Ciprofloxacin

INSTRUCTION for medical use of the medicinal product CIPROFLOXACIN (CIPROFLOXACIN)

Composition:

Active substance: ciprofloxacin;

1 ml of solution contains ciprofloxacin hydrochloride (calculated as ciprofloxacin) 2 mg;

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

Pharmaceutical form. Infusion solution.

Main physico-chemical properties: clear, colourless or slightly yellowish liquid.

Pharmacotherapeutic group. Antibacterials for systemic use. Fluoroquinolones. Ciprofloxacin. ATC code J01M A02.

Pharmacological properties.

Pharmacodynamics.

The bactericidal activity of ciprofloxacin, a fluoroquinolone antimicrobial agent, is due to inhibition of bacterial DNA gyrase (topoisomerase type II) and topoisomerase IV, enzymes required for DNA replication, transcription, repair, and recombination.

Pharmacokinetic/pharmacodynamic relationship

The efficacy of the drug depends primarily on the maximum concentration of the drug in serum (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 in vitro are frequently observed 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 also been reported.

Spectrum of antibacterial activity

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

EUCAST recommendations

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

*Species-independent breakpoints were primarily established based on pharmacokinetic/pharmacodynamic (PK/PD) data and are not dependent on the MIC values for individual species. These breakpoints 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 depending on geographical location and time. Therefore, local information on resistance patterns is necessary, especially when treating severe infections. When local resistance prevalence reaches a level at which the benefit of the medicinal product is questionable, at least for certain types of infections, consultation with specialists should be sought.

The following bacterial genera and species 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 achieved at the end of the infusion. Following intravenous administration, the pharmacokinetics of ciprofloxacin are linear within the dose range up to 400 mg.

Comparison of pharmacokinetic parameters after intravenous administration twice daily versus three times daily did not reveal accumulation of ciprofloxacin or its metabolites.

The 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 ciprofloxacin over 60 minutes every 12 hours, the Cmax 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 similar 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, biopsies), sinuses, sites of inflammation (blister fluid induced by cantharidin), and the urogenital 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.

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.

Non-renal clearance of ciprofloxacin is primarily due to active intestinal secretion and metabolism. One percent of the administered 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 Cmax or AUC were observed. After repeated administration of the drug (10 mg/kg three times daily), no significant increase in Cmax and AUC was observed.

In 10 infants under 1 year of age with severe sepsis, Cmax 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. In children aged 1 to 5 years, Cmax was 7.2 mg/L (range: 4.7–11.8 mg/L). 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 "Pharmacological properties" and "Special instructions"). 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 (only if other antibacterial agents commonly used to treat this infection are considered ineffective or inappropriate);
  • Bronchopulmonary infections in cystic fibrosis or bronchiectasis;
  • Community-acquired pneumonia.
• Chronic suppurative otitis media.
• Malignant (necrotizing) external otitis.
• Acute exacerbations of chronic sinusitis, particularly if caused by Gram-negative bacteria*.
• Urinary tract infections:
  • Acute pyelonephritis;
  • Complicated urinary tract infections;
  • Bacterial prostatitis.
• Genitourinary infections:
  • Epididymo-orchitis, particularly caused by susceptible strains of Neisseria gonorrhoeae;
  • Pelvic inflammatory disease, particularly caused by susceptible strains of Neisseria gonorrhoeae.
• Gastrointestinal infections (e.g., treatment of traveler's diarrhea).
• Intra-abdominal infections.
• Skin and soft tissue infections caused by Gram-negative bacteria.
• Bone and joint infections.
• Pulmonary anthrax (post-exposure prophylaxis and definitive treatment).
• Fever in neutropenic patients, when bacterial infection is suspected.

Children and adolescents

• Bronchopulmonary infections caused by Pseudomonas aeruginosa in patients with cystic fibrosis.
• Complicated urinary tract infections and acute pyelonephritis.
• Pulmonary 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 sections "Interaction with other medicinal products and other forms of interaction" and "Special instructions").

* Only if other antibacterial agents commonly used to treat this infection are considered ineffective or inappropriate.

Contraindications.

• Hypersensitivity to the active substance, to other quinolone antibiotics, or to any of the excipients of the medicinal product.
• 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 used with caution in patients receiving medicinal products that prolong the QT interval (e.g., Class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, neuroleptics) (see section "Special instructions").

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 administered concomitantly 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-fold; increase in AUC by 10-fold, range 6–24-fold). Increased tizanidine plasma concentrations are associated with enhanced hypotensive and sedative effects.

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 adverse toxic reactions caused by methotrexate. Concomitant use is not recommended (see section "Special instructions").

Theophylline

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

Other xanthine derivatives

Elevated 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 with concomitant administration of ciprofloxacin and cyclosporine-containing medicinal products. Therefore, frequent monitoring (twice weekly) of plasma creatinine concentrations is 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, including fluoroquinolones, has been reported in patients receiving antibacterial agents. 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 increase in international normalized ratio (INR). Frequent monitoring of INR is required 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. Despite the lack of clinical data on potential interaction with ciprofloxacin, similar effects may be expected when these agents are used concomitantly (see section "Special instructions").

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 instructions").

Lidocaine

It has been demonstrated in healthy subjects that 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 therapy, interaction with concomitant ciprofloxacin use may occur and is associated with adverse reactions.

Clozapine

Following 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 instructions").

Sildenafil

Cmax and AUC of sildenafil approximately doubled 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 considered.

Agomelatine

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

Zolpidem

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

Special precautions for use.

Avoid using ciprofloxacin in patients with a history of serious adverse reactions associated with quinolone or 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 benefit-risk assessment (also see 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, ciprofloxacin 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

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

Empirical therapy with ciprofloxacin for orchitis and pelvic inflammatory diseases may be used only in combination with other appropriate antibacterial agents (e.g., cephalosporins), except in clinical situations where resistant Neisseria gonorrhoeae strains have been ruled out. Therapy should be re-evaluated if no clinical improvement occurs within 3 days.

Urinary tract infections

In European Union countries, variable resistance of Escherichia coli, the most common causative pathogen of urinary tract infections, to fluoroquinolones has been observed. Prescribers are advised to consider local prevalence of fluoroquinolone resistance in Escherichia coli when selecting 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 therapy, information regarding ciprofloxacin resistance 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 based on microbiological test results.

Pulmonary form of anthrax

The possibility of use in humans is based on in vitro susceptibility data, animal studies, and limited human experience. The physician should follow national and/or international treatment guidelines for anthrax.

Children and adolescents

Administration of ciprofloxacin to children and adolescents should be performed in accordance with current official recommendations. Treatment with ciprofloxacin should be initiated only by a physician experienced in managing children and adolescents with cystic fibrosis and/or severe infections.

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

Respiratory infections in cystic fibrosis

Clinical trials included children and adolescents aged 5–17 years. Experience with treatment in children aged 1–5 years is more limited.

Complicated urinary tract infections and pyelonephritis

Ciprofloxacin therapy for urinary tract infections should be considered when alternative treatments are not feasible. Treatment should be based on microbiological test results.

Clinical studies evaluated ciprofloxacin use in children and adolescents aged 1–17 years.

Other specific severe infections

Ciprofloxacin use may be justified based on microbiological test results for other severe infections, according to official recommendations or after careful benefit-risk assessment, when alternative treatments are not available or standard therapy has proven ineffective.

Ciprofloxacin use for specific severe infections not mentioned above has not been evaluated in clinical trials, and clinical experience is limited. Therefore, treatment of patients with such infections should be approached with caution.

Antibiotic-associated diarrhea caused by Clostridium difficile

Cases of antibiotic-associated diarrhea caused by Clostridium difficile, ranging from mild diarrhea to fatal colitis, have been reported with 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 cause antibiotic-associated diarrhea. Some strains produce high levels of toxin, leading to 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 presenting with diarrhea after antibiotic use. A careful medication history is essential, as Clostridium difficile-associated antibiotic-associated diarrhea may occur up to two months after antibiotic administration. If the diagnosis of Clostridium difficile-associated antibiotic-associated diarrhea is suspected or confirmed, antibiotics not active against Clostridium difficile may need to be discontinued.

Depending on clinical presentation, correction of fluid and electrolyte imbalances should be performed, supplementation with protein preparations should be considered, and antibacterial agents effective against Clostridium difficile should be administered. Surgical intervention may also be necessary.

Hypersensitivity (allergic reactions)

Hypersensitivity and allergic reactions may occur even after the first dose of ciprofloxacin (see section "Adverse reactions"), and patients should immediately inform their physician.

In rare cases, anaphylactic/anaphylactoid reactions may progress to life-threatening shock, sometimes after the first dose of ciprofloxacin. In such cases, ciprofloxacin administration must be stopped immediately, and emergency medical treatment initiated.

Prolonged, disabling, and potentially irreversible serious adverse reactions

Very rare, prolonged (months or years), disabling, and potentially irreversible serious adverse reactions affecting various body systems (musculoskeletal, nervous, and sensory systems) 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 medical advice sought.

Tendinitis and tendon rupture

Ciprofloxacin should generally not be used in patients with tendon disorders or a history of quinolone-related tendon disorders. However, in rare cases, after microbiological testing and benefit-risk assessment, ciprofloxacin may be prescribed for treatment of specific severe infections, particularly when standard therapy is ineffective or bacterial resistance exists, and microbiological results justify its use.

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

Patients with myasthenia gravis

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

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

• Risk factors for aortic aneurysm, 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 rupture is increased in patients receiving systemic corticosteroids concomitantly.

Patients experiencing sudden abdominal pain, chest pain, or back pain should seek immediate medical attention in an emergency department.

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

Visual disturbances

If any visual disturbances or ocular adverse reactions occur during treatment, patients 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. Ciprofloxacin should be discontinued if seizures occur (see section "Adive 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 such as pain, burning, tingling, numbness, and/or weakness occur, to prevent 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 or actions, including suicide or suicide attempts. In such cases, ciprofloxacin should be discontinued and appropriate measures 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);
• Unresolved electrolyte imbalance (e.g., hypokalemia, hypomagnesemia);
• Heart disease (e.g., heart failure, myocardial infarction, bradycardia).

Elderly patients and younger women may be more sensitive to QT-prolonging drugs. Therefore, fluoroquinolones, including ciprofloxacin, should be used with caution in these patient groups (see sections "Interaction with other medicinal products and other forms of interaction", "Method of administration and dosage. Elderly patients", "Overdose", "Adverse reactions").

Blood glucose fluctuations

As with other quinolones, fluctuations in blood glucose levels, including hyperglycemia and hypoglycemia, have been reported, particularly in elderly patients and diabetic patients receiving concomitant therapy with oral hypoglycemic agents (e.g., glyburide) 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 therapy), patients should inform their physician, as this symptom may indicate 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 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, dosage adjustment is necessary in patients with impaired renal function (as described in the section "Method of administration and dosage") to avoid increased adverse reactions due to ciprofloxacin accumulation.

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 occur (anorexia, jaundice, dark urine, pruritus, or abdominal wall tension), treatment should be discontinued.

Glucose-6-phosphate dehydrogenase deficiency

Hemolytic reactions have been reported in patients with glucose-6-phosphate dehydrogenase deficiency receiving ciprofloxacin. Ciprofloxacin should be avoided in these patients unless the expected benefit outweighs the potential risk. In such cases, monitoring for possible hemolysis is recommended.

Resistance

Resistant bacteria may be isolated during or after ciprofloxacin therapy, with or without clinically evident superinfection. There is a certain risk of developing ciprofloxacin resistance 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 concomitantly administered substances metabolized by this enzyme (e.g., theophylline, clozapine, olanzapine, ropinirole, tizanidine, duloxetine, agomelatine). Therefore, patients receiving these substances concomitantly 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 forms of interaction"). 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 forms of interaction").

Effect on laboratory test results

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

Injection site reactions

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 transient local skin reactions that resolve quickly after infusion ends. Further intravenous administration is not contraindicated if reactions do not recur or intensify.

Sodium content

Patients on a low-sodium diet (e.g., patients with congestive heart failure, renal failure, or nephrotic syndrome) should be advised about the additional sodium load.

This medicinal product contains:

15.6 mmol (or 359 mg) of sodium per 200 mg dose (100 mL).

Use during pregnancy or breastfeeding.

Pregnancy

Data on ciprofloxacin use in pregnant women show no evidence of malformations or fetal/neonatal toxicity. Animal studies do not indicate direct or indirect toxic effects on reproductive function. However, effects on immature cartilage tissue have been observed in young animals and animals exposed to quinolones before birth, so a potential risk to the joint cartilage of the newborn/fetus cannot be excluded. Therefore, ciprofloxacin use during pregnancy should be avoided.

Breastfeeding period

Ciprofloxacin passes into breast milk. Due to the risk of joint cartilage damage 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.

Dosage and Administration

Dosing

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

The duration of treatment depends on the severity of the disease and the clinical and bacteriological response.

Treatment with ciprofloxacin may be initiated intravenously and continued orally with oral formulations once the patient is able to tolerate oral therapy, 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 cannot 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 therapy with other appropriate antibacterial agents, depending on the causative organism.

Adults

Children

Geriatric patients

Geriatric patients should be prescribed doses according to 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 prior to use. A precipitate may form in the solution at low temperatures, which will redissolve at room temperature (15–25 °C). The medicinal product should be shaken before use. Do not use if the seal is broken or if the container contents are cloudy. 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 portion should be discarded.

Ciprofloxacin should be administered by intravenous infusion. The infusion duration is 60 minutes for children and 30 minutes for adult patients. Slow infusion into a large vein will minimize patient discomfort and reduce the risk of venous irritation.

The ciprofloxacin infusion solution should be administered separately from other medicinal infusion products.

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 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 performed in overdose (e.g., gastric lavage followed by administration of activated charcoal), monitoring of renal function is recommended, including determination of urine pH and, if necessary, acidification of urine to prevent crystalluria. Patients should receive adequate fluid intake. Antacids containing calcium or magnesium may theoretically reduce the absorption of ciprofloxacin 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 parameters should be monitored, as QT interval prolongation may occur.

Adverse reactions.

The most commonly reported adverse reactions to the medicinal product include nausea, diarrhea, vomiting, transient elevations in transaminase levels, rash, and injection site reactions.

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

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

*Rare cases of very 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, limb pain, gait disturbance, neuropathies associated with paresthesia, depression, fatigue, memory impairment, sleep disorders, hearing disorders, visual disturbances, taste and smell disturbances) have been reported in association with the use of quinolones and fluoroquinolones, regardless of the presence of risk factors (see section "Special precautions").

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

Description of individual adverse reactions.

Anxiety, suicidal thoughts, panic attacks, neuralgia, and attention disturbances as potential features of prolonged and disabling fluoroquinolone-induced adverse reactions.

The undesirable effects listed below occur with higher frequency in subgroups of patients who received intravenous or step-down (switch from intravenous to oral) therapy:

Children

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

Reporting of suspected adverse reactions

Reporting of adverse reactions after drug authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of this medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions.

Store at a temperature not exceeding 25 °C in the original packaging. Do not freeze.

Keep out of reach of children.

Incompatibilities.

This medicinal product must not be mixed with other medicinal products.

Packaging.

100 ml or 200 ml of the preparation in a polyvinyl chloride container (each container additionally packed in a polymer film); 1 container per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Subsidiary enterprise "Pharmatrade".

Manufacturer's address and location of operations.

85 Sambirska Street, Drohobych, Lviv Oblast, 82111, Ukraine.

Marketing Authorization Holder.

Subsidiary enterprise "Pharmatrade".

Pharmacovigilance contact person at State Enterprise Pharmatrade, tel.: (03244) 3-99-94 or e-mail: [email protected] (for reporting suspected adverse reactions and lack of efficacy).

Address of the Marketing Authorization Holder and/or its representative.

85 Sambirska Street, Drohobych, Lviv Oblast, 82111, Ukraine.