (see section "Dosage and administration"). Calcium salts have minimal effect on the oral absorption of levofloxacin.

Sucralfate

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

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

No pharmacokinetic interaction between levofloxacin and theophylline has been observed. However, a significant reduction in seizure threshold may occur with concomitant use of quinolones and theophylline, NSAIDs, or other medicinal products that lower the seizure threshold. The concentration of levofloxacin was approximately 13% higher when fenbufen was coadministered compared to levofloxacin alone.

Probenecid and cimetidine

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

Renal clearance of levofloxacin decreases by 24% with cimetidine and by 34% with probenecid. This is because both drugs can block the tubular secretion of levofloxacin. However, at the doses tested in clinical studies, statistically significant kinetic differences are unlikely to have clinical relevance. Concomitant administration of levofloxacin with medicinal products affecting tubular secretion, such as probenecid and cimetidine, should be done with caution, especially in patients with renal impairment.

Other information

Calcium carbonate, digoxin, glyburide, and ranitidine have no clinically significant effect on the pharmacokinetics of levofloxacin when administered concomitantly.

Effect of levofloxacin on other medicinal products

Cyclosporine

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

Vitamin K antagonists

When used concomitantly with vitamin K antagonists (e.g., warfarin), increased coagulation parameters (PT/INR) and/or bleeding, which may be severe, have been reported. Therefore, patients receiving concomitant vitamin K antagonists should be monitored for coagulation parameters (see section "Special precautions for use").

Medicinal products that prolong the QT interval

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

Other relevant information

No effect of levofloxacin on the pharmacokinetics of theophylline (a marker substrate for the CYP1A2 enzyme) has been observed, indicating that levofloxacin is not an inhibitor of CYP1A2.

Other types of interactions

Food intake

No clinically significant interaction with food has been observed; therefore, levofloxacin may be administered independently of food intake.

Special precautions for use.

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

Prolonged, disabling and potentially irreversible serious adverse reactions

Very rare cases of prolonged (months or years), disabling and potentially irreversible serious adverse reactions affecting various, sometimes multiple organ systems (musculoskeletal, nervous system, psyche and sensory organs) have been reported in patients receiving quinolones and fluoroquinolones, regardless of age and 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 seek medical advice immediately.

Aneurysm and dissection of aorta and cardiac valve regurgitation/insufficiency

Epidemiological studies have reported an increased risk of aortic aneurysm and dissection, especially in elderly patients, and 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 cardiac valve have been reported in patients treated with fluoroquinolones (see section "Adverse reactions").

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

• for both aortic aneurysm and dissection and cardiac valve regurgitation/insufficiency (e.g., connective tissue disorders such as Marfan syndrome or Ehlers-Danlos syndrome, Turner syndrome, Behçet's disease, hypertension, rheumatoid arthritis), or additionally
• for aortic aneurysm and dissection (e.g., vascular disorders such as Takayasu arteritis or giant cell arteritis, or known atherosclerosis, or Sjögren's syndrome), or additionally
• for cardiac valve regurgitation/insufficiency (e.g., infective endocarditis). The risk of aortic aneurysm and dissection and their rupture may be increased in patients concurrently receiving systemic corticosteroids.

In case of sudden abdominal, chest or back pain, patients should seek immediate medical attention at an emergency department.

Patients should be advised to seek immediate medical help in case of acute shortness of breath, new onset palpitations, or development of abdominal or lower limb edema.

Methicillin-resistant S. aureus

Methicillin-resistant Staphylococcus aureus (MRSA) is very likely to exhibit cross-resistance to fluoroquinolones, including levofloxacin. Therefore, levofloxacin is not recommended for treatment of known or suspected MRSA infections, except when laboratory test results confirm pathogen susceptibility to levofloxacin.

Levofloxacin may be used for treatment of acute bacterial sinusitis and acute exacerbation of chronic bronchitis if these infections have been appropriately diagnosed.

Resistance of E. coli, the most common cause of urinary tract infections, to fluoroquinolones varies across European Union countries. When prescribing levofloxacin, physicians should take into account local prevalence of E. coli resistance to fluoroquinolones.

Clinical practice is based on in vitro susceptibility studies of Bacillus anthracis, as well as experimental animal data together with limited human data. Physicians should refer to established national and/or international guidelines for treatment of anthrax.

Tendinitis and tendon rupture

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

At the first signs of tendinitis (e.g., painful swelling, inflammation), levofloxacin treatment should be discontinued and alternative therapy considered. The affected limb(s) should be appropriately managed (e.g., immobilization). Corticosteroids should not be used in case of tendonopathy symptoms.

Myoclonus

Cases of myoclonus have been reported in patients receiving levofloxacin (see section "Adverse reactions"). The risk of myoclonus is increased in elderly patients and in patients with renal impairment if the levofloxacin dose is not adjusted according to creatinine clearance. Levofloxacin should be discontinued immediately upon first occurrence of myoclonus and appropriate treatment initiated.

Clostridium difficile-associated disease

Diarrhea, especially severe, persistent or with blood, occurring during or after treatment with levofloxacin (including several weeks after treatment) may be a symptom of Clostridium difficile-associated disease (CDAD). CDAD may vary in severity from mild to life-threatening, with pseudomembranous colitis being the most severe form (see section "Adverse reactions"). Therefore, this diagnosis should be considered in patients who develop severe diarrhea during or after treatment with levofloxacin. If CDAD is suspected or confirmed, levofloxacin should be discontinued immediately and symptomatic and specific treatment initiated promptly (e.g., oral metronidazole and vancomycin). In such situations, drugs that inhibit intestinal motility are contraindicated.

Patients with predisposition to seizures

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

As with other quinolones, the drug should be used with extreme caution in patients predisposed to seizures, for example, those with pre-existing central nervous system disorders, concomitant therapy with phenylbutazone and similar NSAIDs, or drugs that increase seizure susceptibility (lower seizure threshold), such as theophylline (see section "Interaction with other medicinal products and other forms of interaction"). If seizures occur, treatment with levofloxacin should be discontinued.

Glucose-6-phosphate dehydrogenase deficiency

Patients with latent or manifest deficiency of glucose-6-phosphate dehydrogenase activity may be prone to hemolytic reactions when treated with quinolone antibacterial agents. Therefore, levofloxacin should be used cautiously in such patients, and their condition should be monitored for possible hemolysis.

Renal impairment

Levofloxacin is primarily eliminated via the kidneys; therefore, dose adjustment is required in patients with renal impairment.

Hypersensitivity reactions

Levofloxacin may occasionally cause serious, potentially fatal hypersensitivity reactions (including angioedema, anaphylactic shock), even after the first dose. If hypersensitivity reactions occur, levofloxacin should be discontinued, medical advice sought, and appropriate treatment initiated.

Severe skin adverse reactions

Severe manifestations of skin adverse reactions (SCAR), including toxic epidermal necrolysis (TEN), also known as Lyell's syndrome, Stevens-Johnson syndrome (SJS), and drug reaction with eosinophilia and systemic symptoms (DRESS), which may be life-threatening or fatal, have been reported with levofloxacin (see section "Adverse reactions"). Patients should be warned about signs and symptoms of severe skin reactions and closely monitored. If such signs and symptoms appear, levofloxacin should be discontinued immediately and alternative therapy considered. If a patient develops a serious reaction such as Stevens-Johnson syndrome, toxic epidermal necrolysis, or DRESS syndrome during levofloxacin treatment, reinitiation of levofloxacin therapy in this patient is absolutely contraindicated.

Blood glucose level changes

Alterations in blood glucose levels (both hyperglycemia and hypoglycemia) have been reported during quinolone use, particularly in diabetic patients receiving concomitant oral hypoglycemic agents (including glyburide) or insulin. Cases of hypoglycemic coma have been reported. Diabetic patients should monitor their blood glucose levels.

Prevention of photosensitivity reactions

Photosensitivity reactions have been reported during levofloxacin therapy.

To prevent photosensitivity reactions, patients taking levofloxacin should avoid exposure to sunlight and ultraviolet (UV) radiation (UV lamps, tanning beds) due to possible photosensitization during levofloxacin intake or within 48 hours after discontinuation of levofloxacin.

Patients taking vitamin K antagonists

Due to possible increases in coagulation test parameters (PT/INR) and/or bleeding in patients receiving levofloxacin concomitantly with vitamin K antagonists (e.g., warfarin), coagulation tests should be monitored if these drugs are used together (see section "Interaction with other medicinal products and other forms of interaction").

Psychotic reactions

Psychotic reactions have been observed in patients receiving quinolones, including levofloxacin. In rare cases, these led to suicidal thoughts and self-destructive behavior, sometimes even after a single dose of levofloxacin. If such reactions occur, levofloxacin should be discontinued and appropriate measures taken. Caution is recommended when prescribing levofloxacin to patients with psychiatric disorders or history of psychiatric illness.

QT interval prolongation

Caution should be exercised when administering fluoroquinolones, including levofloxacin, to patients with known risk factors for QT interval prolongation, such as:

• congenital long QT syndrome;
• concomitant use of drugs that prolong the QT interval (including class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics);
• uncorrected electrolyte imbalances (e.g., hypokalemia, hypomagnesemia);
• cardiac diseases (heart failure, myocardial infarction, bradycardia).

Elderly patients and younger women are more sensitive to drugs that prolong the QT interval. Therefore, fluoroquinolones, including levofloxacin, should be used with caution in these patient groups (see sections "Interaction with other medicinal products and other forms of interaction", "Method of administration and dosage" ("Elderly patients"), "Overdose", "Adverse reactions").

Peripheral neuropathy

Cases of sensory or sensorimotor polyneuropathy characterized by paresthesia, hypoesthesia, dysesthesia, or weakness have been reported in patients receiving quinolones and fluoroquinolones, including levofloxacin. Patients receiving levofloxacin should be informed that if symptoms of neuropathy such as pain, burning, tingling, numbness, or weakness occur during continued treatment, they should contact their physician to prevent potential development of irreversible condition (see section "Adverse reactions").

Hepatobiliary disorders

Cases of necrotizing hepatitis, up to life-threatening liver failure, have been reported, primarily in patients with severe underlying conditions such as sepsis (see section "Adverse reactions"). Patients should be advised to discontinue treatment and seek medical advice if symptoms of liver disease occur, such as anorexia, jaundice, dark urine, pruritus, or abdominal pain.

Blood disorders

Bone marrow suppression, including leukopenia, neutropenia, pancytopenia, hemolytic anemia, thrombocytopenia, aplastic anemia, or agranulocytosis, may develop during levofloxacin treatment (see section "Adverse reactions"). If any of these disorders is suspected, blood test results should be monitored. If abnormal results are obtained, discontinuation of levofloxacin treatment should be considered.

Exacerbation of myasthenia gravis

Fluoroquinolones, including levofloxacin, exhibit neuromuscular blocking effects 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 history of myasthenia gravis.

Visual disorders

If visual disturbances or other eye effects occur, immediate consultation with an ophthalmologist is required (see sections "Ability to affect reaction speed when driving or operating machinery" and "Adverse reactions").

Superinfection

The use of levofloxacin, particularly prolonged use, may lead to overgrowth of organisms not susceptible (resistant) to the drug. If superinfection develops during therapy, appropriate measures should be taken.

Laboratory tests

In patients receiving levofloxacin, testing for opioids in urine may yield false-positive results. Confirmation of positive opioid results may require more specific testing methods.

Levofloxacin inhibits the growth of Mycobacterium tuberculosis; therefore, false-negative results may occur in bacteriological testing of patients with tuberculosis.

Use during pregnancy or breastfeeding

Pregnancy. Data on the use of levofloxacin in pregnant women are limited. Animal studies do not indicate direct or indirect harmful effects on reproductive toxicity. Due to the lack of human studies and the potential for quinolones to damage growing cartilage, levofloxacin should not be administered to pregnant women or women who are breastfeeding.

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

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

Ability to affect reaction speed when driving or operating machinery.

Some adverse reactions (e.g., dizziness/vertigo, somnolence, visual disturbances) may impair a patient's ability to concentrate and reaction speed, thereby increasing the risk in situations where these abilities are particularly important (e.g., driving a car or operating machinery).

Dosage and Administration

The drug is taken once 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 testing confirms eradication of the causative agent.

Levomak 750 tablets should be swallowed whole, without chewing, with plenty of fluid. The tablets may be taken with or without food.

Table 4

Dosage for adult patients with normal renal function and creatinine clearance exceeding 50 mL/min

Patients with renal function impairment. Levomak 750 should be prescribed with caution to patients with renal insufficiency. Careful clinical monitoring and appropriate laboratory tests should be performed before and during therapy, as elimination of levofloxacin may be reduced in such patients.

Table 5

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

After hemodialysis or chronic ambulatory peritoneal dialysis, additional doses are not required.

If a lower dosage is needed, levofloxacin in another pharmaceutical form should be used.

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

Elderly patients. If renal function is normal, no dose adjustment is required.

Children.

Levofloxacin is contraindicated in children, as damage to joint cartilage cannot be excluded.

Overdose.

Symptoms. Dizziness, disturbances/confusion of consciousness, seizures, tremor, QT interval prolongation; gastrointestinal reactions such as nausea and erosion of mucous membranes, intensification of other adverse reactions. In cases of overdose, careful monitoring of the patient, including ECG, is required.

Treatment. Symptomatic therapy. In cases of acute overdose, gastric lavage should be performed. Antacid agents are used to protect gastric mucosa.

Hemodialysis, including peritoneal dialysis or continuous ambulatory peritoneal dialysis (CAPD), is not effective in removing levofloxacin from the body. There are no specific antidotes.

CNS effects, including confusion, seizures, myoclonus, hallucinations, and tremor, have been observed in the post-marketing period.

Side effects.

Infections and infestations: fungal infections, including Candida species, proliferation of other resistant microorganisms.

Blood and lymphatic system disorders: leucopenia, eosinophilia, neutropenia, agranulocytosis, pancytopenia, haemolytic anaemia; thrombocytopenia, which may lead to increased tendency to haemorrhage or bleeding.

Blood and lymphatic system disorders:

Frequency unknown (cannot be estimated from available data): bone marrow failure, including aplastic anaemia, pancytopenia, agranulocytosis, haemolytic anaemia.

Immune system disorders: hypersensitivity reactions, including anaphylactic/anaphylactoid shock, angioedema (see section "Special warnings and precautions for use"); anaphylactic and anaphylactoid reactions may sometimes occur even after administration of the first dose.

Metabolism and nutrition disorders: anorexia; hypoglycaemia, particularly in patients with diabetes mellitus (see section "Special warnings and precautions for use"); hyperglycaemia; hypoglycaemic coma. Signs of hypoglycaemia may include increased appetite, nervousness, excessive sweating, and tremor of limbs; as with other fluoroquinolones, porphyria attacks may occur in patients with porphyria.

Psychiatric disorders*: insomnia, agitation, confusion, nervousness, psychiatric disorders (including hallucinations, paranoia), depression, anxiety, restlessness, fear, pathological dreams, nightmares; psychotic reactions with self-destructive behaviour, including suicidal thoughts or actions (see section "Special warnings and precautions for use").

Frequency unknown: mania.

Nervous system disorders*: headache, dizziness, somnolence, tremor, dysgeusia, convulsions, paraesthesia, peripheral sensory or sensorimotor neuropathy, reduced touch sensation; parosmia, including anosmia; ageusia; dyskinesia (movement coordination disorder); extrapyramidal disorders; other movement coordination disorders, including during walking; loss of consciousness; benign intracranial hypertension.

Frequency unknown: myoclonus.

Eye disorders*: visual disturbances, blurred vision, temporary vision loss, transient visual disturbances, uveitis.

Ear and labyrinth disorders: vertigo, tinnitus, hearing disturbances, hearing loss.

Cardiac disorders**: tachycardia, palpitations; ventricular tachycardia, which may lead to cardiac arrest; ventricular arrhythmias and torsade de pointes arrhythmia (mainly in patients with risk factors for QT interval prolongation); QT interval prolongation on ECG (see sections "Special warnings and precautions for use" ("QT interval prolongation") and "Overdose"), arterial hypotension, allergic vasculitis, collapse.

Respiratory system disorders: dyspnoea, bronchospasm, allergic pneumonitis.

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

Gastrointestinal disorders: diarrhoea, nausea, vomiting, abdominal pain, dyspepsia, abdominal distension, constipation; haemorrhagic diarrhoea, which may indicate enterocolitis, including pseudomembranous colitis; pancreatitis.

Hepatobiliary disorders: increased liver enzyme levels (alanine aminotransferase/aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl transferase), increased blood bilirubin, hepatitis, jaundice, and severe liver injury, including cases of acute liver failure, mainly in patients with severe underlying diseases (see section "Special warnings and precautions for use").

Skin and subcutaneous tissue disorders: rash, pruritus, urticaria, hyperhidrosis, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) (see section "Special warnings and precautions for use"), persistent erythema, exudative polymorphic erythema, toxic epidermal necrolysis (Lyell's syndrome), Stevens-Johnson syndrome, photosensitivity reactions (increased sensitivity to sunlight and ultraviolet radiation), leukocytoclastic vasculitis, stomatitis. Such reactions may appear even after the first dose and within minutes or hours after administration.

Frequency unknown: skin hyperpigmentation.

Musculoskeletal and connective tissue disorders: arthralgia; myalgia; tendon disorders (see section "Special warnings and precautions for use"), including tendon inflammation (tendinitis) (e.g., Achilles tendon); muscle weakness, which may be of particular importance in patients with severe myasthenia gravis; rhabdomyolysis; tendon rupture (e.g., Achilles tendon; see section "Special warnings and precautions for use"), ligament, muscle; arthritis.

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

General disorders: asthenia, general weakness, increased body temperature (pyrexia), pain (including back, chest, and limb pain).

Among other adverse effects associated with fluoroquinolone use are porphyria attacks in patients with existing porphyria.

*Very rare cases of long-term (up to months or years), disabling and potentially irreversible serious adverse reactions affecting multiple, sometimes multiple, organ system classes and sensory organs (including such reactions as tendinitis, tendon rupture, arthralgia, limb pain, gait disturbances. In some cases, neuropathy associated with paraesthesia, depression, fatigue, memory impairment, sleep disturbances, and disturbances of hearing, vision, taste, and smell) have been reported with quinolones and fluoroquinolones, regardless of pre-existing risk factors (see section "Special warnings and precautions for use"); anxiety, suicidal thoughts, panic attacks, neuralgia, and concentration disturbances have also been reported as potential aspects of long-term and disabling adverse reactions caused by fluoroquinolones.

**In patients receiving fluoroquinolones, cases of aortic aneurysm and dissection, sometimes complicated by rupture (including fatal cases), and regurgitation/insufficiency of any cardiac valve have been reported (see section "Special warnings and precautions for use").

Shelf life. 2 years.

Storage conditions.

Store at temperatures not exceeding 30 °C in the original packaging.

Keep out of reach and sight of children.

Packaging.

10 tablets in a blister, 1 blister in a cardboard box.

10 tablets in a blister, 10 blisters in a cardboard box.

5 tablets in a blister, 1 blister in a cardboard box.

Prescription category.

Pack size № 5 (5x1) – prescription only.

Pack size № 10 (10x1) – prescription only.

Pack size № 100 (10x10) – for hospital use only.

Manufacturer.

Macleods Pharmaceuticals Limited.

Manufacturer's address and place of business.

Village Theda, P.O. Lodhiamaira, Tehsil Baddi, District Solan, Himachal Pradesh, 174101, India.