Levomak iv

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LEVOMAK I/V (LEVOMAK I/V)

Composition:

Active substance: levofloxacin;

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

Excipients: sodium chloride, disodium edetate, hydrochloric acid diluted, sodium hydroxide, water for injections.

Pharmaceutical form. Infusion solution.

Main physico-chemical properties: clear liquid, yellow to yellow-green in color.

Pharmacotherapeutic group.

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

Pharmacological Properties

Pharmacodynamics

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

Mechanism of action. As a fluoroquinolone-class 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 between the maximum serum concentration (Cmax) or the area under the concentration-time curve (AUC) and the 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.

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

Pharmacokinetics

Absorption

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

After intravenous administration, the drug accumulates in the bronchial mucosa, lung tissue, bronchial secretions, and urine. Levofloxacin penetrates poorly into cerebrospinal fluid.

Distribution

Approximately 30–40% of levofloxacin binds to serum proteins. The cumulative effect of levofloxacin with repeated administration of 500 mg once daily is almost negligible. A slight but predictable accumulation occurs after repeated doses of 500 mg twice daily. Steady-state levels are achieved within 3 days.

Penetration into tissues and body fluids

Penetration into bronchial mucosa and bronchial secretion of lung tissue (BSLT)

The maximum concentration of levofloxacin in the bronchial mucosa and bronchial secretions of the lungs after a single 500 mg oral dose was 8.3 µg/g and 10.8 µg/mL, respectively. These levels were reached within one hour after drug administration.

Penetration into lung tissue

The maximum concentration of levofloxacin in lung tissue after a single 500 mg oral dose was approximately 11.3 µg/g, achieved 4–6 hours after administration. Concentrations in the lungs exceed those in blood plasma.

Penetration into pus content

Maximum concentrations of levofloxacin of 4–6.7 µg/mL in pus content were achieved 2–4 hours after drug administration on day 3 of treatment with doses of 500 mg once or twice daily, respectively.

Penetration into cerebrospinal (CSF) fluid

Levofloxacin penetrates poorly into cerebrospinal fluid.

Penetration into prostate tissue

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

Urine concentration

The mean urine concentration 8–12 hours after a single oral dose of 150 mg, 300 mg, or 500 mg of levofloxacin was 44 mg/L, 91 mg/L, and 200 mg/L, respectively.

Biotransformation

Levofloxacin undergoes minimal metabolism, with metabolites being 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.

Linearity

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

Patients with renal impairment

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

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

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

Clinical characteristics.

Indications.

Levofloxacin, solution for infusion, is indicated for the treatment of the following infections in adults:

• community-acquired pneumonia;
• complicated skin and soft tissue infections;

(regarding the above-mentioned infections, levofloxacin should be prescribed only when other antibacterial medicinal products primarily used for initial treatment of these infections are insufficiently effective);

• pyelonephritis and complicated urinary tract infections;
• chronic bacterial prostatitis.

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

Contraindications.

Levofloxacin should not be prescribed in the following cases:

• hypersensitivity to levofloxacin or to other quinolones, or to any of the excipients;
• tendon-related adverse reactions following prior use of quinolones;
• epilepsy;
• age under 18 years;
• pregnancy or breastfeeding.

Interaction with other medicinal products and other forms of interaction.

Effect of other medicinal products on the drug

Theophylline, fenbufen, or 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 agents that lower the seizure threshold. The concentration of levofloxacin was approximately 13% higher in the presence of fenbufen compared to administration of levofloxacin alone.

Probenecid and cimetidine

Probenecid and cimetidine significantly affect the elimination of levofloxacin. Renal clearance of levofloxacin is reduced by 24% in the presence of cimetidine and by 34% with probenecid, as both drugs can block tubular secretion of levofloxacin. Concomitant use 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

Clinical pharmacology studies have shown that there is no clinically significant effect on the pharmacokinetics of levofloxacin when administered concomitantly with the following medicinal products: calcium carbonate, digoxin, glyburide, ranitidine.

Effect of the drug on other medicinal products

Cyclosporine

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

Vitamin K antagonists

When used concomitantly with vitamin K antagonists (e.g., warfarin), increased values in coagulation tests (PT/INR) and/or bleeding events, which may be severe, have been reported. Therefore, patients receiving concomitant vitamin K antagonists should be monitored for coagulation parameters.

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).

Other significant 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.

Special precautions for use.

Patients with a history of serious adverse reactions to quinolone or fluoroquinolone drugs (see section "Adverse reactions") should avoid the use of levofloxacin. Treatment with levofloxacin in such patients should only be considered after careful assessment of benefit-risk ratio and in the absence of alternative treatment options (see section "Contraindications").

The benefit of levofloxacin therapy should be carefully weighed, especially in cases of mild infections, according to the information provided in this section "Special precautions for use".

Prolonged, disabling, and potentially irreversible serious adverse reactions

Very rare cases of prolonged (lasting for months or years), disabling, and potentially irreversible serious adverse reactions affecting various, sometimes multiple, body systems (musculoskeletal, nervous system, mental health, sensory organs) have been reported in patients receiving quinolones and fluoroquinolones, regardless of age or presence of risk factors. Levofloxacin therapy should be discontinued immediately at the first signs or symptoms of any serious adverse reaction, and patients should be advised to consult a physician.

Methicillin-resistant Staphylococcus aureus (MRSA)

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

Resistance of E. coli

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

Aortic aneurysm and aortic dissection

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

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

Duration of infusion

The recommended duration of infusion is at least 60 minutes for the 500 mg infusion solution. With ofloxacin, tachycardia and transient increases in blood pressure have been observed during infusion. In rare cases, this may lead to sudden hypotension and circulatory collapse. If marked hypotension occurs during levofloxacin (l-isomer of ofloxacin) infusion, the infusion should be stopped immediately.

Tendinitis and tendon rupture

Tendonitis may rarely occur, most commonly affecting the Achilles tendon, and may lead to tendon rupture. Tendinitis and tendon ruptures, sometimes bilateral, may occur within 48 hours after starting levofloxacin or even several months after discontinuation. Patients at highest risk include those aged 60 years or older, patients receiving a daily dose of 1000 mg levofloxacin, and patients receiving corticosteroid therapy. Patients who have undergone transplantation have an increased risk of tendinitis; therefore, fluoroquinolones should be used with caution in this population. The daily dose should be adjusted in elderly patients based on creatinine clearance (see section "Dosage and administration"). Elderly patients receiving levofloxacin should be monitored. Patients should consult a physician if they experience symptoms suggestive of tendinitis. If tendinitis is suspected, treatment should be stopped immediately and appropriate management initiated (e.g., immobilization of the affected tendon).

Clostridium difficile-associated disease

Diarrhea, particularly severe, persistent, or hemorrhagic diarrhea occurring during or after treatment (including several weeks after therapy), may be a symptom of Clostridium difficile-associated disease, the most severe form of which is pseudomembranous colitis. The severity of CDAD ranges from mild to life-threatening. This diagnosis should be considered in patients who develop severe diarrhea during or after levofloxacin therapy. If pseudomembranous colitis is suspected, the infusion should be stopped immediately and appropriate treatment initiated. Antiperistaltic agents are contraindicated in this clinical situation.

Patients predisposed to seizures

Quinolones may lower the seizure threshold and provoke seizures. The drug is contraindicated in patients with a history of epilepsy. The drug (like other quinolones) should be used with extreme caution in patients predisposed to seizures, particularly those with prior central nervous system disorders or those receiving concomitant medications that lower the cerebral seizure threshold, such as theophylline (see section "Interaction with other medicinal products and other forms of interaction"). If seizures occur, levofloxacin therapy should be discontinued.

Patients with glucose-6-phosphate dehydrogenase deficiency

Patients with latent or manifest deficiency in glucose-6-phosphate dehydrogenase activity are prone to hemolytic reactions when treated with quinolone antibiotics; therefore, levofloxacin should be used with caution in such patients, and monitoring for possible hemolysis is recommended.

Patients with renal impairment

Since levofloxacin is primarily eliminated via the kidneys, dose adjustment is required in patients with impaired renal function (renal insufficiency).

Hypersensitivity reactions

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

Disturbances in blood glucose

As with other quinolones, fluctuations in blood glucose levels, including hyperglycemia and hypoglycemia, have been reported, particularly 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.

Prevention of photosensitization

Although photosensitization is very rare with levofloxacin, to avoid it, patients should not be exposed to strong sunlight or artificial UV radiation (e.g., UV lamps, tanning beds) during and for 48 hours after levofloxacin therapy.

Patients receiving vitamin K antagonists

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

Psychiatric reactions

Psychiatric reactions have been reported in patients taking quinolones, including levofloxacin. In rare cases, these progressed to suicidal ideation and self-harming behavior, sometimes after only a single dose of levofloxacin. If such reactions occur, levofloxacin should be discontinued and appropriate measures taken. Levofloxacin should be used with caution in patients with psychiatric disorders or a history of psychiatric illness.

QT interval prolongation

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

• congenital long QT syndrome;
• concomitant use of medicinal products known to prolong the QT interval (e.g., class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics);
• uncorrected electrolyte imbalances (e.g., hypokalemia, hypomagnesemia);
• heart disease (e.g., heart failure, myocardial infarction, bradycardia).

Elderly patients and younger women may be more sensitive to drugs that prolong the QT interval; therefore, caution is required when using fluoroquinolones, including levofloxacin, in these patient groups (see sections "Dosage and administration" – "Elderly patients"; "Interaction with other medicinal products and other forms of interaction"; "Adverse reactions"; "Overdose").

Peripheral neuropathy

Sensory or sensorimotor peripheral neuropathy, which may develop rapidly, has been reported in patients receiving fluoroquinolones, including levofloxacin. Levofloxacin should be discontinued if symptoms of neuropathy occur to prevent development of irreversible damage.

Hepatobiliary disorders

Cases of necrotizing hepatitis up to life-threatening liver failure 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 a physician if symptoms of liver disease occur, such as anorexia, jaundice, dark urine, pruritus, or abdominal pain.

Exacerbation of myasthenia gravis

Fluoroquinolones, including levofloxacin, block neuromuscular transmission and may provoke muscle weakness in patients with myasthenia gravis. Serious adverse reactions, including fatal outcomes and need for respiratory support, have been reported post-marketing in patients with myasthenia gravis receiving fluoroquinolones. Levofloxacin is not recommended for use in patients with a history of myasthenia gravis.

Visual disturbances

If visual disturbances or other ocular effects occur, patients should seek immediate ophthalmological evaluation (see sections "Ability to influence reaction rate when driving or operating machinery", "Adverse reactions").

Superinfection

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

Effect on laboratory tests

In patients receiving levofloxacin, urine opiate screening may yield false-positive results. Positive results may require confirmation by more specific methods. Levofloxacin inhibits the growth of Mycobacterium tuberculosis, which may lead to false-negative results in bacteriological testing of patients with tuberculosis.

Sodium content

This medicinal product contains 39.1 mmol (900 mg) of sodium per 100 ml of solution. This should be taken into account for patients on a sodium-restricted diet.

Use during pregnancy or breastfeeding.

Due to the lack of adequate studies and the potential for quinolones to damage developing joint cartilage, levofloxacin should not be administered to pregnant women or women who are breastfeeding. If pregnancy is diagnosed during treatment, the patient should inform her physician.

Ability to influence reaction rate when driving or operating machinery.

Patients who drive vehicles or operate machinery should be aware of possible nervous system adverse reactions (dizziness, numbness, somnolence, confusion, visual and auditory disturbances, motor disorders, including gait disturbances).

Method of Administration and Dosage

Before administering the drug, a sensitivity test must be performed. The preparation for intravenous infusion should be used immediately (within 3 hours) after piercing the rubber stopper. Protection from light during infusion is not required. The solution for intravenous administration may be stored under room lighting for up to 3 days without protection from light. Dosage depends on the type and severity of the infection.

For treatment of adults with normal renal function, in whom creatinine clearance is over 50 ml/min, the following dosage regimens are generally recommended

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

Since levofloxacin is primarily eliminated via the kidneys, the dose should be reduced in patients with impaired renal function.

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

1 After hemodialysis or continuous ambulatory peritoneal dialysis (CAPD), additional doses are not required.

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

Dosing in elderly patients. If renal function is normal, there is no need for dose adjustment.

Levomak IV solution for intravenous administration is administered intravenously by slow infusion. The infusion of 100 ml of the solution (containing 500 mg of levofloxacin) should last no less than 60 minutes.

The duration of treatment depends on the course of the disease. As with other antibacterial agents, it is recommended to continue treatment for at least 48–72 hours after normalization of body temperature or confirmed microbiological eradication of the causative organisms.

Children.

The drug must not be administered to children (under 18 years of age), as damage to the articular cartilage cannot be excluded.

Overdose.

The most important expected symptoms of overdose involve the central nervous system (confusion and impaired consciousness, dizziness, seizures). According to study results, administration of doses higher than therapeutic ones was associated with QT interval prolongation.

Treatment. In cases of overdose, careful patient monitoring, including ECG, should be performed. Symptomatic therapy.

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

Adverse Reactions.

Infections and infestations: fungal infections, including Candida species; development of resistance in pathogenic microorganisms.

Blood and lymphatic system disorders: leucopenia, eosinophilia, thrombocytopenia, neutropenia, agranulocytosis, pancytopenia, haemolytic anaemia.

Immune system disorders: angioneurotic oedema, hypersensitivity (see section "Special warnings and precautions for use"). Anaphylactic and anaphylactoid reactions may occasionally occur even after administration of the first dose.

Metabolism and nutrition disorders: anorexia, hypoglycaemia, particularly in patients with diabetes mellitus, hyperglycaemia, hypoglycaemic coma (see section "Special warnings and precautions for use").

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

Nervous system disorders *: dizziness, headache, somnolence, convulsions (see sections "Contraindications" and "Special warnings and precautions for use"), tremor, paraesthesia, sensory or sensorimotor peripheral neuropathy (see section "Special warnings and precautions for use"), dysgeusia (disturbance of taste perception), including ageusia (loss of taste), parosmia (disturbance of smell), including anosmia (loss of smell), dyskinesia (disturbance of motor coordination), extrapyramidal disorders, syncope (loss of consciousness), benign intracranial hypertension.

Eye disorders *: visual disturbances such as blurred vision or temporary loss of vision (see section "Special warnings and precautions for use"), uveitis.

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

Cardiac disorders: tachycardia, palpitations, ventricular tachycardia which may lead to cardiac arrest, ventricular arrhythmia of the torsade de pointes type (mainly in patients with risk factors for QT interval prolongation), QT interval prolongation on ECG (see sections "Special warnings and precautions for use" and "Overdose").

Vascular disorders: phlebitis, arterial hypotension.

Respiratory, thoracic and mediastinal disorders: bronchospasm, dyspnoea, allergic pneumonitis.

Gastrointestinal disorders: diarrhoea, nausea, vomiting, abdominal pain, dyspepsia, bloating, constipation, haemorrhagic diarrhoea which in rare cases may indicate enterocolitis, including pseudomembranous colitis (see section "Special warnings and precautions for use"), pancreatitis.

Hepatobiliary disorders: increased liver enzyme levels (ALT/AST, alkaline phosphatase, GGT); increased blood bilirubin; hepatitis; jaundice and severe liver damage, including cases of acute liver failure (sometimes fatal), mainly in patients with severe underlying diseases (see section "Special warnings and precautions for use").

Skin and subcutaneous tissue disorders: rash, pruritus, urticaria, hyperhidrosis, toxic epidermal necrolysis (Lyell's syndrome), Stevens-Johnson syndrome, erythema multiforme, photosensitivity reactions (see section "Special warnings and precautions for use"), leukocytoclastic vasculitis, stomatitis.

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

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

General disorders and administration site conditions *: infusion site reactions (pain, redness), asthenia, pyrexia, pain (including back, chest and limb pain).

Other adverse effects associated with fluoroquinolone use: extrapyramidal symptoms and other disturbances of motor coordination, hypersensitivity vasculitis, porphyria attacks in patients with known porphyria.

*Prolonged (lasting for months or years), disabling and potentially irreversible serious adverse reactions, sometimes affecting multiple body systems and sensory organs, have been reported very rarely with quinolones and fluoroquinolones (including such reactions as tendinitis, tendon rupture, arthralgia, limb pain, gait disturbance, neuropathy associated with paraesthesia, depression, fatigue, memory impairment, sleep disorders, and disturbances of hearing, vision, taste and smell), occasionally occurring independently of the presence of risk factors (see section "Special warnings and precautions for use").

Shelf life. 2 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in a light-protected and out-of-reach-of-children place.

Incompatibilities.

Levofloxacin should not be mixed with heparin or alkaline solutions (e.g., sodium bicarbonate) or with other medicinal products whose compatibility has not been established.

Levofloxacin is compatible with the following infusion solutions:

• 0.9% sodium chloride solution;
• 5% glucose monohydrate solution;
• 2.5% dextrose in Ringer's solution;
• multi-component parenteral nutrition solutions (amino acids, carbohydrates, electrolytes).

Packaging.

100 ml of solution in a polyvinyl chloride container, 1 container in a polyethylene bag, in a cardboard box.

Prescription status. Prescription only.

Manufacturer/Marketing Authorisation Holder.

Manufacturer.

Subsidiary enterprise "Farmatreyd".

Marketing Authorisation Holder.

MACLEODS PHARMACEUTICALS LIMITED.

Address of manufacturer and location of its business activities / Address of marketing authorisation holder.

Address of manufacturer.

85 Sambirska Street, Drohobych, Lviv region, Ukraine.

Address of marketing authorisation holder.

Atlanta Arcade, Marol Church Road, Andheri (East), Mumbai – 400059, India.