Levofloxacin 750

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT LEVOFLOXACIN 250 (LEVOFLOXACIN 250) LEVOFLOXACIN 500 (LEVOFLOXACIN 500) LEVOFLOXACIN 750 (LEVOFLOXACIN 750)

Composition:

Active substance: levofloxacin;

One tablet contains levofloxacin hemihydrate equivalent to levofloxacin 250 mg or 500 mg or 750 mg;

Excipients: microcrystalline cellulose PH 101, microcrystalline cellulose PH 102, hypromellose (15 cps), crospovidone, magnesium stearate, hypromellose (5 cps), 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:

250 mg tablets: biconvex, round-shaped, film-coated tablets of brown-red color, with inscriptions “T” and “62” and a break line on one side and a break line on the other side;

500 mg tablets: biconvex, oblong-shaped, film-coated tablets of brown-red color, with inscriptions “T” and “63” and a break line on one side and a break line on the other side;

750 mg tablets: biconvex, oblong-shaped, film-coated tablets of brown-red color, with inscriptions “T” and “64” 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 J01MA12.

Pharmacological properties.

Pharmacodynamics.

Levofloxacin is a synthetic antibacterial agent from the group of fluoroquinolones, the S-enantiomer of the racemic mixture of the drug ofloxacin. As an antibacterial agent from the group of fluoroquinolones, levofloxacin acts on the DNA-DNA gyrase complex and topoisomerase IV.

Levofloxacin exhibits in vitro activity against M. tuberculosis, as well as against a broad spectrum of Gram-positive and Gram-negative pathogenic microorganisms. The bactericidal effect against M. tuberculosis is achieved due to inhibition of DNA gyrase by levofloxacin, encoded by the gyrA and gyrB genes.

The breakpoint values of the minimum inhibitory concentration (MIC) of levofloxacin for clinical isolates of M. tuberculosis, according to study data, range from 0.125 to 0.5 mg/L. The primary mechanism of resistance results from mutations in the gyrA genes. Cross-resistance among fluoroquinolones occurs frequently but is not universal.

Pharmacokinetics.

Absorption. After oral administration, levofloxacin is rapidly and almost completely absorbed, with maximum plasma concentration reached within 1 hour. Absolute bioavailability is approximately 100%.

Food has almost no effect on the absorption of levofloxacin.

Distribution. Approximately 30–40% of levofloxacin is bound to serum proteins.

Metabolism. Levofloxacin is minimally metabolized; metabolites include desmethyl-levofloxacin and levofloxacin-N-oxide. These metabolites account for less than 5% of the total amount of 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). Elimination occurs primarily via the kidneys (more than 85% of the administered dose).

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

Patients with renal impairment

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

Creatinine clearance (ml/min)	< 20	20-40	50-80
Renal clearance (ml/min)	13	26	57
Half-life (hours)	35	27	9

Elderly patients

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

Gender differences

A separate analysis of male and female patients revealed 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 tablets are used in combination with other drugs for the treatment of tuberculosis caused by Mycobacterium tuberculosis.

Levofloxacin tablets are used only as a second-line agent when first-line antituberculosis drugs are unsuitable due to resistance or intolerance.

The drug should be prescribed in accordance with official tuberculosis treatment guidelines, such as those of the WHO (http://www.who.int/tb/publications/pmdt_companionhandbook/en/).

Contraindications

Hypersensitivity to levofloxacin, to other components of the drug, or to other quinolones. Epilepsy, history of tendon-related adverse reactions following previous quinolone administration. Pregnancy or breastfeeding.

Interaction with other medicinal products and other forms of interaction

Effects 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- and aluminium-containing antacids, or didanosine (only formulations of didanosine containing aluminium- and magnesium-based buffering agents) are administered concomitantly with levofloxacin tablets. Concurrent administration of fluoroquinolones and multivitamin preparations containing zinc reduces their oral absorption. It is not recommended to administer medicinal products containing divalent or trivalent cations, such as iron salts, zinc salts, magnesium- and aluminium-containing antacids, or didanosine (only formulations of didanosine containing aluminium- and magnesium-based buffering agents), within 2 hours before or after levofloxacin intake (see section "Dosage and administration"). Calcium salts have minimal effect on the absorption of levofloxacin following oral administration.

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 administer sucralfate 2 hours after levofloxacin intake (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 administration of quinolones and theophylline, NSAIDs, or other drugs that lower the seizure threshold. It is known that fenbufen increases levofloxacin concentrations by approximately 13% compared to levofloxacin alone.

Systemic corticosteroids (e.g., prednisolone)

Concomitant use with corticosteroids may increase the risk of tendinitis and tendon rupture.

Tendon rupture may occur either during therapy or several months after its completion (see section "Special precautions").

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 cimetidine and by 34% with probenecid. This is explained by the ability of both drugs to block tubular secretion of levofloxacin. Caution should be exercised when administering levofloxacin concomitantly with drugs affecting tubular secretion, such as probenecid and cimetidine, especially in patients with renal impairment.

Medicinal products affecting tubular secretion

Concomitant use of high-dose quinolones and other drugs affecting tubular secretion (probenecid, cimetidine, furosemide, methotrexate) may impair excretion and increase serum levels of quinolones.

Other medicinal products

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

Effects of levofloxacin 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 (prothrombin time/international normalized ratio (PT/INR)) may increase and/or bleeding may occur, which can be severe. Therefore, patients receiving concomitant vitamin K antagonists should be monitored for coagulation parameters (see section "Special precautions").

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 (e.g., class IA and III antiarrhythmics, tricyclic antidepressants, and macrolides) (see section "Special precautions. QT interval prolongation").

Theophylline

Levofloxacin does not affect the pharmacokinetics of theophylline (a CYP1A2 substrate), indicating that levofloxacin is not an inhibitor of CYP1A2.

Other forms of interaction

Food intake

No clinically significant interaction with food has been observed; therefore, the drug may be taken independently of meals.

Special precautions for use

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

Prolonged, disabling and potentially irreversible serious adverse reactions

In very rare cases, prolonged (lasting for months or years), disabling and potentially irreversible serious adverse reactions affecting various organ systems (musculoskeletal, nervous, psychiatric, and sensory organs), sometimes involving multiple systems simultaneously, have been reported in patients receiving fluoroquinolones, regardless of age or existing risk factors. The medicinal product should be discontinued immediately at the first signs or symptoms of any serious adverse reaction, and medical advice should be sought.

Aneurysm and dissection of the aorta, and cardiac valve regurgitation/insufficiency

Epidemiological studies have shown 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 therapeutic options in patients with a positive family history of aneurysm or congenital heart valve defects, or in patients with an existing diagnosis of aneurysm and/or aortic dissection, or heart valve disease, or in the 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, 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 concurrently receiving systemic corticosteroids.

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

Patients should be advised to seek immediate medical help if they experience acute shortness of breath, a new episode of palpitations, or develop abdominal or lower limb swelling.

Methicillin-resistant S. aureus

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

Resistance to fluoroquinolones in E. coli varies across different countries. Local prevalence of E. coli resistance to fluoroquinolones should be considered when prescribing fluoroquinolones.

In severe pneumococcal pneumonia, the drug may not provide optimal therapeutic effect.

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

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 and have been reported even several months after discontinuation of treatment in patients receiving daily doses of 1000 mg levofloxacin. The risk of tendinitis and tendon rupture is higher in elderly patients, patients with renal impairment, patients who have undergone solid organ transplantation, and patients receiving concomitant corticosteroid therapy. Therefore, concomitant use of corticosteroids should be avoided.

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

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 the first occurrence of myoclonus, and appropriate treatment should be initiated.

Clostridium difficile-associated disease

Diarrhea, especially severe, persistent, and/or hemorrhagic, during or after treatment with the medicinal product may be a symptom of Clostridium difficile-associated disease, the most severe form of which is 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). Medicinal products that inhibit intestinal motility 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 central nervous system disorders, concomitant therapy with phenylbutazone and similar NSAIDs, or other medicinal products 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, levofloxacin treatment must be discontinued.

Patients with glucose-6-phosphate dehydrogenase deficiency

Patients with latent or known deficiency in glucose-6-phosphate dehydrogenase activity are prone to hemolytic reactions during treatment with quinolone group antibacterial agents; therefore, levofloxacin should be used with caution in these patients.

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 (allergic 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, seek medical advice, and initiate appropriate treatment if necessary.

Severe bullous reactions

Severe bullous reactions such as Stevens-Johnson syndrome or toxic epidermal necrolysis (also known as Lyell’s syndrome) and drug rash with eosinophilia and systemic symptoms (DRESS syndrome), which may be life-threatening or fatal, have been reported during levofloxacin use. When prescribing the medicinal product, patients should be informed about the signs and symptoms of severe skin reactions and closely monitored. If signs and symptoms suggestive of these reactions occur, levofloxacin should be discontinued immediately and alternative treatment considered. Re-administration of levofloxacin is contraindicated in patients with a history of such serious reactions as toxic epidermal necrolysis, Stevens-Johnson syndrome, or DRESS syndrome associated with prior levofloxacin use.

Alterations in blood glucose levels

Changes in blood glucose levels, including both hypoglycemia and hyperglycemia, have been observed during treatment with all quinolones, 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").

Prevention of photosensitization

Although photosensitization is very rare with levofloxacin, to avoid it, patients should be advised not to expose themselves to strong sunlight or artificial UV radiation (e.g., UV lamps, tanning beds) without specific need, and for 48 hours after discontinuation of the drug.

Patients receiving vitamin K antagonists

Since an increase in coagulation test parameters (INR/PT) and/or bleeding may occur in patients taking levofloxacin in combination with a vitamin K antagonist (e.g., warfarin), coagulation test parameters should be monitored (see section "Interaction with other medicinal products and other forms of interaction").

Psychotic reactions

Psychotic reactions have been reported in patients taking quinolones, including levofloxacin. In rare cases, such reactions have progressed to suicidal thoughts 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. Caution is recommended when prescribing levofloxacin to patients with psychotic disorders or a history of psychiatric illness.

QT interval prolongation

Fluoroquinolones, including levofloxacin, should be used with caution in patients with 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);
• uncorrected electrolyte imbalance (e.g., hypokalemia, hypomagnesemia);
• advanced age;
• 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", and "Adverse reactions").

Peripheral neuropathy

Cases of sensory or sensorimotor polyneuropathy, manifesting as paresthesia, hyposthesia, dysesthesia, or weakness, have been reported in patients receiving quinolones and fluoroquinolones, including levofloxacin. Patients receiving levofloxacin should be informed that if such neuropathic symptoms (e.g., pain, burning, tingling, numbness, or weakness) occur during continued treatment, they should consult a physician to prevent potential development of irreversible conditions (see section "Adverse reactions").

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.

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 test results should be monitored. If abnormal results are obtained, discontinuation of levofloxacin therapy should be considered.

Exacerbation of myasthenia gravis

Fluoroquinolones, including levofloxacin, exhibit 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 ocular adverse reactions occur during levofloxacin therapy, patients should seek immediate consultation with an ophthalmologist (see sections "Ability to affect reaction speed when driving or operating machinery" and "Adverse reactions").

Superinfection

The use of levofloxacin, especially prolonged use, may lead to overgrowth of microorganisms resistant to the drug. If superinfection develops during therapy, appropriate measures should be taken.

Effect on laboratory test results

In patients receiving levofloxacin, urine opiate testing may yield false-positive results. Positive opiate test results may require confirmation using more specific methods.

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

Use during pregnancy or breastfeeding

Due to the lack of studies and the potential for quinolones to damage developing joint cartilage, levofloxacin is contraindicated in pregnant women and those who are breastfeeding. If pregnancy is diagnosed during treatment with this medicinal product, the physician should be informed.

Levofloxacin did not cause impairment of fertility or reproductive function in animal studies.

Ability to affect 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 auditory disturbances, motor disturbances, including gait disturbances).

Method of administration and dosage.

Tablets should be swallowed whole, without chewing, with an adequate amount of liquid. They can be taken either with food or at any other time.

Adults. The recommended daily dose is 750 mg for patients with body weight from 30 kg to 60 kg, and 1000 mg for patients with body weight above 60 kg.

Dosing in patients with renal impairment. For patients with creatinine clearance <30 mL/min, including those undergoing hemodialysis, the dose should be reduced to 750–1000 mg per day and administered three times a week.

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

Dosing in elderly patients. If renal function is not impaired, no dose adjustment is necessary (see section "Special precautions", "Tendinitis and tendon rupture. QT interval prolongation").

Children.

Due to the potential risk of joint cartilage damage, the medicinal product should be used in children and adolescents only after careful benefit-risk assessment and in the absence of alternative treatment options, according to WHO recommendations.

(http://www.who.int/tb/publications/pmdt_companionhandbook/en/).

Overdose.

The most likely symptoms of overdose involve the central nervous system (dizziness, altered consciousness, and seizures); gastrointestinal reactions such as nausea and mucosal erosions may also occur. Administration of doses higher than therapeutic ones may lead to QT interval prolongation. In case of overdose, careful patient monitoring, including ECG monitoring, is required.

Treatment: symptomatic therapy. In acute overdose, gastric lavage should be performed. Antacids should be used to protect gastric mucosa.

Hemodialysis, including peritoneal dialysis or chronic ambulatory peritoneal dialysis, 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 (and proliferation of other resistant microorganisms), disruption of normal intestinal flora, and development of secondary infection.

Blood system disorders: leukopenia, eosinophilia, thrombocytopenia, neutropenia, agranulocytosis, pancytopenia, hemolytic anemia.

Blood and lymphatic system disorders:
Frequency unknown (cannot be estimated from available data): bone marrow failure, including aplastic anemia, pancytopenia, agranulocytosis, hemolytic anemia.

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

Metabolism and nutrition disorders: anorexia, hypoglycemia, especially in diabetic patients (see section "Special precautions for use"), hyperglycemia, hypoglycemic coma. Symptoms of hypoglycemia may include increased appetite, nervousness, excessive sweating, and tremors in limbs. As with other fluoroquinolones, porphyria attacks are possible in patients with porphyria.

Psychiatric disorders: insomnia, unusual dreams, night terrors, nervousness, psychotic disorders, depression, confusion, anxiety, agitation, restlessness, fear, psychotic reactions with self-destructive behavior, including suicidal ideation or actions (see section "Special precautions for use"), psychotic disorders (including paranoia, hallucinations).

Frequency unknown: mania.

Nervous system disorders: dizziness, confusion, numbness, headache, drowsiness, sleep disorders, seizures, tremor, paresthesia, sensory or sensorimotor peripheral neuropathy, decreased sense of touch, dysgeusia (subjective taste disturbance), including ageusia (loss of taste), parosmia (disturbance of smell), including anosmia (loss of smell); dyskinesia (impaired motor coordination), syncope (fainting), benign intracranial hypertension.

Frequency unknown: myoclonus.

Eye disorders: rarely – visual disturbances, including blurred vision; frequency unknown – transient visual disturbance, temporary loss of vision, uveitis.

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

Respiratory, thoracic and mediastinal disorders: uncommon – dyspnea, shortness of breath; frequency unknown – bronchospasm, allergic pneumonitis.

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

Cardiovascular disorders **: common – phlebitis; tachycardia, palpitations, ventricular arrhythmia, ventricular tachycardia, and polymorphic ventricular tachycardia of the torsade de pointes type (mainly in patients with risk factors for QT interval prolongation), which may lead to cardiac arrest, QT interval prolongation on ECG (see sections "Special precautions for use. QT interval prolongation" and "Overdose"), arterial hypotension, collapse with shock-like symptoms, allergic vasculitis.

Respiratory system disorders: bronchospasm, dyspnea, allergic pneumonitis.

Gastrointestinal disorders: diarrhea, nausea, vomiting, abdominal pain, dyspepsia, bloating, constipation, hemorrhagic diarrhea, which in rare cases may indicate enterocolitis, including pseudomembranous colitis.

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

Skin and subcutaneous tissue disorders: skin redness, rash, pruritus, urticaria, angioedema, hives, hyperhidrosis, drug eruptions with eosinophilia and systemic symptoms (DRESS syndrome), localized drug eruptions, increased sensitivity to sunlight and ultraviolet radiation, leukocytoclastic vasculitis, stomatitis, toxic epidermal necrolysis (Lyell's syndrome), Stevens-Johnson syndrome, exudative multiform erythema, hyperhidrosis, swelling of skin and mucous membranes.

Skin and mucous membrane reactions may occasionally occur even after the first dose.

Frequency unknown: skin hyperpigmentation.

Musculoskeletal and connective tissue disorders: tendon disorders (see section "Special precautions for use"), including tendon inflammation (tendinitis) (e.g., Achilles tendon); arthralgia; myalgia; ligament rupture, muscle rupture, tendon rupture (e.g., Achilles tendon) (see section "Special precautions for use"). This adverse effect may occur within 48 hours of starting treatment and may affect the Achilles tendons of both legs. Muscle weakness is possible, which is particularly significant in patients with severe myasthenia gravis; muscle disorders (rhabdomyolysis), arthritis, joint pain, muscle pain.

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

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

Other adverse effects associated with fluoroquinolone use include: extrapyramidal symptoms and other movement coordination disorders, hypersensitivity vasculitis, porphyria attacks in patients with porphyria.

*Very rare cases of long-term (up to months or years), disabling, and potentially irreversible serious adverse reactions involving multiple, sometimes multiple, organ systems and sensory organs (including such reactions as tendinitis, tendon rupture, arthralgia, limb pain, gait disturbance, and in some cases neuropathy associated with paresthesia, 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 precautions for use"); anxiety, suicidal thoughts, panic attacks, neuralgia, and attention disturbances have also been reported as potential aspects of long-term and disabling adverse reactions caused by fluoroquinolones.

** Cases of aneurysm and dissection of the aorta, sometimes complicated by rupture (including fatal cases), and regurgitation/insufficiency of any heart valve have been reported in patients receiving fluoroquinolones (see section "Special precautions for use").

Shelf life.

Tablets 250 mg, 500 mg: 4 years.

Tablets 750 mg: 2 years.

Storage conditions.

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

Keep out of the reach of children.

Packaging.

Tablets 250 mg, 500 mg

20 tablets in a blister pack, 5 blisters in a cardboard box.

10 tablets in a blister pack, 9 or 10 blisters in a cardboard box.

Tablets 750 mg

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

Prescription category. Prescription only.

Manufacturer.

Macleods Pharmaceuticals Limited.

Manufacturer's address and location of business activity.

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