Ciprofloxacin

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

Composition:

Active substance: ciprofloxacin hydrochloride;

1 ml of solution contains ciprofloxacin hydrochloride 2.220 mg (equivalent to ciprofloxacin 2 mg);

Excipients: sodium chloride, sodium lactate solution, disodium edetate, hydrochloric acid concentrated*, water for injections.

* For adjusting the pH of the preparation to specified values.

Pharmaceutical form. Infusion solution.

Main physicochemical properties: clear, colorless or slightly greenish-yellow solution.

Pharmacotherapeutic group. Antibacterials for systemic use. Fluoroquinolones. Ciprofloxacin. ATC code J01MA02.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

The bactericidal activity of ciprofloxacin, a fluorinated quinolone antibiotic, is due to inhibition of type II topoisomerase (DNA gyrase) and topoisomerase IV, enzymes essential for replication, transcription, repair, and recombination of bacterial DNA.

Pharmacokinetic/pharmacodynamic relationship

The efficacy of the drug primarily depends on the maximum serum concentration of the drug (Cmax) and the minimum inhibitory concentration (MIC) of ciprofloxacin for the bacterial pathogen, as well as on the ratio between the area under the concentration–time curve (AUC) and MIC.

Mechanism of resistance

Resistance to ciprofloxacin in vitro may develop stepwise through mutations in the target sites of DNA gyrase and topoisomerase IV. The degree of cross-resistance between ciprofloxacin and other fluoroquinolones resulting from this varies. Single mutations may not lead to clinical resistance, but multiple mutations usually result in clinical resistance to many or all agents within the class.

Resistance mediated by impermeability or efflux pump mechanisms differentially affects susceptibility to fluoroquinolones, depending on the physicochemical properties of the active substances of a given class and the affinity of the transport system for each of them. All resistance mechanisms observed in vitro are frequently encountered in clinical isolates. Resistance mechanisms that inactivate other antibiotics, such as impermeable barriers (common in Pseudomonas aeruginosa) and efflux pump mechanisms, may also affect susceptibility to ciprofloxacin.

Plasmid-mediated resistance, encoded by qnr genes, has been reported.

Spectrum of antibacterial activity

Breakpoints distinguish susceptible strains from strains with intermediate susceptibility, and the latter from resistant strains.

EUCAST recommendations

1 Staphylococcus spp. — the breakpoints for ciprofloxacin apply to high-dose therapy.

* Species-unrelated breakpoints were primarily established based on pharmacokinetic/pharmacodynamic data and are not dependent on MIC values for individual species. They are used only for species lacking their own specific breakpoints, and not for species for which susceptibility testing is not recommended.

The prevalence of acquired resistance among isolated species may vary geographically and over time; therefore, local information on resistance patterns is necessary, especially when treating severe infections. When local resistance prevalence reaches a level at which the utility of the agent becomes questionable, at least for certain types of infections, consultation with specialists should be sought.

The following genera and species of bacteria are generally susceptible to ciprofloxacin (for the genus Streptococcus, see section "Special Warnings and Precautions for Use").

Pharmacokinetics.

Absorption

After intravenous infusion, the mean maximum concentration of ciprofloxacin is reached at the end of the infusion. The pharmacokinetics of ciprofloxacin following intravenous administration are linear within the dose range up to 400 mg.

When comparing pharmacokinetic parameters after twice-daily and three-times-daily intravenous administration, no accumulation of ciprofloxacin or its metabolites was observed.

The area under the concentration–time curve (AUC) after a 60-minute intravenous infusion of 200 mg ciprofloxacin was similar to that after oral administration of 250 mg ciprofloxacin every 12 hours.

A 60-minute intravenous infusion of 400 mg ciprofloxacin every 12 hours was bioequivalent to an oral dose of 500 mg every 12 hours with respect to AUC.

After intravenous administration of 400 mg over 60 minutes every 12 hours, the Cmax value was similar to that achieved after oral administration of 750 mg.

After intravenous administration of 400 mg ciprofloxacin over 60 minutes every 8 hours, the AUC was comparable to that observed after oral administration of 750 mg every 12 hours.

Distribution

The degree of protein binding of ciprofloxacin is low (20–30%). In plasma, ciprofloxacin is predominantly present in the non-ionized form; the volume of distribution at steady state is large—2–3 L/kg body weight. Ciprofloxacin concentrations reach high levels in various tissues, such as lungs (epithelial lining fluid, alveolar macrophages, biopsy specimens), sinuses, sites of inflammation (blister fluid induced by cantharidin), and genitourinary tract (urine, prostate, endometrium), where total concentrations exceed plasma levels.

Biotransformation

Low concentrations of four metabolites have been identified: desethylene-ciprofloxacin (M1), sulfociprofloxacin (M2), oxociprofloxacin (M3), and formylciprofloxacin (M4). The metabolites also exhibit antimicrobial activity in vitro, although to a lesser extent than the parent compound.

Ciprofloxacin is a moderate inhibitor of the CYP450 1A2 isoenzyme.

Elimination

Ciprofloxacin is primarily eliminated via the kidneys and to a lesser extent in feces.

Renal clearance is 180–300 mL/kg/h, and total body clearance is 480–600 mL/kg/h. Ciprofloxacin undergoes both glomerular filtration and tubular secretion. In severe renal impairment, the elimination half-life of ciprofloxacin is prolonged up to 12 hours.

Extrarenal clearance of ciprofloxacin is primarily due to active intestinal secretion and metabolism. One percent (1%) of the dose is excreted in bile. Ciprofloxacin is present in bile at high concentrations.

Children

Pharmacokinetic data in children are limited.

In studies involving children aged 1 year and older, no age-dependent differences in C_max and AUC values were observed. After repeated administration of the drug (10 mg/kg three times daily), no significant increase in C_max and AUC was observed.

In 10 infants under 1 year of age with severe sepsis, C_max was 6.1 mg/L (range 4.6–8.3 mg/L) after a 1-hour intravenous infusion at a dose of 10 mg/kg. This value was 7.2 mg/L (range 4.7–11.8 mg/L) in children aged 1 to 5 years. AUC values were 17.4 mg*h/L (range 11.8–32.0 mg*h/L) and 16.5 mg*h/L (range 11–23.8 mg*h/L) in the respective age groups.

These values are within the range observed in adults receiving therapeutic doses. According to pharmacokinetic analyses in pediatric patients with various infections, the predicted mean elimination half-life in children is approximately 4–5 hours, and the bioavailability of the oral suspension ranges from 50% to 80%.

Clinical characteristics.

Indications.

Ciprofloxacin is indicated for the treatment of the following infections (see also sections "Special precautions for use" and "Pharmacological properties"). Before initiating therapy, careful consideration should be given to all available information regarding resistance to ciprofloxacin.

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

Adults

• Lower respiratory tract infections caused by Gram-negative bacteria:
  • exacerbations of chronic obstructive pulmonary disease*;
  • bronchopulmonary infections in cystic fibrosis or bronchiectasis;
  • community-acquired pneumonia.
• Chronic suppurative otitis media.
• Acute exacerbations of chronic sinusitis, particularly if caused by Gram-negative bacteria*.
• Urinary tract infections:
  • acute pyelonephritis;
  • complicated urinary tract infections;
  • bacterial prostatitis.
• Genital system infections:
  • orchitis and epididymitis, including those caused by susceptible strains of Neisseria gonorrhoeae;
  • pelvic inflammatory disease, including that caused by susceptible strains of Neisseria gonorrhoeae.
• Gastrointestinal tract infections (e.g., treatment of traveler's diarrhea).
• Intra-abdominal infections.
• Skin and soft tissue infections caused by Gram-negative bacteria.
• Malignant external otitis.
• Bone and joint infections.
• Inhalational anthrax (post-exposure prophylaxis and definitive treatment).
• Febrile neutropenia caused by bacterial infection.

Children and adolescents

• Bronchopulmonary infections caused by Pseudomonas aeruginosa in patients with cystic fibrosis.
• Complicated urinary tract infections and acute pyelonephritis.
• Inhalational anthrax (post-exposure prophylaxis and definitive treatment).

Ciprofloxacin may also be used for the treatment of severe infections in children and adolescents when the physician considers it necessary.

Treatment should be initiated by a physician experienced in managing cystic fibrosis and/or severe infections in children and adolescents (see also sections "Special precautions for use" and "Pharmacological properties").

* Only when other antibacterial agents typically used for treatment of this infection have been found ineffective or inappropriate.

Contraindications.

• Hypersensitivity to the active substance, to other quinolone antibiotics, or to any of the excipients.
• Concomitant administration of ciprofloxacin and tizanidine (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Effects of other medicinal products on ciprofloxacin

Medicinal products that prolong the QT interval

Ciprofloxacin, like other fluoroquinolones, should be administered with caution to patients receiving medicinal products that prolong the QT interval (e.g., Class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, neuroleptics) (see section "Special precautions for use").

Probenecid

Probenecid affects the renal secretion of ciprofloxacin. Concomitant administration of probenecid-containing medicinal products and ciprofloxacin results in increased serum concentrations of ciprofloxacin.

Effects of ciprofloxacin on other medicinal products

Tizanidine

Tizanidine must not be co-administered with ciprofloxacin (see section "Contraindications"). In a clinical study involving healthy volunteers, concomitant administration of ciprofloxacin and tizanidine resulted in increased plasma concentrations of tizanidine (increase in Cmax by 7-fold, range 4–21; increase in AUC by 10-fold, range 6–24). Elevated tizanidine plasma concentrations are associated with hypotensive and sedative adverse reactions.

Methotrexate

Concomitant administration of ciprofloxacin may slow tubular transport (renal metabolism) of methotrexate, potentially leading to increased plasma concentrations of methotrexate. This increases the risk of methotrexate-induced toxic side effects. Concomitant use is not recommended (see section "Special precautions for use").

Theophylline

Concomitant administration of ciprofloxacin and theophylline-containing medicinal products may lead to undesirable increases in serum theophylline concentrations, which may in turn cause adverse reactions. In rare cases, such adverse reactions may be fatal. If concomitant use cannot be avoided, serum theophylline concentrations should be monitored and the dose adjusted accordingly (see section "Special precautions for use").

Other xanthine derivatives

Increased serum concentrations of xanthines such as caffeine or pentoxifylline (oxpentifylline) have been reported following concomitant administration with ciprofloxacin.

Phenytoin

Concomitant administration of ciprofloxacin and phenytoin may lead to increased or decreased serum phenytoin concentrations; therefore, monitoring of phenytoin levels is recommended.

Cyclosporine

Transient increases in plasma creatinine have been observed when ciprofloxacin and cyclosporine-containing medicinal products are administered concomitantly. Frequent monitoring (twice weekly) of plasma creatinine concentrations is therefore required in these patients.

Vitamin K antagonists

Concomitant administration of ciprofloxacin and vitamin K antagonists may enhance their anticoagulant effect. Increased activity of oral anticoagulants has been reported in patients receiving antibacterial agents, including fluoroquinolones. The degree of risk may vary depending on the underlying infection, age, and general condition of the patient, making it difficult to precisely assess the impact of ciprofloxacin on the international normalized ratio (INR). Frequent monitoring of INR is recommended during and immediately after concomitant administration of ciprofloxacin and vitamin K antagonists (e.g., warfarin, acenocoumarol, phenprocoumon, fluindione).

Duloxetine

Clinical studies have shown that concomitant administration of duloxetine with strong CYP450 1A2 inhibitors, such as fluvoxamine, may increase the AUC and Cmax of duloxetine. Although there are no clinical data on potential interaction with ciprofloxacin, similar effects may be expected when these agents are used concomitantly (see section "Special precautions for use").

Ropinirole

Clinical studies have shown that concomitant administration of ropinirole with ciprofloxacin, a moderate inhibitor of the CYP450 1A2 isoenzyme, increases the Cmax and AUC of ropinirole by 60% and 84%, respectively. Monitoring for ropinirole-related adverse effects and appropriate dose adjustment are recommended during and immediately after co-administration with ciprofloxacin (see section "Special precautions for use").

Lidocaine

It has been demonstrated that in healthy subjects, concomitant administration of ciprofloxacin, a moderate inhibitor of cytochrome P450 1A2 isoenzymes, and intravenous lidocaine-containing medicinal products reduces lidocaine clearance by 22%. Despite normal tolerability of lidocaine treatment, interaction with concomitant ciprofloxacin use may be associated with adverse reactions.

Clozapine

After concomitant administration of 250 mg ciprofloxacin with clozapine for 7 days, serum concentrations of clozapine and N-desmethylclozapine were increased by 29% and 31%, respectively. Clinical monitoring and appropriate dose adjustment of clozapine are recommended during and immediately after concomitant administration with ciprofloxacin (see section "Special precautions for use").

Sildenafil

Cmax and AUC of sildenafil increased approximately two-fold in healthy volunteers after oral administration of 50 mg sildenafil and concomitant administration of 500 mg ciprofloxacin. Therefore, caution should be exercised when co-prescribing ciprofloxacin with sildenafil, and the benefit-risk ratio should be carefully considered.

Agomelatine

Clinical studies have demonstrated that fluvoxamine, a strong inhibitor of the CYP450 1A2 isoenzyme, markedly inhibits the metabolism of agomelatine, resulting in a 60-fold increase in its exposure. Despite the lack of clinical data on potential interaction with ciprofloxacin, a moderate CYP450 1A2 inhibitor, similar effects may be expected with concomitant administration (see section "Special precautions for use. Cytochrome P450").

Zolpidem

Concomitant administration of ciprofloxacin may increase blood levels of zolpidem. Concomitant use is not recommended.

Special precautions for use.

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

Severe infections and mixed infections caused by Gram-positive or anaerobic bacteria

Ciprofloxacin should not be used as monotherapy for the treatment of severe infections or infections caused by Gram-positive or anaerobic bacteria. In such cases, ciproflox inflammable should be used in combination with appropriate antibacterial agents.

Streptococcal infections (including Streptococcus pneumoniae)

Ciprofloxacin is not recommended for the treatment of streptococcal infections due to insufficient efficacy.

Genitourinary infections

Orchiepididymitis and pelvic inflammatory diseases may be caused by fluoroquinolone-resistant Neisseria gonorrhoeae.

Empirical therapy with ciprofloxacin for orchiepididymitis and pelvic inflammatory diseases may be used only in combination with other appropriate antibacterial agents (e.g., cephalosporins), except in clinical situations where resistance of Neisseria gonorrhoeae strains to ciprofloxacin is excluded. If no clinical improvement occurs within 3 days, the therapy should be re-evaluated.

Urinary tract infections

In European Union countries, variable resistance of Escherichia coli, the most common causative agent of urinary tract infections, to fluoroquinolones has been observed. Physicians are advised to consider local prevalence of Escherichia coli resistance to fluoroquinolones when prescribing therapy.

Intra-abdominal infections

Data on the efficacy of ciprofloxacin in the treatment of postoperative intra-abdominal infections are limited.

Traveler's diarrhea

When selecting a treatment, information regarding resistance to ciprofloxacin of relevant microorganisms in the countries visited should be taken into account.

Bone and joint infections

Ciprofloxacin should be used in combination with other antimicrobial agents depending on the results of microbiological testing.

Pulmonary form of anthrax

The possibility of use in humans is based on in vitro susceptibility data, animal studies, and limited data from human use. The physician should act according to national and/or international treatment protocols for anthrax.

Children and adolescents

The use of ciprofloxacin in children and adolescents should be conducted in accordance with current official recommendations. Treatment with ciprofloxacin should be administered only by a physician experienced in managing children and adolescents with cystic fibrosis and/or severe infections.

Ciprofloxacin has been shown to cause arthropathy in weight-bearing joints in immature animals. The increase in the number of arthropathy cases associated with the use of the drug was statistically insignificant. However, treatment with ciprofloxacin in children and adolescents should be initiated only after careful assessment of the benefit-risk ratio due to the risk of developing adverse reactions affecting joints and/or adjacent tissues.

Respiratory infections in cystic fibrosis

Children and adolescents aged 5–17 years were included in clinical trials. Limited experience exists in treating children aged 1–5 years.

Complicated urinary tract infections and pyelonephritis

Treatment of urinary tract infections with ciprofloxacin should be considered when other treatments are not possible. Treatment should be based on the results of microbiological testing.

The use of ciprofloxacin in children and adolescents aged 1–17 years has been evaluated in clinical studies.

Other specific severe infections

The use of ciprofloxacin may be justified based on microbiological testing results in cases of other severe infections, according to official recommendations or after careful assessment of the benefit-risk ratio, when other treatments cannot be used or standard therapy has proven ineffective.

The use of ciprofloxacin for specific severe infections other than those mentioned above has not been evaluated in clinical trials, and clinical experience is limited. Therefore, caution is recommended when treating patients with such infections.

Antibiotic-associated diarrhea caused by Clostridium difficile

Cases of antibiotic-associated diarrhea caused by Clostridium difficile, ranging in severity from mild diarrhea to fatal colitis, have been reported with the use of nearly all antibacterial agents, including ciprofloxacin. Antibacterial therapy alters the normal flora of the colon, leading to overgrowth of Clostridium difficile.

Clostridium difficile produces toxins A and B, which contribute to the development of antibiotic-associated diarrhea. Clostridium difficile producing large amounts of toxin is associated with increased morbidity and mortality due to possible resistance to antimicrobial therapy and the need for colectomy. The possibility of Clostridium difficile-associated antibiotic-associated diarrhea should be considered in all patients with diarrhea following antibiotic use. A careful medication history is required, as Clostridium difficile-associated antibiotic-associated diarrhea may develop up to two months after administration of antibacterial agents. If the diagnosis of Clostridium difficile-associated antibiotic-associated diarrhea is considered or confirmed, the use of antibiotics not active against Clostridium difficile may need to be discontinued.

Depending on clinical data, correction of fluid and electrolyte balance is necessary, consideration should be given to additional protein supplementation, and antibacterial agents to which Clostridium difficile is sensitive should be used. Surgical intervention may also be required.

Hypersensitivity (allergic reactions)

In some cases, hypersensitivity and allergic reactions may occur after the first dose of ciprofloxacin (see section "Adverse reactions"), and this should be immediately reported to the physician.

In rare cases, anaphylactic/anaphylactoid reactions may progress to a life-threatening shock state. Such reactions may occur after the first dose of ciprofloxacin. In such cases, administration of ciprofloxacin should be stopped immediately, and appropriate medical treatment should be initiated.

Prolonged, disabling, and potentially irreversible serious adverse reactions

Very rare, prolonged (several months or years), disabling, potentially irreversible serious adverse reactions affecting various body systems (musculoskeletal, nervous, and sensory systems, organs of sense) have been reported in patients receiving quinolones or fluoroquinolones, regardless of age or presence of risk factors. If any signs or symptoms of serious adverse reactions appear, ciprofloxacin should be discontinued immediately, and the patient should seek medical advice.

Tendinitis and tendon rupture

Generally, ciprofloxacin should not be used in patients with tendon disorders or a history of quinolone-related disorders. Nevertheless, in rare cases, after microbiological testing and benefit-risk assessment, ciprofloxacin may be prescribed to these patients for the treatment of certain severe infections, particularly when standard therapy is ineffective or bacterial resistance is present, and microbiological test results justify the use of ciprofloxacin.

Tendinitis and tendon rupture (especially of the Achilles tendon), sometimes bilateral, may occur within 48 hours of starting treatment with quinolones and fluoroquinolones, and sometimes even several months after discontinuation of ciprofloxacin (see section "Adverse reactions"). The risk of tendinitis and tendon rupture is increased in elderly patients, patients with renal impairment, patients after solid organ transplantation, and 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 ciprofloxacin should be discontinued immediately, and alternative treatment should be considered. The affected limb should be properly managed (e.g., immobilization should be ensured). Corticosteroids should not be used if signs of tendinopathy appear.

Patients with myasthenia gravis

Due to the risk of exacerbation of symptoms, ciprofloxacin should be used with caution in patients with myasthenia gravis (see section "Adverse reactions").

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

Epidemiological studies indicate an increased risk of aortic aneurysm and aortic dissection, especially 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 regurgitation/insufficiency of any heart valve 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 treatment options in patients with a significant family history (presence of aortic aneurysm or congenital heart valve defects), diagnosed aortic aneurysm and/or aortic dissection, or heart valve disease, or in the presence of other risk factors, namely:

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

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

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

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

Visual disturbances

If any visual disturbances or adverse reactions affecting the eyes occur during treatment, the patient should immediately consult an ophthalmologist (see section "Adverse reactions").

Photosensitivity

Ciprofloxacin has been shown to cause photosensitivity reactions. Patients taking ciprofloxacin are advised to avoid direct sunlight or UV radiation during treatment (see section "Adverse reactions").

Seizures

Ciprofloxacin, like other quinolones, may cause seizures or lower the seizure threshold. Cases of epileptic status have been reported. Ciprofloxacin should be used with caution in patients with central nervous system (CNS) disorders predisposing to seizures. If seizures occur, ciprofloxacin should be discontinued (see section "Adverse reactions").

Peripheral neuropathy

Cases of sensory or sensorimotor polyneuropathy have been reported in patients taking quinolones or fluoroquinolones, leading to paresthesia, hypoesthesia, dysesthesia, or weakness. Patients receiving ciprofloxacin should inform their physician before continuing treatment if symptoms of neuropathy, including pain, burning, tingling, numbness, and/or weakness, are present, to prevent the development of irreversible conditions (see section "Adverse reactions").

Psychotic reactions

Psychotic reactions may occur even after the first dose of ciprofloxacin. In rare cases, depression or psychosis may progress to suicidal thoughts and actions, including suicide or suicide attempts. In such cases, ciprofloxacin should be discontinued, and appropriate measures should be taken.

Cardiac disorders

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

• congenital long QT syndrome;
• concomitant use of medicinal products known to prolong the QT interval (e.g., class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, neuroleptics);
• uncorrected electrolyte imbalance (e.g., hypokalemia, hypomagnesemia);
• heart 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 ciprofloxacin, should be used with caution in these patient groups (see sections "Method of administration and dosage. Elderly patients", "Interaction with other medicinal products and other types of interactions", "Overdose", "Adverse reactions").

Glucose level fluctuations

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

Gastrointestinal tract

If severe and persistent diarrhea occurs during or after treatment (even several weeks after treatment), the physician should be informed, as this symptom may mask a serious gastrointestinal condition (e.g., antibiotic-associated colitis, which may be fatal) requiring immediate treatment (see section "Adverse reactions"). In such cases, ciprofloxacin should be discontinued, and appropriate therapy should be initiated. Medicinal products that inhibit peristalsis are contraindicated.

Kidneys and urinary system

Crystalluria associated with ciprofloxacin use has been reported (see section "Adverse reactions"). Patients taking ciprofloxacin should receive adequate fluid intake. Excessive alkalinity of urine should be avoided.

Renal function impairment

Since ciprofloxacin is primarily excreted unchanged by the kidneys, dose adjustment is necessary for patients with impaired renal function (as described in the section "Method of administration and dosage") to avoid increased adverse reactions due to accumulation of ciprofloxacin.

Hepatobiliary system

Cases of hepatic necrosis and life-threatening hepatic failure have been reported with ciprofloxacin use (see section "Adverse reactions"). If any symptoms of liver disease (e.g., anorexia, jaundice, dark urine, pruritus, or abdominal wall tension) occur, treatment should be discontinued.

Glucose-6-phosphate dehydrogenase deficiency

Hemolytic reactions have been reported with ciprofloxacin use in patients with glucose-6-phosphate dehydrogenase deficiency. The use of ciprofloxacin should be avoided in these patients, except when potential benefit outweighs potential risk. In such cases, monitoring for possible hemolysis is recommended.

Resistance

Resistant bacteria may be isolated during or after a course of ciprofloxacin treatment, with or without clinically evident superinfection. There is a certain risk of developing resistance to ciprofloxacin in bacteria during prolonged treatment courses and in the treatment of nosocomial infections and/or infections caused by Staphylococcus and Pseudomonas species.

Cytochrome P450

Ciprofloxacin moderately inhibits CYP450 1A2 and may therefore increase serum concentrations of concurrently administered substances metabolized by this enzyme (e.g., theophylline, clozapine, olanzapine, ropinirole, tizanidine, duloxetine, agomelatine). Therefore, patients receiving these substances concurrently with ciprofloxacin should be closely monitored for clinical signs of overdose. Serum concentration monitoring (e.g., theophylline) may also be necessary (see section "Interaction with other medicinal products and other types of interactions"). Concomitant administration of ciprofloxacin and tizanidine is contraindicated.

Methotrexate

Concomitant administration of ciprofloxacin and methotrexate is not recommended (see section "Interaction with other medicinal products and other types of interactions").

Effect on laboratory test results

Ciprofloxacin may in vitro affect the results of Mycobacterium tuberculosis culture by inhibiting mycobacterial growth, potentially leading to false-negative culture results in patients taking ciprofloxacin.

Reactions at the site of administration

Reactions at the site of ciprofloxacin administration have been reported. The frequency of such reactions increases if the infusion duration is 30 minutes or less. Reactions may manifest as local skin reactions that resolve quickly after the end of the infusion. Further intravenous administration is not contraindicated if reactions do not recur or intensify.

Sodium content

This medicinal product contains sodium in the following amounts (per vial): 354 mg (200 mg / 100 ml), 708.1 mg (400 mg / 200 ml), equivalent to 17.7% and 35.4%, respectively, of the WHO recommended maximum daily sodium intake of 2 g for adults. The maximum daily dose of this product is equivalent to 108% of the WHO recommended maximum daily sodium intake. Ciprofloxacin is considered a high-sodium product. This should be particularly considered if the patient follows a low-salt diet, i.e., when sodium intake by the patient is a medical concern (patients with congestive heart failure, renal impairment, nephrotic syndrome, etc.).

Use during pregnancy or breastfeeding.

Pregnancy

Data on the use of ciprofloxacin in pregnant women show no evidence of malformations or fetotoxic/neonatal toxicity. Animal studies do not indicate direct or indirect toxic effects on reproductive function. In young animals and animals exposed to quinolones before birth, effects on immature cartilage tissue have been observed; therefore, the possibility that the drug may be harmful to the joint cartilage of the newborn/fetus cannot be excluded. Therefore, ciprofloxacin use should be avoided during pregnancy.

Lactation period

Ciprofloxacin passes into breast milk. Due to the risk of damage to joint cartilage in newborns, ciprofloxacin should not be used during breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

Ciprofloxacin may cause central nervous system (CNS) reactions. Therefore, the ability to drive or operate machinery may be impaired.

Method of Administration and Dosage.

Dosing

The dosage regimen should be determined individually by a physician depending on the site and severity of the infection, pathogen susceptibility, patient's renal function, and in children and adolescents, according to body weight.

The duration of treatment depends on the severity of the disease, as well as clinical and bacteriological findings.

Treatment with ciprofloxacin, after initial intravenous administration, may be completed with the oral formulation, provided such a switch is appropriate for the individual patient. The transition from initial intravenous administration to oral intake should be made as soon as possible.

In severe cases or when the patient is unable to take oral formulations (e.g., the patient is on enteral nutrition), it is recommended to initiate and continue treatment with intravenous ciprofloxacin until switching to the oral form becomes feasible.

Treatment of infections caused by certain bacteria (e.g., Pseudomonas aeruginosa, Acinetobacter, or Staphylococci) may require higher doses of ciprofloxacin and combination with other appropriate antibacterial agents.

Treatment of certain infections (e.g., pelvic inflammatory disease, intra-abdominal infections, infections in neutropenic patients, and bone and joint infections) may require combination with other appropriate antibacterial agents depending on the causative organism.

Adults

Children

Geriatric patients

Geriatric patients should be prescribed doses based on the severity of the disease and creatinine clearance.

Patients with renal or hepatic impairment

Recommended initial and maintenance doses for patients with renal impairment

For patients with hepatic impairment, dose adjustment is not required.

The dosing regimen in children with renal or hepatic impairment has not been studied.

Method of administration

The solution should be inspected visually before use. A precipitate may form in the solution at low temperatures, which redissolves at room temperature (15–25 °C). The medicinal product should be shaken before administration. Use only clear solution. The product should be used immediately after perforation of the rubber stopper to prevent bacterial contamination. The medicinal product is intended for single use only. Any unused solution should be discarded.

When protected from daylight, the solution maintains full efficacy for up to 3 days.

Ciprofloxacin should be administered by intravenous infusion. For children, the infusion duration is 60 minutes. For adult patients, the infusion duration is 60 minutes for the "Ciprofloxacin, infusion solution" containing 400 mg ciprofloxacin, and 30 minutes for the "Ciprofloxacin, infusion solution" containing 200 mg ciprofloxacin. Slow infusion into a large vein should be performed to minimize patient discomfort and reduce the risk of venous irritation.

The infusion solution may be administered either separately or after mixing with other compatible infusion solutions.

Compatibility with other solutions

Ciprofloxacin infusion solution is compatible with Ringer's solution, Ringer's lactate solution, 5% and 10% glucose solutions, and 5% and 10% fructose solutions. If compatibility with other infusion solutions has not been confirmed, ciprofloxacin infusion solution should be administered separately. Visible signs of incompatibility include precipitation, cloudiness, or change in solution color.

Children

Ciprofloxacin is not recommended for use in children for the treatment of infectious diseases other than those specified in the section "Indications".

Overdose

Cases of overdose with ingestion of 12 g of the medicinal product have been reported to result in symptoms of moderate toxicity. Acute overdose with a dose of 16 g has led to the development of acute renal failure.

Symptoms of overdose included dizziness, tremor, headache, fatigue, seizures, hallucinations, confusion, abdominal discomfort, renal and hepatic dysfunction, as well as crystalluria and hematuria. Reversible nephrotoxicity has also been reported.

In addition to standard emergency measures taken in overdose (e.g., gastric lavage followed by activated charcoal administration), monitoring of renal function is recommended, including determination of urine pH and, if necessary, alkalinization of urine to prevent crystalluria. Patients should receive adequate fluid intake. Antacids containing calcium or magnesium may theoretically reduce ciprofloxacin absorption in overdose.

Only a small amount of ciprofloxacin (< 10%) is removed by hemodialysis or peritoneal dialysis.

In case of overdose, symptomatic treatment should be administered. ECG monitoring is required, as QT interval prolongation may occur.

Adverse reactions.

The most commonly reported adverse reactions to the medicinal product were nausea, diarrhoea, vomiting, transient elevation of transaminase levels, rash, and injection site reactions.

Data on adverse reactions to ciprofloxacin obtained from clinical trials and post-marketing surveillance (oral, parenteral, and sequential administration) are provided below.

When analysing the frequency of occurrence, data on both oral and intravenous administration routes of ciprofloxacin are considered.

The following classification is used to assess the frequency of adverse reactions: very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1000 and < 1/100), rare (≥ 1/10,000 and < 1/1000), very rare (< 1/10,000), frequency not known (cannot be estimated from the available data).

Infections and infestations

Uncommon: fungal superinfections.

Blood and lymphatic system disorders

Uncommon: eosinophilia; rare: leucopenia, anaemia, neutropenia, leukocytosis, thrombocytopenia, thrombocytosis.

Very rare: haemolytic anaemia, agranulocytosis, pancytopenia (life-threatening), bone marrow function suppression (life-threatening).

Immune system disorders

Rare: allergic reactions, allergic/angioneurotic oedema.

Very rare: anaphylactic reactions, anaphylactic shock (life-threatening) (see section "Special precautions for use"), serum sickness-like reactions.

Endocrine disorders

Frequency not known: syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Metabolism and nutrition disorders

Uncommon: decreased appetite.

Rare: hyperglycaemia, hypoglycaemia (see section "Special precautions for use").

Frequency not known: hypoglycaemic coma (see section "Special precautions for use").

Psychiatric disorders*

Uncommon: psychomotor hyperactivity/agitation.

Rare: confusion and disorientation, anxiety, pathological dreams, depression (with possible suicidal ideation/thoughts or suicide attempts/acts) (see section "Special precautions for use"), hallucinations.

Very rare: psychotic reactions (with possible suicidal ideation/thoughts or suicide attempts/acts) (see section "Special precautions for use"); frequency not known: mania, hypomania.

Nervous system disorders*

Uncommon: headache, dizziness, sleep disorders, taste disturbances.

Rare: paraesthesia and dysaesthesia, hypoaesthesia, tremor, convulsions (including epileptic status — see section "Special precautions for use"), vertigo.

Very rare: migraine, coordination disorders, gait disturbances, olfactory disturbances, benign intracranial hypertension.

Frequency not known: peripheral neuropathy and polyneuropathy (see section "Special precautions for use").

Eye disorders*

Rare: visual disturbances, e.g., diplopia.

Very rare: colour vision disturbances.

Aural and vestibular disorders*

Rare: tinnitus, hearing loss/hearing impairment.

Cardiac disorders**

Rare: tachycardia.

Frequency not known: ventricular arrhythmia, torsade de pointes (observed mainly in patients with additional risk factors for QT interval prolongation), QT interval prolongation (see sections "Special precautions for use", "Overdose").

Vascular disorders**

Rare: vasodilation, arterial hypotension, syncope.

Very rare: vasculitis.

Respiratory, thoracic and mediastinal disorders

Rare: dyspnoea (including asthmatic condition).

Gastrointestinal disorders

Common: nausea, diarrhoea.

Uncommon: vomiting, stomach and intestinal pain, abdominal pain, dyspeptic disorders, flatulence.

Rare: antibiotic-associated colitis (very rare with fatal outcome) (see section "Special precautions for use").

Very rare: pancreatitis.

Hepatobiliary disorders

Uncommon: increased levels of transaminases and bilirubin.

Rare: liver function disturbances, cholestatic jaundice, hepatitis.

Very rare: hepatic necrosis (very rarely progressing to life-threatening liver failure) (see section "Special precautions for use").

Skin and subcutaneous tissue disorders

Uncommon: rash, pruritus, urticaria.

Rare: photosensitivity reactions (see section "Special precautions for use").

Very rare: petechiae, erythema multiforme, nodular erythema, Stevens-Johnson syndrome (life-threatening), toxic epidermal necrolysis (life-threatening).

Frequency not known: acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS).

Musculoskeletal and connective tissue disorders*

Uncommon: musculoskeletal pain (e.g., limb, back, chest pain), arthralgia.

Rare: myalgia, arthritis, increased muscle tone and muscle spasms.

Very rare: muscle weakness, tendinitis, tendon rupture (predominantly Achilles tendon) (see section "Special precautions for use"), exacerbation of symptoms of myasthenia gravis (see section "Special precautions for use").

Renal and urinary disorders

Uncommon: renal function disturbances.

Rare: renal failure, haematuria, crystalluria (see section "Special precautions for use"), tubulointerstitial nephritis.

General disorders and administration site conditions*

Common: injection and infusion site reactions (only with intravenous administration).

Uncommon: asthenia, fever.

Rare: oedema, increased sweating (hyperhidrosis).

Investigations

Uncommon: increased alkaline phosphatase activity in blood.

Rare: increased amylase activity.

Frequency not known: prolonged PT/INR in patients receiving vitamin K antagonists.

* There have been reports of very rare, prolonged (several months or years), disabling and potentially irreversible serious adverse reactions affecting various organ systems associated with the use of quinolones and fluoroquinolones, regardless of the presence of risk factors (see section "Special precautions for use"), including such reactions as tendinitis, tendon rupture, arthralgia, limb pain, gait disturbances, neuropathies associated with paraesthesia and neuralgia, fatigue, psychiatric symptoms (including sleep disturbances, anxiety, panic attacks, depression, and suicidal thoughts), memory and concentration disturbances, hearing impairment, visual disturbances, and disturbances of taste and smell.

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

The following adverse events have a higher frequency category in subgroups of patients who received intravenous or sequential (intravenous to oral) treatment:

Common: vomiting, transient elevation of transaminases, rash.

Uncommon: thrombocytopenia, thrombocytosis, confusion and disorientation, hallucinations, paraesthesia and dysaesthesia, convulsions, vertigo, visual disturbances, hearing disturbances, tachycardia, vasodilation, hypotension, transient liver function disturbances, cholestatic jaundice, renal failure, oedema.

Rare: pancytopenia, bone marrow function suppression, anaphylactic shock, psychotic reactions, migraine, olfactory nerve disorders, hearing impairment, vasculitis, pancreatitis, hepatic necrosis, petechiae, tendon rupture.

Children

The frequency of arthropathy (arthralgia, arthritis) mentioned above was determined in studies involving adult patients. Arthropathy occurs more frequently in children (see section "Special precautions for use").

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicinal product authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions through the national pharmacovigilance system.

Shelf life. 2 years.

Storage conditions.

Keep out of the reach of children. Store at a temperature not exceeding 25 °C in the original packaging.

Incompatibilities.

This medicinal product should not be mixed with other medicinal products except those specified in the section "Method of administration and dosage".

If compatibility with another infusion product has not been confirmed, the ciprofloxacin infusion solution should be administered separately.

Incompatibility occurs when used with all infusion solutions/products that are physically or chemically unstable (e.g., penicillins, heparin solutions), especially in combination with solutions whose pH has been adjusted to alkaline.

Packaging.

100 ml or 200 ml in polymer bottles; 1 bottle in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

LLC "Yuria-Pharm".

Manufacturer's address and location of business activity.

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