Levolet

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

Composition:

Active substance: levofloxacin;

One film-coated tablet contains levofloxacin 250 mg or 500 mg,

or 750 mg as levofloxacin hemihydrate;

Excipients: microcrystalline cellulose, corn starch, colloidal anhydrous silicon dioxide, crospovidone, hypromellose, magnesium stearate, Opadry white OY58900 (hypromellose, titanium dioxide (E 171), polyethylene glycols).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white, capsule-shaped, biconvex tablets, film-coated, with the logo "RDY" on one side and "279" on the other side (250 mg tablets);

white, capsule-shaped, biconvex tablets, film-coated, with the logo "RDY" on one side and "280" on the other side (500 mg tablets);

white, capsule-shaped, biconvex, film-coated tablets, smooth on both sides (750 mg tablets).

Pharmacotherapeutic group. Antibacterial agents of the quinolone group. Fluoroquinolones. ATC code J01MA12.

Pharmacological Properties

Pharmacodynamics

Levofloxacin is characterized by a broad spectrum of antibacterial activity. The bactericidal effect is achieved through inhibition of the bacterial enzyme DNA gyrase, a type II topoisomerase, by levofloxacin. This inhibition prevents bacterial DNA from transitioning from the "relaxed" to the "supercoiled" state, thereby making further division (reproduction) of bacterial cells impossible. The spectrum of activity of levofloxacin includes both Gram-positive and Gram-negative bacteria, including non-fermenting bacteria.

Microorganisms susceptible to the drug

Gram-positive aerobes: Enterococcus faecalis, Staphylococcus aureus methi-S, Streptococci group C, G, Streptococcus agalactiae, Streptococcus pneumoniae peni-I/S/R, Streptococcus pyogenes.

Gram-negative aerobes: Acinetobacter baumannii, Citrobacter freundii, Eikenella corrodens, Enterobacter agglomerans, Enterobacter cloacae, Escherichia coli, Haemophilus influenzae ampi-S/R, Haemophilus parainfluenzae, Klebsiella oxytoca, Klebsiella pneumoniae, Moraxella catarrhalis β+/β-, Morganella morganii, Pasteurella multocida, Proteus mirabilis, Proteus vulgaris, Providencia rettgeri, Providencia stuartii, Pseudomonas aeruginosa, Serratia marcescens.

Anaerobes: Bacteroides fragilis, Clostridium perfringens, Peptostreptococcus.

Others: Chlamydia pneumoniae, Chlamydia psittaci, Legionella pneumophila, Mycoplasma pneumoniae, Ureaplasma, H. pylori.

Microorganisms with variable sensitivity to the drug

Gram-positive aerobes: Staphylococcus aureus methi-R.

Gram-negative aerobes: Burkholderia cepacia.

Anaerobes: Bacteroides ovatus, Bacteroides thetaiotaomicron, Bacteroides vulgaris, Clostridium difficile.

Microorganisms resistant to the drug

Gram-positive aerobes: Staphylococcus aureus methi-R, Staphylococcus coagulase-negative methi-S(1).

Like other fluoroquinolones, levofloxacin is inactive against spirochetes.

Pharmacokinetics

Absorption

Orally administered levofloxacin is rapidly and almost completely absorbed. Maximum plasma concentration is observed within 1 hour after intake. Absolute bioavailability is nearly 100%. Levofloxacin exhibits linear pharmacokinetics within the dose range of 50 mg to 600 mg. Food intake slightly affects its absorption.

Distribution

Approximately 30–40% of levofloxacin is protein-bound in plasma. Accumulation of levofloxacin with a dosage of 500 mg once daily is not clinically significant and can be disregarded. A slight but predictable accumulation occurs with a dosage of 500 mg twice daily. Steady-state distribution is achieved within 3 days.

Distribution in tissues and body fluids

Distribution in bronchial mucosa and bronchial epithelial secretions

Maximum concentrations of levofloxacin in bronchial mucosa and bronchial epithelial secretions after oral doses exceeding 500 mg were 8.3 and 10.8 μg/mL, respectively.

Distribution in lung tissue

Maximum concentration of levofloxacin in lung tissue after oral doses exceeding 500 mg was approximately 11.3 μg/mL, reached within 4–6 hours after administration. Concentrations in lung tissue consistently exceeded those in plasma.

Distribution in blister fluid

Maximum concentration of levofloxacin in blister fluid after a single or twice-daily 500 mg dose was 4.0 and 6.7 μg/mL, respectively.

Distribution in cerebrospinal fluid

Levofloxacin poorly penetrates into cerebrospinal fluid.

Distribution in prostate tissue

Following 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 tissue/plasma concentration ratio was 1.84.

Concentration in urine

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

Metabolism

Levofloxacin undergoes minimal metabolism. The metabolites are desmethyl-levofloxacin and levofloxacin N-oxide. These metabolites account for less than 5% of the total amount of drug excreted in urine.

Excretion

After oral administration, levofloxacin is eliminated from plasma relatively slowly (elimination half-life is 6–8 hours). Excretion 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.

Clinical characteristics.

Indications.

Infections caused by microorganisms sensitive to levofloxacin:

community-acquired pneumonia, chronic bacterial prostatitis, complicated urinary tract infections, and acute pyelonephritis.

The drug should be used only when it is considered inappropriate to use other antibacterial agents usually recommended for the treatment of such infections:

• exacerbations of chronic obstructive pulmonary disease, including bronchitis;
• acute bacterial sinusitis;
• complicated skin and soft tissue infections.

When prescribing the drug, official guidelines on the appropriate use of antibacterial agents should be followed.

Contraindications.

Hypersensitivity to levofloxacin, to other quinolones, or to any other component of the drug; epilepsy; patients with a history of tendon-related adverse reactions following previous use of quinolones. Pregnancy or breastfeeding. Pediatric age.

Interaction with other medicinal products and other forms of interaction.

Iron salts, zinc salts, magnesium- or aluminum-containing antacids, didanosine. Absorption of levofloxacin is significantly reduced when administered with didanosine (this applies only to didanosine formulations containing aluminum- or magnesium-based buffering agents). Concomitant 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 aluminum-containing antacids, or didanosine (this applies only to didanosine formulations containing aluminum- or magnesium-based buffering agents) within 2 hours before or after taking levofloxacin (see section "Dosage and administration").

Calcium salts have minimal effect on the absorption of levofloxacin after oral administration.

Sucralfate. The bioavailability of levofloxacin is significantly reduced when administered concomitantly with sucralfate. The interval between administration of these drugs should be at least 2 hours.

Theophylline, fenbufen, or other similar nonsteroidal anti-inflammatory drugs

In a pharmacokinetic interaction study, levofloxacin did not affect the pharmacokinetics of theophylline (a substrate of the CYP1A2 enzyme), indicating that levofloxacin is not an inhibitor of CYP1A2. However, a significant reduction in seizure threshold may occur with concomitant use of quinolones and theophylline, nonsteroidal anti-inflammatory drugs, or other agents that lower the seizure threshold. The concentration of levofloxacin increases by approximately 13% in the presence of fenbufen.

Probenecid and cimetidine. Caution should be exercised when co-administering levofloxacin with medicinal products that affect tubular secretion, such as probenecid and cimetidine, especially in patients with renal impairment.

Probenecid and cimetidine statistically significantly affect the elimination of levofloxacin. Renal clearance of levofloxacin decreases by 34% with probenecid and by 24% with cimetidine. Thus, both agents can block tubular excretion of levofloxacin.

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 tests (PT/INR) and/or bleeding may increase, potentially becoming severe. Therefore, patients receiving vitamin K antagonists concurrently require monitoring of coagulation parameters.

The pharmacokinetics of levofloxacin are not significantly affected by concomitant administration of calcium carbonate, digoxin, glyburide, or ranitidine.

Meds 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 (e.g., class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics).

Concomitant use of levofloxacin with alcohol is not recommended.

Antidiabetic medicinal products

Cases of glucose fluctuations, including hyperglycemia or hypoglycemia, have been reported in patients receiving fluoroquinolones concomitantly with antidiabetic agents. Close monitoring of blood glucose levels is recommended when these medicinal products are used together.

Other forms of interaction. Food intake. No clinically significant interaction with food has been observed. Therefore, the drug may be taken regardless of food intake.

Special precautions for use.

MRSA (Methicillin-resistant S. aureus). There is a very high likelihood of co-resistance of methicillin-resistant S. aureus (MRSA) to fluoroquinolones, including levofloxacin. Therefore, levofloxacin is not recommended for the treatment of infections known or suspected to be caused by MRSA, except in cases where laboratory testing has confirmed susceptibility of the pathogen to levofloxacin.

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

When initiating therapy, local prevalence of fluoroquinolone resistance in E. coli should be taken into account.

Tendinitis and tendon rupture. Rare cases of tendinitis, which may lead to tendon rupture, have been reported. This most commonly affects the Achilles tendon. This adverse effect may occur within 48 hours of starting treatment and may be bilateral. Cases of tendon rupture have been reported several years after discontinuation of the drug. The risk of tendinitis and tendon rupture is increased in patients aged 60 years and older, in patients with renal impairment, in transplant recipients, in patients receiving doses of 1000 mg daily, and in patients taking corticosteroids; therefore, concomitant use of corticosteroids with this medicinal product should be avoided. Corticosteroids should not be used in patients with tendinopathy. In elderly patients, the daily dose of the drug should be adjusted according to creatinine clearance (see section "Dosage and administration"). Due to the above, careful monitoring of these patient groups is recommended when levofloxacin is prescribed. At the first signs of tendinitis (e.g., swelling, inflammation), levofloxacin therapy should be discontinued immediately and the patient should seek medical advice and alternative treatment options should be considered. If tendinitis is suspected, appropriate treatment of the affected tendon (including immobilization) should be initiated promptly (see sections "Contraindications" and "Adverse reactions").

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 dose of levofloxacin is not adjusted according to creatinine clearance. Levofloxacin should be discontinued immediately at the first occurrence of myoclonus, and appropriate treatment initiated.

Clostridium difficile-associated disease.

Diarrhea, particularly severe, persistent, and/or with blood, occurring during or after treatment with levofloxacin (including several weeks after treatment) may be a symptom of Clostridium difficile-associated disease. The severity of Clostridium difficile-associated disease may range from mild to life-threatening; the most severe form is pseudomembranous colitis (see section "Adverse reactions"). Therefore, it is important to consider this diagnosis in patients who develop severe diarrhea during or after treatment with levofloxacin. If Clostridium difficile-associated disease is suspected, levofloxacin should be discontinued immediately and appropriate treatment initiated without delay. Antiperistaltic agents 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"), and like other quinolones, should be used with extreme caution in patients with a history of seizures or when used concomitantly with drugs that lower the seizure threshold, such as theophylline (see section "Interaction with other medicinal products and other forms of interaction"). If a seizure occurs (see section "Adverse reactions"), levofloxacin should be discontinued.

Patients with glucose-6-phosphate dehydrogenase deficiency. Patients with known or occult deficiency in glucose-6-phosphate dehydrogenase activity may be at increased risk of hemolytic reactions when treated with quinolone antibiotics. Therefore, if levofloxacin must be used in such patients, monitoring for possible hemolysis is recommended.

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

Hypersensitivity reactions. Levofloxacin may cause serious, potentially fatal hypersensitivity reactions (from angioneurotic edema to anaphylactic shock), sometimes after the first dose. Patients should discontinue the drug immediately and contact their physician or seek emergency medical assistance.

Levofloxacin should be avoided in patients who have previously experienced serious adverse reactions to quinolones or to medicinal products containing fluoroquinolones (see section "Adverse reactions"). Treatment with levofloxacin in such cases should only be initiated if no alternative therapy is available and after careful benefit-risk assessment (see section "Indications").

Prolonged, disabling, potentially irreversible serious adverse reactions.

Very rare cases of prolonged, disabling, potentially irreversible serious adverse reactions affecting various organ systems (musculoskeletal, nervous system, psychiatric, and sensory organs), sometimes involving multiple systems simultaneously, have been reported in patients receiving quinolones and fluoroquinolones, regardless of age or previously identified risk factors. Levofloxacin should be discontinued immediately at the first signs or symptoms of any serious adverse reaction, and the patient should seek immediate medical advice.

Severe skin reactions.

Severe cutaneous adverse reactions such as 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 careful monitoring is required. 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 treatment.

Phototoxicity prevention. Cases of phototoxicity have been reported with levofloxacin (see section "Adverse reactions"). To prevent phototoxicity, patients should avoid exposure to strong sunlight or artificial sources of UV radiation (e.g., UV lamps, sunlamps, tanning beds) during treatment and for 48 hours after discontinuation of the drug.

Patients receiving vitamin K antagonists. Due to the potential for increased coagulation parameters (prothrombin time/international normalized ratio) and/or increased risk of hemorrhagic complications in patients receiving levofloxacin in combination with vitamin K antagonists (e.g., warfarin), coagulation parameters should be monitored when these agents are used concomitantly (see section "Interaction with other medicinal products and other forms of interaction").

Psychotic reactions. Psychotic reactions have been reported in patients taking quinolones, including levofloxacin. Very rarely, these reactions progressed to suicidal ideation and self-harming behavior, sometimes after only a single dose of levofloxacin (see section "Adverse reactions"). If such reactions occur, levofloxacin should be discontinued and appropriate measures taken. Caution is recommended when prescribing levofloxacin to patients with a history of psychotic disorders or 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 medicinal products known to prolong the QT interval (e.g., class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics);
• Unresolved electrolyte imbalances (e.g., hypokalemia, hypomagnesemia);
• Cardiac disease (e.g., heart failure, myocardial infarction, bradycardia) (see sections "Interaction with other medicinal products and other forms of interaction", "Dosage and administration" (Elderly patients), "Overdose", "Adverse reactions").

Elderly patients and women may be more sensitive to drugs that prolong the QT interval. Therefore, fluoroquinolones, including levofloxacin, should be used with caution in these patient subgroups.

Peripheral neuropathy. Cases of sensory or sensorimotor peripheral neuropathy, manifesting as paresthesia, hyposthesia, dysesthesia, or weakness, have been reported in patients receiving fluoroquinolones, including levofloxacin, and may occur rapidly. Levofloxacin should be discontinued if symptoms of neuropathy such as pain, burning, tingling, numbness, or weakness occur, and medical advice should be sought before continuing treatment to prevent irreversible damage.

Hepatobiliary disorders. Cases of necrotizing hepatitis, progressing to liver failure and sometimes fatal, have been reported with levofloxacin, primarily in patients with severe underlying conditions such as sepsis (see section "Adverse reactions"). Patients should be advised to discontinue treatment and consult their 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 respiratory failure requiring respiratory support, and even fatal outcomes, have been associated with fluoroquinolone use in patients with myasthenia gravis.

Levofloxacin is not recommended for use in patients with known history of myasthenia gravis.

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

Visual disturbances. Any visual disturbances or ocular adverse effects require immediate consultation with an ophthalmologist (see sections "Effect on ability to drive and use machines" and "Adverse reactions").

Superinfection. The use of levofloxacin, especially prolonged use, may lead to overgrowth of microorganisms not susceptible to the drug. If superinfection develops during therapy, appropriate measures should be taken.

Blood glucose fluctuations.

Fluoroquinolones may cause disturbances in blood glucose levels, including symptomatic hyperglycemia and hypoglycemia, in diabetic patients receiving concomitant therapy with oral hypoglycemic agents (e.g., glyburide) or insulin. Close monitoring of blood glucose levels is recommended for such patients. Severe cases of hypoglycemia leading to coma or death have been reported. If a hypoglycemic reaction occurs in a patient receiving levofloxacin, the drug should be discontinued and appropriate therapy initiated immediately.

Effect on laboratory test results. In patients receiving levofloxacin, urine screening tests for opiates may yield false-positive results. Confirmation of positive opiate screening results by a more specific method may be necessary.

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

Aortic aneurysm and dissection, and valve regurgitation/insufficiency.

Epidemiological studies report 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 cardiac valve have been reported in patients receiving fluoroquinolones (see section "Adverse reactions").

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

• For aortic aneurysm and/or cardiac valve regurgitation/insufficiency (e.g., connective tissue disorders such as Marfan syndrome, Ehlers-Danlos syndrome, Turner syndrome, Behçet's disease, arterial hypertension, rheumatoid arthritis), or additionally
• For aortic aneurysm and dissection (e.g., vascular disorders such as Takayasu arteritis or giant cell arteritis, known atherosclerosis, or Sjögren's syndrome), or additionally
• For cardiac valve regurgitation/insufficiency (e.g., infective endocarditis).

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

Patients should be advised to seek immediate medical attention in case of sudden abdominal, chest, or back pain.

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

Use during pregnancy or breastfeeding.

Due to the lack of studies and the potential for quinolones to damage growing cartilage, levofloxacin should not be administered to pregnant women or women who are breastfeeding. If pregnancy occurs during treatment with levofloxacin, this should be reported to the physician.

Effect on ability to drive and use machines.

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

Dosage and Administration

Take tablets once daily. The dosage depends on the type and severity of the infection. The duration of treatment depends on the course of the disease and is as specified in the tables below. It is recommended to continue treatment for at least 48–72 hours after body temperature normalization or until microbiological tests confirm eradication of the causative pathogens.

Tablets should be swallowed whole without chewing, with an adequate amount of liquid. Tablets may be taken with or without food.

Table 1

Recommendations for adult patients with normal renal function, in whom creatinine clearance is over 50 mL/min

Indications	Daily dose, mg	Number of doses per day	Treatment duration, days
Acute bacterial sinusitis	500	1	10-14
	750	1	5
Exacerbation of chronic obstructive pulmonary disease, including bronchitis	500	1	7
Community-acquired pneumonia	500	1	7-14
	750	1	5
Complicated urinary tract infections and acute pyelonephritis	250	1	10
	750	1	5
Complicated skin and soft tissue infections	750	1	7-14
Chronic bacterial prostatitis	500	1	28

Table 2

Dosage adjustment for patients with renal impairment with creatinine clearance less than 50 ml/min

Dose for patients with normal renal function	Dose adjustment for patients with creatinine clearance 20–49 mL/min	Dose adjustment for patients with creatinine clearance 10–19 mL/min	Dose adjustment for patients undergoing hemodialysis or chronic ambulatory peritoneal dialysis (CAPD)
750 mg every 24 hours	750 mg every 48 hours	Initial dose – 750 mg, then 500 mg every 48 hours	Initial dose – 750 mg, then 500 mg every 48 hours
500 mg every 24 hours	Initial dose – 500 mg, then 250 mg every 24 hours	Initial dose – 500 mg, then 250 mg every 48 hours	Initial dose – 500 mg, then 250 mg every 48 hours
250 mg every 24 hours	No dose adjustment required	250 mg every 48 hours	No dose adjustment information available

Dosage in patients with hepatic impairment. Dose adjustment is not required, since levofloxacin is minimally metabolized in the liver.

Dosage in elderly patients. If renal function is not impaired, there is no need for dose adjustment.

Children.

Levofloxacin should not be administered to children due to the potential for damage to joint cartilage.

Overdose.

The most important expected symptoms of levofloxacin overdose involve the central nervous system (confusion, dizziness, disturbances of consciousness, seizures, myoclonus, hallucinations, and tremor) and gastrointestinal reactions (nausea and erosion of mucous membranes). According to study results, administration of doses higher than therapeutic has been associated with QT interval prolongation. In case of overdose, careful patient monitoring, including ECG, is required. Treatment is symptomatic. In acute overdose, gastric lavage should be performed and adequate hydration maintained. Antacid agents should be used to protect the gastric mucosa.

Hemodialysis, including peritoneal dialysis or CRRT, is not effective for elimination of levofloxacin from the body. There are no specific antidotes.

Adverse Reactions

The following is general information on adverse reactions observed in patients during clinical trials and in the post-marketing period.

Infections and infestations: Fungal infections (including Candida and proliferation of other resistant microorganisms).

Skin, subcutaneous tissue disorders, and general hypersensitivity reactions: Itching and skin redness; general hypersensitivity reactions (anaphylactic and anaphylactoid reactions) with symptoms such as urticaria, bronchospasm, and possibly severe dyspnea; skin and mucous membrane edema (e.g., facial skin and pharyngeal mucosa), sudden drop in blood pressure, shock, QT interval prolongation, increased sensitivity to sunlight and ultraviolet radiation, phototoxic reactions, skin and mucous membrane rashes, hyperhidrosis, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome), acute generalized exanthematous pustulosis, drug-induced erythema multiforme, exudative polymorphic erythema, leukocytoclastic vasculitis; rarely – drug-induced eosinophilia with systemic symptoms (DRESS syndrome) (see section "Special Warnings and Precautions for Use"), localized drug-induced skin eruptions.

Frequency not known (cannot be estimated from available data) – skin hyperpigmentation.

General hypersensitivity reactions may occur after the first dose and within minutes or hours of administration.

Gastrointestinal disorders: Nausea, vomiting, dyspepsia, diarrhea, abdominal distension, constipation, glossitis, gastritis, stomatitis, loss of appetite, abdominal pain, digestive disorders, pancreatitis, esophagitis, gastroenteritis, bloody diarrhea which may sometimes indicate intestinal inflammation including pseudomembranous colitis.

Metabolism and nutrition disorders: Anorexia, hyperkalemia, hyperglycemia, hypoglycemia (reduced blood glucose levels), which is particularly significant for diabetic patients, hypoglycemic coma. Signs of hypoglycemia may include increased appetite, nervousness, sweating, and limb tremors.

Psychiatric disorders*: Sleep disturbances, insomnia, nervousness, psychotic disorders (e.g., with hallucinations, paranoia), depression, anxiety, agitation; psychotic reactions with self-destructive behavior, including suicidal ideation or actions; unusual dreams, night terrors; frequency not known – mania.

Nervous system disorders*: Headache, dizziness, paresthesia, somnolence, vertigo, hypertonia, hyperkinesia, tremor, restlessness, fear, seizures, confusion; visual and auditory disturbances, taste disturbances, loss of taste and smell, syncope, reduced tactile sensation, dysphonia, benign intracranial hypertension, sensory or sensorimotor peripheral neuropathy, movement disorders including gait disturbances; frequency not known – myoclonus.

Eye disorders*: Uveitis, visual disturbances including blurred vision, decreased visual acuity, diplopia, scotoma, transient loss of vision.

Ear and labyrinth disorders*: Vertigo, hearing disturbances, hearing loss, tinnitus.

Cardiac disorders**: Tachycardia; decreased blood pressure; shock-like collapse; palpitations; ventricular arrhythmia and polymorphic ventricular tachycardia (torsade de pointes), which may lead to cardiac arrest, observed primarily in patients with risk factors for QT interval prolongation (see section "Special Warnings and Precautions for Use").

Vascular disorders**: Vasodilation, arterial hypotension, phlebitis, allergic reactions affecting small blood vessels (leukocytoclastic vasculitis).

Musculoskeletal and connective tissue disorders*: Joint, bone, or muscle pain; tendon disorders, including inflammation and tendon rupture (e.g., Achilles tendon rupture). This adverse effect may occur within 48 hours of starting treatment and may affect the Achilles tendons of both legs. Muscle disorders, including rupture and rhabdomyolysis, may also occur. Muscle weakness is possible, which may be particularly significant in patients with severe myasthenia gravis.

Hepatobiliary disorders: Liver function abnormalities, elevated liver enzyme levels (e.g., ALT, AST), increased alkaline phosphatase and GGT levels, elevated serum bilirubin, hepatitis, jaundice, liver reactions such as liver inflammation. Severe liver injury, including cases of acute liver failure, sometimes fatal, mainly observed in patients with serious underlying diseases (see section "Special Warnings and Precautions for Use").

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

Blood and lymphatic system disorders: Anemia, increased levels of certain blood cells (eosinophilia), decreased white blood cell count (leukopenia), reduced levels of specific leukocytes (neutropenia), decreased platelet count (thrombocytopenia), which may lead to increased susceptibility to hemorrhage or bleeding, thrombocytopenic purpura, marked reduction in certain leukocytes potentially leading to severe disease symptoms (prolonged or recurrent fever, pharyngitis, pronounced malaise), reduced red blood cell count due to hemolysis, decreased numbers of all blood cell types; frequency not known – bone marrow failure, including aplastic anemia, pancytopenia, agranulocytosis, hemolytic anemia.

Immune system disorders: Allergic reactions, hypersensitivity reactions, sometimes fatal, including anaphylactic/anaphylactoid reactions, anaphylactic shock, angioedema, serum sickness.

Respiratory system disorders: Dyspnea, bronchospasm, allergic lung reactions (allergic pneumonitis), epistaxis.

Reproductive system disorders: Vaginitis.

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

Investigations: Prolonged prothrombin time, prolonged international normalized ratio (INR), elevated muscle enzyme levels.

General disorders and administration site conditions*: General weakness (asthenia), fever, dyskinesia, pain (including back, chest, and limb pain), porphyria attacks in patients with known porphyria, extrapyramidal symptoms and other movement coordination disorders, multi-organ failure, pyrexia, edema, injection site reactions.

The use of any antibacterial agents may lead to disturbances due to their effect on the normal human microbiota. Secondary infections may thus develop, requiring additional treatment.

Description of selected adverse reactions: Anxiety, suicidal thoughts, panic attacks, neuralgia, and attention disturbances as potential aspects of prolonged and disabling adverse reactions induced by fluoroquinolones.

*- Very rare reports of long-term (from several months to several years), disabling, potentially irreversible serious adverse reactions affecting various organ systems or sensory organs, sometimes multiple simultaneously (including tendonitis, tendon rupture, arthralgia, limb pain, gait disturbances, neuropathies associated with paresthesia, depression, fatigue, memory impairment, sleep disturbances, hearing, vision, taste, and smell disturbances) in patients treated with quinolones and fluoroquinolones, regardless of previously identified risk factors.

** - 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 receiving fluoroquinolones (see section "Special Warnings and Precautions for Use").

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is of great importance. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: http://aisf.dec.gov.ua

Shelf life. 2 years.

Storage conditions. Store in a dry, light-protected place, out of reach of children, at a temperature not exceeding 25 °C.

Packaging. 10 tablets in a blister, 1 blister per cardboard box (250 mg tablets).

10 tablets in a blister, 1 blister per cardboard box (500 mg tablets).

5 or 10 tablets in a blister, 1 blister per cardboard box (750 mg tablets).

Prescription status. Prescription only.

Manufacturer. Dr. Reddy’s Laboratories Ltd, FTO – II

Manufacturer's address and place of business.
Plot Nos. 42R, 43, 44R, 45R, 46R, 53, 54, 83, Bachupally Village, Bachupally Mandal, Medchal Malkajgiri District – 500090, Telangana State, India