Grandazol

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT GRANDAZOL® (GRANDAZOL)

Composition:

Active substances: ornidazole; levofloxacin;

1 ml of solution contains ornidazole 5 mg, levofloxacin 2.5 mg;

Excipients: edetate disodium, sodium chloride, water for injections.

Pharmaceutical form. Infusion solution.

Main physicochemical properties: clear colorless or pale yellow liquid.

Pharmacotherapeutic group. Antimicrobial agents for systemic use. Levofloxacin, combinations with other antibacterial agents.

ATC code J01RA05.

Pharmacological properties.

Levofloxacin

Pharmacodynamics.

Levofloxacin is a synthetic antibacterial agent of the fluoroquinolone group and 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 gyrase-DNA complex and topoisomerase IV.

Pharmacokinetic/pharmacodynamic relationship

The degree of antibacterial activity of levofloxacin depends on the ratio of maximum serum concentration (Cmax) or area under the pharmacokinetic curve (AUC) to minimum inhibitory 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 antibacterial agents of other classes is generally not observed.

Antibacterial spectrum

The prevalence of resistance may vary geographically and over time for individual species. Local information on microbial resistance should be obtained, especially when treating severe infections. Advice from a specialist should be sought if local resistance prevalence is such that the benefit of the drug, at least for certain types of infections, is questionable.

Typically sensitive species Aerobic gram-positive bacteria Staphylococcus aureus methicillin-sensitive, Staphylococcus saprophyticus, Streptococci group C and G, Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes Aerobic gram-negative bacteria Burkholderia cepacia, Eikenella corrodens, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella oxytoca, Klebsiella pneumoniae, Moraxella catarrhalis, Pasteurella multocida, Proteus vulgaris, Providencia rettgeri Anaerobic bacteria Peptostreptococcus Others Chlamydophila pneumoniae, Chlamydophila psittaci, Chlamydia trachomatis, Legionella pneumophila, Mycoplasma pneumoniae, Mycoplasma hominis, Ureaplasma urealyticum

Species for which acquired (secondary) resistance may be problematic Aerobic gram-positive bacteria Enterococcus faecalis, Staphylococcus aureus methicillin-resistant, Staphylococcus coagulase spp. Aerobic gram-negative bacteria Acinetobacter baumannii, Citrobacter freundii, Enterobacter aerogenes, Enterobacter agglomerans, Enterobacter cloacae, Escherichia coli, Morganella morganii, Proteus mirabilis, Providencia stuartii, Pseudomonas aeruginosa, Serratia marcescens Anaerobic bacteria Bacteroides fragilis, Bacteroides ovatus, Bacteroides thetaiotamicron, Bacteroides vulgatus, Clostridium difficile

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 is bound to serum proteins. There is virtually no accumulation of levofloxacin with repeated administration of 500 mg once daily. A slight but predictable cumulative effect occurs after administration of 500 mg twice daily. Steady state is achieved within 3 days.

Penetration into Tissues and Body Fluids

Penetration into Bronchial Mucosa and Bronchial Secretions of Lung Tissue

Maximum concentrations of levofloxacin in bronchial mucosa and bronchial secretions of lung tissue after oral administration of 500 mg were 8.3 µg/g and 10.8 µg/mL, respectively. These levels were achieved within one hour after drug administration.

Penetration into Lung Tissue

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

Penetration into Bladder Contents

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

Penetration into Cerebrospinal (CSF) Fluid

Levofloxacin penetrates poorly into cerebrospinal fluid.

Penetration into Prostatic Tissue

After administration of 500 mg levofloxacin once daily for 3 days, mean concentrations in prostatic tissue were 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

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

Biotransformation

Levofloxacin undergoes minimal metabolism. Metabolites include desmethyl-levofloxacin and levofloxacin N-oxide. These metabolites account for less than 5% of the administered dose excreted in urine. Levofloxacin is stereochemically stable and does not undergo chiral inversion.

Elimination

After both oral and intravenous administration, levofloxacin is eliminated from plasma relatively slowly (elimination half-life is 6–8 hours). Elimination occurs primarily via the kidneys (over 85% of the administered dose).

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

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 renal function, renal excretion and clearance decrease, and elimination half-life increases.

Elderly Patients

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

Gender Differences

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

Ornidazole

Pharmacodynamics.

The mechanism of action of ornidazole is related to disruption of DNA structure in susceptible microorganisms. Ornidazole is active against Trichomonas vaginalis, Entamoeba histolytica, Giardia lamblia (Giardia intestinalis), and certain anaerobic bacteria such as Bacteroides spp., Fusobacterium spp.; anaerobic Gram-positive bacteria Clostridium spp., sensitive strains of Eubacterium spp.; and anaerobic Gram-positive cocci Peptococcus spp., Peptostreptococcus spp.

It readily penetrates microbial cells and, by binding to DNA, disrupts the replication process.

Pharmacokinetics.

Ornidazole penetrates well through the blood-brain barrier and placental barrier, enters cerebrospinal fluid and bile, and is excreted in breast milk. After intravenous administration at a dose of 15 mg/kg and subsequent administration at 7.5 mg/kg every 6 hours, steady-state concentrations range from 18 to 26 µg/mL. Approximately 30–60% of the drug is metabolized in the body via hydroxylation, oxidation, and glucuronidation.

Elimination. Ornidazole is excreted primarily in urine (60–80%), with nearly 20% excreted unchanged and 6–15% in feces.

Clinical characteristics.

Indications.

Treatment of mixed infections of the urogenital tract caused by pathogens (microorganisms and protozoa) sensitive to the components of the drug.

Treatment of acute respiratory tract infections.

Prevention of purulent-inflammatory complications following surgical interventions on the abdominal organs.

Prevention of purulent-inflammatory complications following gynecological surgeries.

Contraindications.

• Hypersensitivity to levofloxacin or other fluoroquinolones, ornidazole or other nitroimidazole derivatives, or to any other component of the drug;
• Glucose-6-phosphate dehydrogenase deficiency;
• Organic disorders of the central nervous system, epilepsy, multiple sclerosis;
• History of adverse reactions affecting tendons following prior use of quinolones;
• Circulatory disorders, blood pathology or other hematological abnormalities;
• Chronic alcoholism;
• Pediatric age (under 18 years);
• Pregnancy;
• Breastfeeding period.

Interaction with other medicinal products and other forms of interaction.

Levofloxacin.

Theophylline, fenbufen, or similar nonsteroidal anti-inflammatory drugs

No pharmacokinetic interaction between levofloxacin and theophylline has been observed. However, a significant lowering of the seizure threshold may occur with concomitant administration of quinolones and theophylline, nonsteroidal anti-inflammatory drugs, or other agents that reduce the seizure threshold. The concentration of levofloxacin in the presence of fenbufen was approximately 13% higher than when levofloxacin was administered alone.

Probenecid and cimetidine

Probenecid and cimetidine statistically significantly affect the elimination of levofloxacin. Renal clearance of levofloxacin decreases by 24% in the presence of cimetidine and by 34% with probenecid. This is explained by the ability of both drugs to block tubular secretion of levofloxacin. However, at the doses tested in clinical studies, statistically significant kinetic differences are unlikely to have clinical relevance. Concomitant use of levofloxacin with drugs affecting tubular secretion, such as probenecid and cimetidine, should be approached with caution, especially in patients with renal impairment.

Other information

Clinical pharmacology studies have demonstrated that coadministration of levofloxacin with calcium carbonate, digoxin, glyburide, or ranitidine does not produce any clinically significant effect on the pharmacokinetics of levofloxacin.

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 coagulation test parameters (prothrombin time/international normalized ratio) and/or bleeding, sometimes severe, have been reported. Therefore, coagulation parameters should be monitored in patients receiving concomitant vitamin K antagonists (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, macrolides, neuroleptics) [see section "Special precautions. QT interval prolongation"].

Other information

Levofloxacin does not affect the pharmacokinetics of theophylline, which is primarily metabolized via CYP1A2; therefore, levofloxacin is not considered an inhibitor of CYP1A2.

Ornidazole.

Concomitant use with indirect anticoagulants may potentiate the effect of coumarin-type anticoagulants (e.g., warfarin), requiring appropriate dose adjustment. Ornidazole prolongs the muscle-relaxant effect of vecuronium bromide.

The plasma concentration of ornidazole is reduced when administered concomitantly with microsomal enzyme inducers (e.g., phenobarbital, rifampicin) and increased when administered with inhibitors of hepatic microsomal systems, particularly H₂-receptor blockers (e.g., cimetidine).

When used with other 5-nitroimidazole derivatives, isolated cases of peripheral neuropathy, psychic depression, and epileptic-like seizures have been reported.

Unlike other nitroimidazole derivatives, ornidazole does not inhibit aldehyde dehydrogenase and is therefore compatible with alcohol.

Special precautions for use.

Use with caution and only if clearly indicated in patients with severe hepatic impairment and in elderly patients.

Renal and hepatic function should be monitored throughout the entire treatment course.

Alcohol consumption should be avoided during treatment with this medicinal product.

During treatment, patients should receive adequate fluid intake to prevent crystalluria.

Levofloxacin should be avoided in patients with a history of serious adverse reactions associated with quinolone or fluoroquinolone-containing medicinal products (see section "Adverse Reactions"). Treatment with levofloxacin in such patients should be initiated only if no alternative treatment options are available and after careful assessment of the benefit-risk ratio (see also section "Contraindications").

Risk of resistance

There is a very high likelihood of co-resistance to fluoroquinolones, including levofloxacin, in methicillin-resistant Staphylococcus aureus (MRSA). Therefore, levofloxacin is not recommended for the treatment of infections where MRSA is known or suspected, except when laboratory test results confirm susceptibility of the pathogen to levofloxacin (and usually when the use of recommended antibacterial agents for MRSA infections is considered inappropriate).

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

Long-term, disabling and potentially irreversible serious adverse reactions

Rare, long-lasting (months or years), disabling, potentially irreversible serious adverse reactions affecting various body systems (musculoskeletal, nervous and psychiatric systems, sensory organs) have been reported in patients receiving quinolones or fluoroquinolones, regardless of their age or presence of risk factors. At the first signs and/or symptoms of any serious adverse reaction, levofloxacin should be discontinued immediately and medical advice should be sought.

Tendinitis and tendon rupture

Tendinitis and tendon rupture (especially of the Achilles tendon), sometimes bilateral, may occur within 48 hours of starting treatment with quinolones or fluoroquinolones, and occasionally even several months after discontinuation of the drug. The risk of tendinitis and tendon rupture is increased in patients receiving levofloxacin at a daily dose of 1000 mg, in elderly patients, in patients with renal impairment, in patients after solid organ transplantation, and in patients concurrently receiving corticosteroids. Concomitant use of corticosteroids and fluoroquinolones should be avoided. If early signs of tendinitis (e.g., painful swelling or joint inflammation) occur, treatment with levofloxacin should be discontinued immediately and alternative therapy should be considered. The affected limb should be appropriately managed (e.g., immobilization should be ensured). Corticosteroids should not be administered if signs of tendinopathy appear.

Clostridium difficile-associated disease

Diarrhea, particularly (in severe cases) persistent and/or hemorrhagic, during or after treatment with Grandazol® (including several weeks after treatment) may be a symptom of Clostridium difficile-associated disease (CDAD). The severity of CDAD ranges from mild to life-threatening. The most severe form of this disease is pseudomembranous colitis (see section "Adverse Reactions"). It is therefore important to consider this diagnosis in patients who develop severe diarrhea during or after treatment with levofloxacin. If pseudomembranous colitis is suspected, infusion of Grandazol® should be discontinued immediately and appropriate treatment initiated promptly (e.g., oral vancomycin). Antiperistaltic agents are contraindicated in this clinical situation.

Patients predisposed to seizures

Quinolones may lower the seizure threshold and provoke seizures.

The medicinal product is contraindicated in patients with a history of epilepsy (see section "Contraindications"). As with other quinolones, it should be used with extreme caution in patients predisposed to seizures (e.g., patients with central nervous system disorders), during concomitant therapy with fenbufen and similar non-steroidal anti-inflammatory drugs or drugs that increase seizure susceptibility (lower the seizure threshold), such as theophylline. If seizures occur, treatment with the medicinal product should be discontinued.

Patients with glucose-6-phosphate dehydrogenase deficiency

Patients with latent or existing defects in glucose-6-phosphate dehydrogenase activity may be susceptible to hemolytic reactions during treatment with quinolone-class antibacterial agents; therefore, levofloxacin should be used with caution in such patients, with continuous monitoring for risk of hemolysis.

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 (e.g., angioedema up to anaphylactic shock), occasionally after administration of the first dose (see section "Adverse Reactions"). If hypersensitivity reactions occur, the medicinal product should be discontinued, medical advice should be sought, and appropriate treatment initiated.

Severe skin adverse reactions

Severe skin adverse reactions, including potentially fatal outcomes such as toxic epidermal necrolysis (also known as Lyell's syndrome), Stevens-Johnson syndrome, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), have been reported in patients receiving levofloxacin (see section "Adverse Reactions"). When prescribing levofloxacin, patients should be informed about signs and symptoms of severe skin reactions and closely monitored. At the first signs and symptoms suggestive of these reactions, levofloxacin should be discontinued immediately and alternative therapy considered. If a serious reaction such as Stevens-Johnson syndrome, toxic epidermal necrolysis, or DRESS syndrome occurs during treatment with levofloxacin, re-initiation of levofloxacin therapy in this patient is absolutely contraindicated.

Blood glucose fluctuations

As with other quinolones, fluctuations in blood glucose levels, including cases of hyperglycemia and hypoglycemia, have been reported, particularly in elderly patients, especially in patients with diabetes mellitus receiving concomitant therapy with oral hypoglycemic agents (e.g., glibenclamide) or insulin. Cases of hypoglycemic coma have been reported. In patients with diabetes mellitus, careful monitoring of blood glucose levels is recommended (see section "Adverse Reactions").

If a patient reports fluctuations in blood glucose levels, the medicinal product should be discontinued immediately and alternative antibacterial therapy not belonging to the fluoroquinolone class should be considered.

Phototoxicity prevention

Cases of phototoxicity have been reported during treatment with levofloxacin (see section "Adverse Reactions"). To avoid this, patients should avoid unnecessary exposure to strong sunlight or artificial UV radiation (e.g., sunlamps, tanning beds) during treatment and for 48 hours after discontinuation of levofloxacin.

Patients receiving vitamin K antagonists

Due to the potential for increased coagulation test parameters (prothrombin time/international normalized ratio) and/or bleeding in patients taking Grandazol® in combination with a vitamin K antagonist (e.g., warfarin), coagulation parameters should be monitored when these medicinal products 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. In rare cases, these progressed to suicidal thoughts and self-destructive behavior, sometimes after only a single dose of levofloxacin (see section "Adverse Reactions"). At the first signs or symptoms of such reactions, patients should discontinue levofloxacin immediately and consult their physician. The physician should consider alternative antibacterial therapy not belonging to the fluoroquinolone class and take appropriate measures. Levofloxacin should be used with caution in patients with psychotic 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, neuroleptics);
• uncorrected electrolyte imbalance (e.g., hypokalemia, hypomagnesemia);
• cardiac disease (e.g., heart failure, myocardial infarction, bradycardia).

Elderly patients and women may be more sensitive to medicinal products that prolong the QT interval. Therefore, fluoroquinolones, including levofloxacin, should be used with caution in these patient groups [see sections "Dosage and administration. Elderly patients", "Interaction with other medicinal products and other forms of interaction", "Overdose", "Adverse Reactions"].

Peripheral neuropathy

Cases of sensory or sensorimotor peripheral polyneuropathy have been reported in patients receiving quinolones or fluoroquinolones, leading to paresthesia, hypoesthesia, dysesthesia, or weakness. Patients receiving levofloxacin should inform their physician before continuing treatment if symptoms of neuropathy occur, such as pain, burning, tingling, numbness, and/or weakness, to prevent development of potentially irreversible conditions (see section "Adverse Reactions").

Exacerbation of disorders of the central or peripheral nervous system may occur during treatment with ornidazole. If peripheral neuropathy, coordination disturbances (ataxia), dizziness, or confusion occur, treatment should be discontinued.

Hepatobiliary disorders

Cases of necrotic hepatitis, up to life-threatening hepatic failure, have been reported, primarily in patients with severe underlying conditions such as sepsis (see section "Adverse Reactions"). Patients should be advised to discontinue treatment and consult a physician if symptoms or signs of liver disease occur, such as anorexia, jaundice, darkening of urine, pruritus, or abdominal pain.

Exacerbation of myasthenia gravis

Fluoroquinolones, including levofloxacin, have neuromuscular blocking effects and may exacerbate muscle weakness in patients with myasthenia gravis. In the post-marketing period, serious adverse reactions, including fatal cases and conditions requiring respiratory support, have been associated with fluoroquinolone use in patients with myasthenia gravis. Levofloxacin is not recommended for use in patients with a history of myasthenia gravis.

Visual disturbances

If any visual disturbances or adverse reactions affecting the eyes occur during levofloxacin treatment, immediate consultation with an ophthalmologist is required (see sections "Ability to influence reaction speed when driving or operating machinery" and "Adverse Reactions").

Superinfection

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

Candidiasis exacerbation may occur, requiring appropriate treatment.

Effect on laboratory test results

In patients receiving levofloxacin, urine opiate testing may yield false-positive results. Confirmation of positive opiate screening results may require more specific testing methods.

Levofloxacin may inhibit the growth of Mycobacterium tuberculosis and thus may lead to false-negative results in bacteriological diagnosis of tuberculosis.

Aortic aneurysm and aortic dissection (aortic wall dissection) and valvular regurgitation/insufficiency

Epidemiological studies suggest an increased risk of aortic aneurysm and aortic dissection, particularly in elderly patients, as well as aortic and mitral valve regurgitation following fluoroquinolone use. Cases of aortic aneurysm and aortic dissection, sometimes complicated by rupture (including fatal cases), and valvular regurgitation/insufficiency have been reported in patients receiving fluoroquinolones (see section "Adverse Reactions").

Therefore, fluoroquinolones should be used only after careful assessment of the benefit-risk ratio and consideration of alternative therapies in patients with a significant family history (presence of aneurysm or congenital heart valve defect), patients with diagnosed aortic aneurysm and/or aortic dissection, or heart valve disease, or in the presence of other risk factors, namely:

• risk factors for both aortic aneurysm and aortic dissection, and valvular regurgitation/insufficiency: connective tissue disorders such as Marfan syndrome, Ehlers-Danlos syndrome, Turner syndrome, Behçet's disease, arterial hypertension, rheumatoid arthritis;
• risk factors for aortic aneurysm and aortic dissection: vascular diseases such as Takayasu arteritis or giant cell arteritis, atherosclerosis, Sjögren's syndrome;
• risk factors for valvular regurgitation/insufficiency: infective endocarditis.

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

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

Patients should be advised to seek immediate medical help if dyspnea, palpitations, or abdominal or lower limb edema occur.

Blood system disorders

In patients with a history of blood system disorders, monitoring of leukocytes is recommended, especially during repeated treatment courses.

Hemodialysis

When hemodialysis is performed, the shortened elimination half-life should be taken into account, and additional doses of the medicinal product should be administered before or after hemodialysis.

Lithium

Serum levels of lithium salts, creatinine, and electrolytes should be monitored during concomitant lithium therapy.

The effect of other medicinal products may be enhanced or diminished during ornidazole treatment.

Sodium content

This medicinal product contains:

15.4 mmol (or 355 mg) of sodium per 100 mL dose;

30.8 mmol (or 710 mg) of sodium per 200 mL dose.

Caution is advised when administering to patients on a sodium-controlled diet.

Use during pregnancy or breastfeeding.

Use is contraindicated.

Ability to influence reaction speed when driving or operating machinery.

Some adverse reactions (e.g., dizziness/vertigo, muscle rigidity, tremor, seizures, coordination disturbances, including while walking, transient loss of consciousness, somnolence, confusion, visual and hearing disturbances) may impair a patient's ability to concentrate and reaction speed, thereby increasing the risk in situations where these abilities are particularly important (e.g., driving or operating machinery).

Method of Administration and Dosage

The drug is administered intravenously by drip infusion.

The daily dose of Grandazol® is 100 ml (500 mg ornidazole and 250 mg levofloxacin) to 200 ml (1000 mg ornidazole and 500 mg levofloxacin) given in 1–2 infusions. Duration of treatment and dosage depend on the course of the disease and are determined by the physician. After the patient's condition has stabilized, oral administration of levofloxacin and ornidazole should be initiated. Treatment should continue for 48–72 hours after the disappearance of clinical symptoms of the disease or until laboratory confirmation of pathogen eradication.

The maximum daily dose of Grandazol® is 200 ml (1000 mg ornidazole and 500 mg levofloxacin) given in 1–2 infusions per day.

Dosage for adult patients with impaired renal function, in whom creatinine clearance is less than 50 ml/min (dosage is calculated based on levofloxacin)

Creatinine clearance	Dosing regimen
50–20 mL/min	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 mL/min	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 (also during hemodialysis and CAPD1)	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 After hemodialysis or chronic ambulatory peritoneal dialysis (CAPD), additional doses are not required.

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

Dosing in elderly patients. If renal function is not impaired, dose adjustment is not required. Grandazol®, solution for infusion, should be administered intravenously by slow infusion. The duration of infusion of 100 mL of Grandazol® solution (500 mg ornidazole and 250 mg levofloxacin) should be no less than 60 minutes.

Depending on the patient's condition, after several days it may be possible to switch from intravenous administration to oral administration at the same dosage.

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

Children.

Use is contraindicated.

Overdose.

Levofloxacin. According to toxicity studies in animals and clinical pharmacological studies conducted with doses higher than therapeutic ones, the most serious signs expected after acute levofloxacin overdose are central nervous system symptoms such as confusion, dizziness, disturbances of consciousness, seizures, and QT interval prolongation.

During post-marketing surveillance, the following adverse effects of the central nervous system have been observed: confusion, convulsions, hallucinations, and tremor.

Ornidazole. In case of overdose, possible symptoms include loss of consciousness, headache, dizziness, tremor, seizures, peripheral neuritis, dyspeptic disorders, and intensification of symptoms of other adverse reactions.

Treatment. In case of overdose, symptomatic treatment should be administered. ECG monitoring is necessary due to the potential for QT interval prolongation. Hemodialysis, including peritoneal dialysis and chronic ambulatory peritoneal dialysis, is not effective for removing levofloxacin from the body.

There are no specific antidotes. In case of seizures, diazepam should be administered.

Adverse Reactions

Adverse reactions are listed by system organ classes according to MedDRA.

Frequency is defined as follows: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1,000, < 1/100), rare (≥ 1/10,000, < 1/1,000), very rare (< 1/10,000), frequency not known (cannot be estimated from the available data).

Body systems	Common	Uncommon	Rare	Frequency unknown
Infections and infestations		fungal infections, including infections caused by Candida species; resistance of pathogenic microorganisms
Blood and lymphatic system disorders		leukopenia, eosinophilia	thrombocytopenia, neutropenia	pancytopenia, agranulocytosis, hemolytic anemia, signs of bone marrow suppression
Immune system disorders			Quincke's edema, hypersensitivity reactions (see section "Special precautions for use")	anaphylactic shock1 with symptoms such as urticaria, bronchospasm and severe dyspnea; anaphylactoid shock1; angioneurotic edema (see section "Special precautions for use")
Endocrine disorders			syndrome of inappropriate antidiuretic hormone secretion (SIADH)
Metabolism and nutrition disorders		anorexia	hypoglycemia, especially in patients with diabetes mellitus; hypoglycemic coma (see section "Special precautions for use")	hyperglycemia (see section "Special precautions for use")
Psychiatric disorders*	insomnia	anxiety, confusion, nervousness	psychotic reactions (e.g., with hallucinations, paranoia), depression, agitation, sleep disturbances, night terrors, delirium	psychotic disorders with behavior dangerous to the patient, including suicidal thoughts or suicide attempts (see section "Special precautions for use")
Nervous system disorders*	headache, dizziness	drowsiness, tremor, dysgeusia (subjective taste disturbance)	seizures (see section "Special precautions for use"), paresthesia, memory impairment	sensory or sensorimotor peripheral neuropathy (see section "Special precautions for use"), parosmia (olfactory disturbance), including anosmia (loss of smell), dyskinesia, extrapyramidal disorders, muscle rigidity, coordination disturbances, ataxia, ageusia (loss of taste), transient loss of consciousness, excitement, benign intracranial hypertension
Eye disorders*			visual disturbances, such as blurred vision (see section "Special precautions for use")	transient vision loss (see section "Special precautions for use"), uveitis
Ear and labyrinth disorders*		vertigo	tinnitus	hearing deterioration, hearing loss
Cardiac disorders**			tachycardia, palpitations	ventricular tachycardia, which may lead to cardiac arrest; ventricular arrhythmia and torsades de pointes-type ventricular tachycardia (observed predominantly in patients with risk factors for QT interval prolongation); QT interval prolongation as recorded on ECG (see sections "Special precautions for use" and "Overdose")
Vascular disorders**	phlebitis (vein inflammation)		decreased blood pressure
Respiratory, thoracic and mediastinal disorders		dyspnea		bronchospasm, allergic pneumonitis
Gastrointestinal disorders	diarrhea, vomiting, nausea	abdominal pain, dyspepsia, flatulence, constipation		hemorrhagic diarrhea, which rarely may indicate enterocolitis, including pseudomembranous colitis (see section "Special precautions for use"), pancreatitis, taste disturbances, metallic taste in mouth, dry mouth, coated tongue, epigastric heaviness and tenderness
Hepatobiliary disorders	elevation of liver enzymes (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl transpeptidase)	elevated serum bilirubin levels		jaundice and severe liver damage, including cases of fatal acute liver failure with levofloxacin, a component of the drug, mainly in patients with severe underlying diseases (see section "Special precautions for use"); hepatotoxicity; hepatitis
Skin and subcutaneous tissue disorders2		rash, pruritus, urticaria, hyperhidrosis	drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) (see section "Special precautions for use"), persistent drug eruption	toxic epidermal necrolysis (Lyell's syndrome), Stevens-Johnson syndrome, exudative multiform erythema, photosensitivity reactions (increased sensitivity to sunlight and ultraviolet radiation) (see section "Special precautions for use"), leukocytoclastic vasculitis, stomatitis, skin hyperemia
Musculoskeletal and connective tissue disorders*		arthralgia, myalgia	tendon disorders (see sections "Special precautions for use" and "Overdose"), including inflammation (tendinitis) (e.g., Achilles tendon), muscle weakness which may be significant in patients with myasthenia gravis (see section "Special precautions for use")	acute necrosis of skeletal muscles, tendon rupture (e.g., Achilles tendon) (see sections "Special precautions for use" and "Contraindications"), ligament rupture, muscle rupture, arthritis
Renal and urinary disorders		elevated serum creatinine levels	acute renal failure (e.g., due to interstitial nephritis)	darkening of urine color
General disorders and administration site conditions*	infusion site pain and redness	asthenia	pyrexia	burning sensation at the site of administration, elevated body temperature, changes at the site of administration, pain (including back, chest and limb pain), chills, general weakness, fatigue, dyspnea

1. Anaphylactic and anaphylactoid reactions may sometimes occur even after administration of the first dose of the drug.

2. Mucous membrane reactions may sometimes occur even after administration of the first dose of the drug.

* There have been reports of rare, prolonged (several months or years), disabling and potentially irreversible serious adverse reactions affecting various organ systems (including such reactions as tendinitis, tendon rupture, arthralgia, pain in extremities, gait disturbance, neuropathies associated with paresthesia, depression, fatigue, memory impairment, sleep disturbances, hearing disturbances, visual disturbances, disturbances of taste and smell) associated with the use of quinolones and fluoroquinolones, regardless of the presence of risk factors (see section "Special precautions for use").

** There have been reports of development of aneurysms and aortic dissection, sometimes complicated by rupture (including fatal cases), and regurgitation/insufficiency of any heart valve in patients receiving fluoroquinolones (see section "Special precautions for use").

Other adverse effects associated with the use of fluoroquinolones include porphyria attacks in patients with porphyria.

The use of any antibacterial agents may lead to disturbances related to their effect on the normal human body microflora. For this reason, secondary infections may develop, requiring additional treatment.

Shelf life. 2 years.

Storage conditions.

Store in a place protected from light and inaccessible to children, at a temperature not exceeding 25 °C. Do not freeze.

Incompatibility.

The drug should not be mixed with other injectable solutions during administration.

Packaging.

200 ml in a bottle; 1 bottle in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

LLC "Yuria-Pharm".

Manufacturer's address and location of its business activity.

108, Kozbartska Street, Cherkasy, 18030, Cherkasy region, Ukraine. Tel.: (044) 281-01-01.