Instructions Levomac IV solution for infusion 500 mg/100 ml bottle 100 ml No. 1
Composition
active ingredient: levofloxacin;
100 ml of solution contains levofloxacin hemihydrate equivalent to 100% anhydrous levofloxacin 500 mg;
Excipients: sodium chloride, disodium edetate, diluted hydrochloric acid, sodium hydroxide, water for injections.
Dosage form
Solution for infusion.
Main physicochemical properties: clear liquid from yellow to greenish-yellow color.
Pharmacotherapeutic group
Antibacterials of the quinolone group. Fluoroquinolones. ATX code J01M A12.
Pharmacological properties
Pharmacodynamics
Levofloxacin is a synthetic antibacterial agent from the fluoroquinolone group, the S-enantiomer of the racemic mixture of the drug ofloxacin.
Mechanism of action. As an antibacterial drug from the fluoroquinolone group, levofloxacin acts on the DNA-DNA gyrase complex and topoisomerase IV.
Pharmacokinetics/pharmacodynamics relationship. The degree of bactericidal activity of levofloxacin depends on the ratio of the maximum serum concentration (Cmax) or the area under the pharmacokinetic concentration-time curve (AUC) and the minimum inhibitory concentration (MIC).
Mechanism of resistance. The main mechanism of resistance is due to mutations in the gyr-A genes. In vitro, there is cross-resistance between levofloxacin and other fluoroquinolones.
Due to its mechanism of action, there is usually no cross-resistance between levofloxacin and other classes of antibacterial agents.
Other data: Hospital-acquired infections caused by P. aeruginosa may require combination therapy.
Pharmacokinetics
Absorption
There is no significant difference between the pharmacokinetics of levofloxacin after intravenous and oral administration.
After intravenous administration, the drug accumulates in the bronchial mucosa and bronchial secretions of lung tissue (the concentration in the lungs exceeds that in blood plasma), urine. Levofloxacin penetrates poorly into the cerebrospinal fluid.
Distribution
Approximately 30–40% of levofloxacin is bound to serum proteins. The cumulative effect of levofloxacin when administered 500 mg once daily is almost absent with multiple administration. There is a small but predictable cumulative effect after administration of doses of 500 mg twice daily. Steady state is reached within 3 days.
Penetration into body tissues and fluids
Penetration into the bronchial mucosa, bronchial secretion of lung tissues (BSTL)
The maximum concentration of levofloxacin in the bronchial mucosa and bronchial secretions of the lungs after oral administration of 500 mg was 8.3 μg/g and 10.8 μg/ml, respectively. These values were achieved within one hour after administration of the drug.
Penetration into lung tissue
The maximum concentration of levofloxacin in lung tissue after oral administration of 500 mg was approximately 11.3 μg/g and was reached 4-6 hours after administration. The concentration in the lungs exceeds that in blood plasma.
Penetration into the contents of the pustule
The maximum concentration of levofloxacin of 4–6.7 μg/ml in the pustule contents was reached 2–4 hours after application of the drug after 3 days of application of the drug at doses of 500 mg 1 or 2 times a day, respectively.
Penetration into cerebrospinal fluid
Levofloxacin penetrates poorly into the cerebrospinal fluid.
Penetration into prostate tissue
After administration of 500 mg levofloxacin once daily for 3 days, mean prostate tissue concentrations 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.
Concentration in urine
The mean urinary 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, or 200 mg/L, respectively.
Biotransformation
Levofloxacin is metabolized to a minor extent, the metabolites are desmethyl-levofloxacin and levofloxacin-N-oxide. These metabolites account for less than 5% of the drug excreted in the urine. Levofloxacin is stereochemically stable and is not subject to inversion of the chiral structure.
Breeding
After oral and intravenous administration, levofloxacin is eliminated from the blood plasma relatively slowly (half-life 6–8 hours). Excretion occurs mainly by 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 has linear pharmacokinetics in the range of 50–600 mg.
Patients with renal insufficiency
The pharmacokinetics of levofloxacin are affected by renal insufficiency. With decreased renal function, renal excretion and clearance are reduced and the half-life is increased, as shown in the table below:
| Creatinine clearance (ml/min) | < 20 | 20-40 | 50-80 |
| Renal clearance (ml/min) | 13 | 26 | 57 |
| Half-life (hours) | 35 | 27 | 9 |
There are no significant differences in the pharmacokinetics of levofloxacin in young and elderly patients, except for differences related to creatinine clearance.
Gender differences
Separate analyses of male and female patients demonstrated slight gender differences in the pharmacokinetics of levofloxacin. There is no evidence that gender differences are clinically relevant.
Indication
Levofloxacin, solution for infusion is indicated for the treatment of the following infectious diseases in adults:
community-acquired pneumonia; complicated skin and soft tissue infections
(with regard to the above infectious diseases, levofloxacin should be prescribed only in cases of insufficient effectiveness of other antibacterial drugs, which are mainly used for the initial treatment of these infections);
pyelonephritis and complicated urinary tract infections; chronic bacterial prostatitis.
Official recommendations on the appropriate use of antibacterial agents should be considered.
Contraindication
Levofloxacin should not be prescribed in the following cases:
Hypersensitivity to levofloxacin or to other quinolones or to any other components of the drug; adverse reactions from the tendons after previous use of quinolones; epilepsy; children's age (up to 18 years); pregnancy or breastfeeding.
Interaction with other medicinal products and other types of interactions
Effect of other medicines on the drug
Theophylline, fenbufen, or similar nonsteroidal anti-inflammatory drugs
No pharmacokinetic interaction of levofloxacin with theophylline has been observed. However, a significant decrease in the seizure threshold may occur when quinolones are administered concomitantly with theophylline, nonsteroidal anti-inflammatory drugs, and other agents that lower the seizure threshold. Levofloxacin concentrations in the presence of fenbufen were approximately 13% higher than when levofloxacin was administered alone.
Probenecid and cimetidine
Probenecid and cimetidine have a statistically significant effect on the elimination of levofloxacin. The renal clearance of levofloxacin is reduced by 24% in the presence of cimetidine and by 34% in the presence of probenecid, as both drugs are capable of blocking the tubular secretion of levofloxacin. Levofloxacin should be used with caution with drugs that affect tubular secretion, such as probenecid and cimetidine, especially in patients with renal insufficiency.
Other information
Clinical pharmacology studies have demonstrated that there was no clinically significant effect on the pharmacokinetics of levofloxacin when levofloxacin was taken together with the following drugs: calcium carbonate, digoxin, glibenclamide, ranitidine.
Effect of the drug on other medicines
Cyclosporine
The half-life of cyclosporine is increased by 33% when co-administered with levofloxacin.
Vitamin K antagonists
Coagulation tests (PT/international normalized ratio) and/or bleeding, which may be severe, have been reported with concomitant use of vitamin K antagonists (e.g. warfarin). Therefore, coagulation parameters should be monitored in patients receiving concomitant vitamin K antagonists.
QT-prolonging drugs
Levofloxacin, like other fluoroquinolones, should be used with caution in patients receiving drugs known to prolong the QT interval (e.g., class IA and III antiarrhythmics, tricyclic antidepressants, and macrolides).
Other significant information
There was no effect of levofloxacin on the pharmacokinetics of theophylline (which is a marker substrate for the CYP1A2 enzyme), indicating that levofloxacin is not a CYP1A2 inhibitor.
Application features
Levofloxacin should be avoided in patients with a history of serious adverse reactions to quinolones or fluoroquinolones (see section 4.8). Levofloxacin should only be used in such patients after careful benefit-risk assessment and in the absence of alternative treatment options (see section 4.8).
The benefits of levofloxacin treatment should be weighed against those of mild infections, especially in accordance with the information provided in the section "Special warnings and precautions for use".
Prolonged, disabling and potentially irreversible serious adverse drug reactions
In patients treated with quinolones and fluoroquinolones, regardless of their age and the presence of risk factors, very rare cases of prolonged (over months or years), disabling and potentially irreversible serious adverse drug reactions affecting various, sometimes multiple, body systems (musculoskeletal, nervous system, psyche, sensory organs) have been observed. Levofloxacin should be discontinued immediately at the first signs or symptoms of any serious adverse reaction, and patients should be advised to consult a doctor.
Methicillin-resistant Staphylococcus aureus is highly likely to be cross-resistant to fluoroquinolones, including levofloxacin. Therefore, levofloxacin is not recommended for the treatment of known or suspected MRSA infections unless laboratory testing has confirmed susceptibility to levofloxacin.
E. coli resistance
Resistance of E. coli, the most common cause of urinary tract infections, to fluoroquinolones varies across the European Union. When prescribing levofloxacin, physicians should take into account the local prevalence of fluoroquinolone resistance in E. coli.
Aortic aneurysm and dissection
Epidemiological data suggest an increased risk of aortic aneurysm or dissection with fluoroquinolones, particularly in the elderly. Therefore, fluoroquinolone antibiotics should only be used after careful benefit-risk assessment and after consideration of other treatment options in patients with aortic aneurysm/dissection, in patients with a family history of aortic aneurysm, and in patients with risk factors or conditions that may predispose to the development of aortic aneurysm/dissection (e.g. Marfan syndrome, Ehlers-Danlos vascular syndrome, Takayasu arteritis, giant cell arteritis, Behçet's disease, hypertension, and atherosclerosis).
In case of sudden abdominal pain, chest pain or back pain, patients should seek emergency medical attention immediately.
Duration of administration
The recommended duration of administration is at least 60 minutes for 500 mg of the drug solution for infusion. With ofloxacin, tachycardia and a temporary increase in blood pressure are known to occur during infusions. In rare cases, a sudden decrease in blood pressure and circulatory collapse may occur as a result. If a pronounced decrease in blood pressure is observed during the administration of levofloxacin (the l-isomer of ofloxacin), the drug should be discontinued immediately.
Tendinitis and tendon ruptures
Tendinitis may occur rarely. This most commonly affects the Achilles tendon and may lead to tendon rupture. Tendinitis and tendon ruptures, sometimes bilateral, may occur 48 hours after levofloxacin administration and even several months after discontinuation of levofloxacin. Patients over 60 years of age, patients receiving daily doses of 1000 mg levofloxacin, and patients treated with corticosteroids are most susceptible to tendinitis and tendon rupture. Transplant patients are at increased risk of developing tendinitis, therefore caution is recommended when using fluoroquinolones in this population. The daily dose should be adjusted for elderly patients, taking into account creatinine clearance (see section 4.2). Elderly patients should be monitored if levofloxacin is prescribed to them. Patients should consult their doctor if they experience symptoms of tendinitis. If tendinitis is suspected, treatment with the drug should be discontinued immediately and appropriate treatment should be initiated (e.g., by ensuring tendon immobilization).
Diseases caused by Clostridium difficile
Diarrhea, particularly severe, persistent and/or haemorrhagic, during or after treatment with the drug (including several weeks after treatment), may be a symptom of Clostridium difficile disease, the most severe form of which is pseudomembranous colitis. The severity of CDAD ranges from mild to life-threatening. It is important to consider this diagnosis in patients who develop severe diarrhoea during or after treatment with levofloxacin. If pseudomembranous colitis is suspected, the drug infusion should be stopped immediately and appropriate treatment should be initiated immediately. Anti-motility agents are contraindicated in this clinical situation.
Patients prone to seizures
Quinolones may lower the seizure threshold and cause seizures. The drug is contraindicated in patients with a history of epilepsy. The drug (as with other quinolones) should be used with extreme caution in patients prone to seizures, in particular in patients with previous central nervous system lesions, or in patients 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 treatment should be discontinued.
Patients with glucose-6-phosphate dehydrogenase deficiency
Patients with latent or existing defects in glucose-6-phosphate dehydrogenase activity are prone to hemolytic reactions when treated with quinolone antibacterial agents, therefore levofloxacin should be used with caution and monitored for possible hemolysis.
Patients with renal insufficiency
Since levofloxacin is excreted primarily by the kidneys, dose adjustment is required for patients with impaired kidney function (renal failure).
Levofloxacin may occasionally cause serious, potentially fatal hypersensitivity reactions (e.g. angioedema, up to and including anaphylactic shock) after the initial dose (see section 4.8). In such cases, patients should discontinue treatment immediately and consult a doctor.
Dysglycemia
As with other quinolones, blood glucose fluctuations, including hyperglycemia and hypoglycemia, have been reported, particularly in diabetic patients receiving concomitant oral hypoglycemic agents (e.g. glibenclamide) or insulin. Hypoglycemic coma has been reported. Close monitoring of blood glucose levels is recommended in diabetic patients.
Prevention of photosensitivity
Although photosensitivity occurs very rarely with levofloxacin, in order to avoid it, patients are advised not to be exposed to strong sunlight or artificial UV radiation (e.g. artificial ultraviolet lamps, solariums) while taking levofloxacin and for 48 hours after stopping the drug.
Patients receiving vitamin K antagonists
Due to the possible increase in coagulation tests (PC/international normalized ratio) and/or bleeding in patients taking the drug in combination with a vitamin K antagonist (e.g. warfarin), coagulation tests should be monitored if these drugs are used concomitantly (see section 4.5).
Psychotic reactions
Psychotic reactions have been reported in patients taking quinolones, including levofloxacin. In rare cases, these have progressed to suicidal ideation and self-harm, sometimes after only a single dose of levofloxacin. If a patient develops these reactions, levofloxacin should be discontinued and appropriate measures taken. Levofloxacin should be used with caution in patients with psychotic disorders or a history of psychiatric illness.
QT prolongation
Fluoroquinolones, including levofloxacin, should be used with caution in patients with known risk factors for QT 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 imbalance (e.g. hypokalaemia, hypomagnesaemia); Cardiac 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 should be exercised when using fluoroquinolones, including levofloxacin, in these categories of patients (see sections “Method of administration and dosage”, “Elderly patients”; “Interaction with other medicinal products and other types of interactions”, “Adverse reactions”, “Overdose”).
Peripheral neuropathy
Sensory or sensorimotor peripheral neuropathy, which may develop very rapidly, has been reported in patients receiving fluoroquinolones, including levofloxacin. Levofloxacin should be discontinued if a patient develops symptoms of neuropathy to prevent the development of an irreversible condition.
Hepatobiliary disorders
Cases of necrotizing hepatitis up to life-threatening hepatic failure have been reported with levofloxacin, predominantly in patients with severe underlying diseases such as sepsis (see section 4.8). Patients should be advised to discontinue treatment and seek medical advice if signs and symptoms of liver disease such as anorexia, jaundice, dark urine, pruritus or abdominal pain occur.
Exacerbation of myasthenia gravis
Fluoroquinolones, including levofloxacin, block neuromuscular transmission and may cause muscle weakness in patients with myasthenia gravis. Serious adverse reactions, including fatalities and the need for respiratory support, have been reported post-marketing with fluoroquinolones in patients with myasthenia gravis. Levofloxacin is not recommended for use in patients with a history of myasthenia gravis.
Vision impairment
If visual impairment or other effects on the eyes are observed, an ophthalmologist should be consulted immediately (see sections “Ability to influence the reaction speed when driving vehicles or using other mechanisms”, “Adverse reactions”).
Superinfection
The use of levofloxacin, especially for prolonged periods, may lead to overgrowth of non-susceptible microorganisms. If superinfection develops during therapy, appropriate measures should be taken.
Impact on laboratory tests
Sodium
This medicinal product contains 39.1 mmol (900 mg) sodium per 100 ml solution. This should be taken into consideration by patients on a controlled sodium diet.
Ability to influence reaction speed when driving vehicles or other mechanisms
Patients who drive vehicles, work with machines and mechanisms should take into account possible adverse reactions from the nervous system (dizziness, numbness, drowsiness, confusion, visual and hearing disorders, motor disorders, including when walking).
Use during pregnancy or breastfeeding
Due to the lack of studies and the possible damage of quinolones to articular cartilage in a growing body, the drug should not be prescribed to pregnant and breastfeeding women. If pregnancy is diagnosed during treatment with the drug, the doctor should be informed.
Method of administration and doses
Before using the drug, a sensitivity test must be performed. The drug for intravenous administration is used immediately (within 3 hours) after perforation of the rubber stopper. Protection from light during infusion is not required. At room temperature, the solution for intravenous administration can be stored for no more than 3 days without protection from light. The dosage depends on the type and severity of the infection.
For the treatment of adults with normal renal function, whose creatinine clearance is greater than 50 ml/min, the following doses of the drug are usually recommended:
| Indication | Daily dosage regimen* (taking into account the patient's body weight) |
| Community-acquired pneumonia | 500 mg 1–2 times daily, 7–14 days |
| Complicated urinary tract infections | 500 mg once daily, 7–14 days |
| Pyelonephritis | 500 mg once daily, 7–10 days |
| Chronic bacterial prostatitis | 500 mg once daily, 28 days |
| Skin and soft tissue infections | 500 mg 1–2 times daily, 7–14 days |
* Depending on the patient's clinical condition, a switch from initial intravenous to oral administration at the same dosage may be possible after a few days (usually 2–4 days).
Since levofloxacin is excreted primarily by the kidneys, the dose should be reduced in patients with impaired renal function.
Dosage for adult patients with renal impairment whose creatinine clearance is less than 50 mL/min
| Creatinine clearance, ml/min | Dosage regimen (depending on the severity of the infection) | | |
| 250 mg/24 hours | 500 mg/24 hours | 500 mg/12 hours |
| 50–20 | first dose – 250 mg, subsequent - 125 mg/24 hours | first dose – 500 mg, subsequent - 250 mg/24 hours | first dose – 500 mg, subsequent - 250 mg/12 hours |
| 19–10 | first dose – 250 mg, subsequent - 125 mg/48 hours | first dose – 500 mg, subsequent - 125 mg/24 hours | first dose – 500 mg, subsequent - 125 mg/12 hours |
| < 10 ml/min (including hemodialysis and HAPD 1) | first dose – 250 mg, subsequent - 125 mg/48 hours | first dose: 500 mg, subsequent - 125 mg/24 hours | first dose – 500 mg, subsequent - 125 mg/24 hours |
1 No additional doses are required after hemodialysis or chronic ambulatory peritoneal dialysis (CHAPD).
Dosage for patients with hepatic impairment: No dosage adjustment is required since levofloxacin is only slightly metabolized in the liver.
Dosage for elderly patients: If renal function is not impaired, no dose adjustment is necessary.
Levomac IV solution is administered intravenously slowly by drip infusion. The duration of administration of 100 ml of the drug (100 ml of solution contains 500 mg of levofloxacin) should be at least 60 minutes.
The duration of treatment depends on the course of the disease. As with other antibacterial agents, it is recommended to continue treatment with the drug for at least 48-72 hours after normalization of body temperature or confirmed destruction of pathogens by microbiological tests.
Children
Children (under 18 years of age) should not be prescribed the drug, as damage to the articular cartilage cannot be ruled out.
Overdose
The most important expected symptoms of overdose with the drug concern the central nervous system (confusion and impaired consciousness, dizziness, seizures). According to the results of studies, prolongation of the QT interval was observed when doses higher than therapeutic were used.
Treatment. In cases of overdose, the patient should be carefully monitored, including ECG. Symptomatic therapy.
Hemodialysis, including peritoneal dialysis or HAPD, is not effective in removing levofloxacin from the body. There are no specific antidotes.
Adverse reactions
Infections and infestations: fungal infections, including Candida species, resistance of pathogenic microorganisms.
Immune system disorders: angioedema, hypersensitivity (see section 4.4). Anaphylactic and anaphylactoid reactions may occasionally occur even after the first dose.
Metabolic disorders: anorexia, hypoglycemia, especially in patients with diabetes mellitus, hyperglycemia, hypoglycemic coma (see section "Special warnings and precautions for use").
Psychiatric*: insomnia, nervousness, psychotic reactions (including hallucinations, paranoia), depression, confusion, anxiety, agitation, restlessness, unusual dreams, nightmares, psychotic reactions with self-destructive behavior, including suicidal thoughts or actions (see section "Special warnings and precautions for use").
Nervous system*: dizziness, headache, drowsiness, convulsions (see sections "Contraindications" and "Special instructions"), tremor, paresthesia, sensory or sensorimotor peripheral neuropathy (see section "Special instructions"), dysgeusia (subjective taste disorder), including ageusia (loss of taste), parosmia (smell disorder), including anosmia (absence of smell), dyskinesia (impaired coordination of movements), extrapyramidal disorders, syncope (fainting), benign intracranial hypertension.
On the part of the organs of vision*: visual disturbances, such as blurred vision or temporary loss of vision (see section "Special instructions for use"), uveitis.
From the auditory system*: vertigo, hearing impairment, tinnitus, hearing loss.
Cardiac: tachycardia, palpitations, ventricular tachycardia, which can lead to cardiac arrest, ventricular arrhythmia such as torsade de pointes (predominantly in patients with risk factors for QT prolongation), prolongation of the QT interval on the ECG (see sections "Special instructions" and "Overdose").
Vascular disorders: phlebitis, arterial hypotension.
Respiratory system: bronchospasm, dyspnea, allergic pneumonitis.
On the part of the digestive tract: diarrhea, nausea, vomiting, abdominal pain, dyspepsia, bloating, constipation, hemorrhagic diarrhea, which in rare cases may indicate enterocolitis, including pseudomembranous colitis (see section "Special instructions for use"), pancreatitis.
Hepatobiliary system: increased liver enzymes (ALT/AST, alkaline phosphatase, GGTP); 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: rash, itching, urticaria, hyperhidrosis, toxic epidermal necrolysis (Lyell's syndrome), Stevens-Johnson syndrome, erythema multiforme, photosensitivity reactions (see "Special instructions"), leukocytoplastic vasculitis, stomatitis.
Musculoskeletal system:* 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"). Muscle weakness is possible, which may be of particular importance for patients with myasthenia gravis; muscle damage (rhabdomyolysis).
On the part of the urinary system: increased serum creatinine levels, acute renal failure (for example, due to interstitial nephritis).
General disorders and administration site conditions*: infusion site reactions (pain, redness), asthenia, pyrexia, pain (including back, chest and extremity pain).
Other undesirable side effects associated with the use of fluoroquinolones: extrapyramidal symptoms and other motor coordination disorders, hypersensitivity vasculitis, attacks of porphyria in patients with porphyria.
*Very rare cases of prolonged (months or years), disabling and potentially irreversible serious adverse drug reactions, sometimes affecting multiple body systems and senses (including reactions such as tendinitis, tendon rupture, arthralgia, pain in extremities, gait disturbance, neuropathy associated with paraesthesia, depression, fatigue, memory impairment, sleep disorders and disturbances of hearing, vision, taste and smell) have been reported with the use of quinolones and fluoroquinolones, in some cases regardless of the presence of risk factors (see section "Special instructions").
Expiration date
2 years.
Storage conditions
Store at a temperature not exceeding 25 °C, protected from light and out of the reach of children.
Packaging
100 ml in a bottle; 1 bottle in a cardboard box.
Vacation category
According to the recipe.
Producer
Subsidiary company "Pharmatrade".
Location of the manufacturer and its business address
Lviv region, Drohobych city, Sambirska street, 85, Ukraine.
