CIPROFLOXACIN

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

Composition:

Active substance: ciprofloxacin;

1 tablet contains 250 mg of ciprofloxacin;

Excipients: maize starch, microcrystalline cellulose, povidone, colloidal anhydrous silicon dioxide, magnesium stearate, macrogol 6000 (polyethylene glycol 6000), dry mixture "Opadry II white" containing titanium dioxide (E 171), talc, polyethylene glycol, polyvinyl alcohol.

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics: film-coated tablets of white with slightly yellowish hue color.

Pharmacotherapeutic group. Antibacterials for systemic use. Fluoroquinolone group. ATC code J01M A02.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action. The bactericidal effect of ciprofloxacin, a fluoroquinolone antibacterial agent, is due to its ability to inhibit type II topoisomerases (DNA gyrase and topoisomerase IV), which are essential in several DNA life cycle processes such as replication, transcription, repair, and recombination.

Pharmacokinetic/pharmacodynamic relationships. Efficacy is primarily dependent on the ratio between the maximum serum concentration (Cmax) and the minimum inhibitory concentration (MIC) of ciprofloxacin for the bacterial pathogen, as well as on the area under the concentration-time curve (AUC) relative to the MIC.

Mechanism of resistance. Resistance to ciprofloxacin in vitro is usually associated with target-site mutations occurring in topoisomerase IV and DNA gyrase through multiple-step mutations. The extent of cross-resistance between ciprofloxacin and other fluoroquinolones resulting from the above mechanisms may vary. Single mutations generally do not lead to clinical resistance, whereas multiple mutations typically result in clinical resistance to several or all fluoroquinolone class members. Resistance mechanisms such as reduced permeability and/or efflux pumps may differentially affect susceptibility to fluoroquinolones, depending on the physicochemical properties of individual agents within this class and the affinity of transport systems for each active substance. All resistance mechanisms observed in vitro are generally found in clinical isolates. Resistance mechanisms that inactivate other antibacterial agents, such as permeability barriers (inherent in Pseudomonas aeruginosa) and efflux mechanisms, may also influence susceptibility to ciprofloxacin.

Plasmid-mediated resistance encoded by the qnr gene has been reported.

Spectrum of antibacterial activity. Breakpoints distinguish susceptible strains from strains with intermediate susceptibility, and the latter from resistant strains.

Microorganism susceptibility according to European Committee on Antimicrobial Susceptibility Testing (EUCAST) criteria

The prevalence of acquired resistance in isolated species may vary depending on the geographical region and time; therefore, local information on resistance is necessary, especially when treating severe infections. When the local prevalence of resistance reaches a level that makes the benefit of using the drug at least questionable for certain types of infections, consultation with specialists should be sought.

Generally, the following bacterial genera and species are susceptible to ciprofloxacin (for the genus Streptococcus, see section "Special precautions for use").

Preclinical safety data. No special hazard to humans was identified based on standard single-dose toxicity, repeated-dose toxicity, carcinogenic potential, or reproductive toxicity studies.

Pharmacokinetics.

Absorption. After oral administration of 250 mg, 500 mg, and 750 mg ciprofloxacin tablets, ciprofloxacin is rapidly and well absorbed, primarily from the upper part of the small intestine. Maximum serum concentrations are reached within 1–2 hours.

Single doses ranging from 100 to 750 mg resulted in dose-dependent peak serum concentrations (Cmax) between 0.56 and 3.7 mg/L. Serum concentrations increase proportionally with doses up to 1000 mg.

The absolute bioavailability of the drug is 70–80%. An oral dose of 500 mg ciprofloxacin every 12 hours results in a total area under the concentration-time curve (AUC) equivalent to that achieved after intravenous infusion of 400 mg ciprofloxacin administered over 60 minutes every 12 hours.

Distribution. The percentage of ciprofloxacin protein binding in blood is low (20–30%). Ciprofloxacin is predominantly present in plasma in its non-ionized form and has a large steady-state volume of distribution of 2–3 L/kg body weight. It achieves high concentrations in various tissues, such as lungs (epithelial lining fluid, alveolar macrophages, biopsy specimens), sinuses, inflamed and damaged tissues, and tissues of the genitourinary tract (urine, prostate, endometrium), where total concentrations exceed those in plasma.

Biotransformation. Low concentrations of four metabolites have been detected: desethyleneciprofloxacin (M1), sulfociprofloxacin (M2), oxociprofloxacin (M3), and formylciprofloxacin (M4). The metabolites exhibit antimicrobial activity in vitro, but to a lesser extent than the parent compound.

Ciprofloxacin is known to be a moderate inhibitor of the CYP450 1A2 isoenzymes.

Elimination. Ciprofloxacin is primarily excreted unchanged by the kidneys, with a smaller portion eliminated via the intestine. The plasma elimination half-life in individuals with normal renal function is approximately 4–7 hours.

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

Non-renal clearance of ciprofloxacin is primarily due to transintestinal secretion and metabolism. One percent (1%) of the dose is excreted via the biliary tract. Ciprofloxacin is present in high concentrations in bile.

Children. Pharmacokinetic data in children are limited. In studies involving children, no age-dependent differences in Cmax or AUC were observed (in children aged 1 year and older). After repeated administration (10 mg/kg three times daily), no significant increase in Cmax and AUC was observed. In ten infants under 1 year of age with severe sepsis, Cmax was 6.1 mg/L (range: 4.6–8.3 mg/L) after a one-hour intravenous infusion 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: 11.0–23.8 mg*h/L), respectively, in the corresponding 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 average 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 infections listed below (see 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 when caused by Gram-negative bacteria*.
• Urinary tract infections:
  • uncomplicated acute cystitis*;
  • acute pyelonephritis;
  • complicated urinary tract infections;
  • bacterial prostatitis.
• Genital tract infections:
  • gonococcal urethritis and cervicitis caused by susceptible strains of Neisseria gonorrhoeae;
  • orchioepididymitis, particularly caused by susceptible strains of Neisseria gonorrhoeae;
  • pelvic inflammatory disease, particularly 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.
• Bone and joint infections.
• Pulmonary form of anthrax (post-exposure prophylaxis and definitive treatment).
• Fever in neutropenic patients caused by bacterial infection.

Ciprofloxacin may be used in the management of neutropenic patients with fever when a bacterial infectious etiology is suspected in this patient population.

Children and adolescents

• Bronchopulmonary infections caused by Pseudomonas aeruginosa in patients with cystic fibrosis.
• Complicated urinary tract infections and acute pyelonephritis.
• Pulmonary form of 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.

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

Contraindications.

Hypersensitivity to the active substance or to other fluoroquinolone antibiotics, or to any of the excipients of the medicinal product.

Concomitant administration of ciprofloxacin and tizanidine is contraindicated.

Interaction with other medicinal products and other forms of interaction.

Effect of other medicinal products on ciprofloxacin

QT-prolonging agents. 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, antipsychotics).

Chelation. Concomitant administration of ciprofloxacin (oral) with medicinal products containing polyvalent cations, mineral supplements (e.g., calcium, magnesium, aluminium, iron), phosphate binders (e.g., sevelamer or lanthanum carbonate), sucralfate, or antacids, as well as medicinal products with high buffering capacity (such as didanosine tablets) containing magnesium, aluminium, or calcium reduces the absorption of ciprofloxacin. Therefore, ciprofloxacin should be taken either 1–2 hours before or at least 4 hours after administration of these products.

This restriction does not apply to medicinal products belonging to the class of H2-receptor blockers.

Food and dairy products. Calcium in food has a minor effect on absorption. However, simultaneous intake of ciprofloxacin with dairy or mineral-fortified products (such as milk, yogurt, or calcium-fortified orange juice) should be avoided, as absorption of ciprofloxacin may be reduced.

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

Metoclopramide. Metoclopramide accelerates the absorption of oral ciprofloxacin, resulting in a faster attainment of peak plasma concentration. No effect on the bioavailability of ciprofloxacin has been observed.

Omeprazole. Concomitant administration of ciprofloxacin and medicinal products containing omeprazole results in a slight reduction in Cmax and AUC of ciprofloxacin.

Effect of ciprofloxacin on other medicinal products

Tizanidine. Tizanidine must not be administered concomitantly with ciprofloxacin. 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). Elevated plasma concentrations of tizanidine are associated with hypotensive and sedative adverse reactions.

MTX (Methotrexate). Concomitant administration of ciprofloxacin may slow tubular transport of methotrexate, potentially leading to increased plasma concentrations of methotrexate. This may increase the risk of methotrexate-induced toxic side effects; therefore, concomitant use is not recommended.

Theophylline. Concomitant administration of ciprofloxacin and theophylline may lead to an undesirable increase in theophylline plasma concentrations, which may result in adverse reactions. In isolated cases, such adverse reactions may be life-threatening or fatal. Therefore, when ciprofloxacin and theophylline are used concomitantly, serum theophylline concentrations should be monitored and the dose adjusted as necessary.

Other xanthine derivatives. Increased serum concentrations of caffeine or pentoxifylline (oxpentifylline) have been reported after concomitant administration with ciprofloxacin.

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

Cyclosporine. Transient increases in serum creatinine have been observed with concomitant administration of ciprofloxacin and cyclosporine-containing medicinal products. Therefore, frequent monitoring (twice weekly) of serum creatinine concentrations is required in these patients.

Vitamin K antagonists. Concomitant administration of ciprofloxacin and vitamin K antagonists may potentiate their anticoagulant effect. The degree of risk may vary depending on the underlying type of 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 recommended during and immediately after concomitant use of ciprofloxacin and vitamin K antagonists (e.g., warfarin, acenocoumarol, phenprocoumon, fluindione).

Duloxetine. It is known that concomitant administration of duloxetine with strong CYP450 1A2 inhibitors, such as fluvoxamine, may increase 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.

Ropinirole. It is known that concomitant administration of ropinirole with ciprofloxacin, a moderate inhibitor of CYP450 1A2 isoenzyme, increases 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 concomitant use with ciprofloxacin.

Lidocaine. In healthy subjects, concomitant administration of ciprofloxacin, a moderate inhibitor of cytochrome P450 1A2 isoenzymes, and lidocaine-containing medicinal products has been shown to reduce the clearance of intravenous lidocaine by 22%. Despite normal tolerability of lidocaine treatment, interaction with ciprofloxacin associated with adverse reactions may occur when these agents are used concomitantly.

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 use with ciprofloxacin.

Sildenafil. Cmax and AUC of sildenafil increased approximately 2-fold in healthy volunteers after concomitant oral administration of 50 mg sildenafil and 500 mg ciprofloxacin. Therefore, caution should be exercised when co-prescribing ciprofloxacin with sildenafil, and the benefit-risk ratio should be carefully considered.

Special precautions for use.

The use of ciprofloxacin should be avoided in patients who have previously experienced serious adverse reactions to quinolones or fluoroquinolones. Treatment with ciprofloxacin in such patients should be initiated only if no alternative treatment options are available and after careful benefit/risk assessment.

Severe and/or 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. For treatment of such infections, 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. Fluoroquinolone-resistant strains of Neisseria gonorrhoeae may cause gonococcal urethritis, cervicitis, orchiepididymitis, and pelvic inflammatory disease.

Therefore, ciprofloxacin should be used for the treatment of gonococcal urethritis or cervicitis only if resistance of Neisseria gonorrhoeae to ciprofloxacin has been ruled out.

Empirical therapy with ciprofloxacin for orchiepididymitis and pelvic inflammatory disease may be used only in combination with other appropriate antibacterial agents (e.g., cephalosporins), except in clinical situations where ciprofloxacin-resistant strains of Neisseria gonorrhoeae have been excluded.

If there is no clinical improvement within 3 days, the therapy should be reassessed.

Urinary tract infections. In European countries, there is variable resistance of Escherichia coli, the most common pathogen causing urinary tract infections, to fluoroquinolones. Physicians are advised to consider local prevalence of fluoroquinolone resistance in Escherichia coli when prescribing therapy.

Single-dose regimens of ciprofloxacin used in uncomplicated cystitis in premenopausal women are considered less effective than longer treatment courses. This should be taken into account, especially in light of the increasing resistance of Escherichia coli to quinolones.

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 on resistance to ciprofloxacin of relevant microorganisms in the countries visited should be considered.

Bone and joint infections. Ciprofloxacin should be used in combination with other antimicrobial agents based on microbiological test results.

Pulmonary form of anthrax. Use in humans is based on in vitro susceptibility data, animal studies, and limited human experience. The physician should act in accordance with national and/or international treatment guidelines for anthrax.

Respiratory tract infections in cystic fibrosis. Clinical trials have included children and adolescents aged 5–17 years. Experience in treating children aged 1–5 years is more limited.

Complicated urinary tract infections and pyelonephritis. Treatment of urinary tract infections with ciprofloxacin should be considered only when other treatments are not feasible. Therapy should be based on microbiological test results.

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

Other specific severe infections. Use of ciprofloxacin 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 possible or standard therapy has failed.

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

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

Therefore, fluoroquinolones should be used only after careful benefit/risk assessment and consideration of alternative therapies in patients with a history of aortic aneurysm or congenital heart valve defects, or diagnosed with aortic aneurysm and/or dissection, or with heart valve disease, or in the presence of other risk factors or predisposing conditions:

• for aortic aneurysm and dissection, and valvular regurgitation/insufficiency (e.g., connective tissue disorders such as Marfan syndrome or Ehlers-Danlos syndrome, Turner syndrome, Behçet's disease, arterial hypertension, rheumatoid arthritis), or additionally
• for aortic aneurysm and dissection (e.g., vascular disorders such as Takayasu arteritis or giant cell arteritis, or atherosclerosis, or Sjögren's syndrome), or additionally
• for valvular regurgitation/insufficiency (e.g., infective endocarditis). The risk of aortic aneurysm and dissection and their rupture may be increased in patients concurrently receiving systemic corticosteroids.

Patients should seek immediate medical attention at an emergency department if they experience sudden abdominal, chest, or back pain.

Patients should be advised to seek immediate medical help if they develop acute shortness of breath, new palpitations, or onset of abdominal or lower limb edema.

Hypersensitivity to the drug. Hypersensitivity and allergic reactions, including anaphylactic/anaphylactoid reactions, may occur after a single dose of ciprofloxacin (see section "Adverse reactions") and may be life-threatening. In such cases, ciprofloxacin must be discontinued and appropriate medical treatment initiated if necessary.

Musculoskeletal system. Generally, ciprofloxacin should not be used in patients with a history of tendon disorders associated with quinolone use. Nevertheless, in rare cases, after microbiological testing and benefit/risk assessment, ciprofloxacin may be prescribed for the treatment of certain severe infections—specifically when standard therapy is ineffective or bacterial resistance exists, and microbiological results justify its use. Tendinitis or tendon rupture (especially, but not limited to, Achilles tendon), sometimes bilateral, may occur during ciprofloxacin therapy, even within the first 48 hours of treatment. Inflammation or rupture of tendons may occur even several months after completion of ciprofloxacin therapy. The risk of tendinopathy may be increased in elderly patients, patients with renal impairment, transplant recipients, and patients concurrently receiving corticosteroids. If any signs of tendinitis (e.g., painful swelling, inflammation) occur, ciprofloxacin should be discontinued and alternative therapy considered. Appropriate management of the affected limb (e.g., immobilization) is required. Corticosteroids should not be used if signs of tendinopathy occur.

Ciprofloxacin should be used with caution in patients with myasthenia gravis due to the potential for worsening of symptoms.

Photosensitivity. Ciprofloxacin has been shown to cause photosensitivity reactions. Patients receiving ciprofloxacin are advised to avoid direct sunlight or UV radiation during treatment.

Central nervous system (CNS). Ciprofloxacin, like other quinolones, may cause seizures or lower the seizure threshold. Cases of status epilepticus have been reported. Ciprofloxacin should be used with caution in patients with CNS disorders that may predispose to seizures. If seizures occur, ciprofloxacin should be discontinued. Psychotic reactions may occur even after the first dose of ciprofloxacin. In isolated cases, depression or psychosis may progress to suicidal thoughts and actions, including suicide or attempted suicide. In such cases, ciprofloxacin should be discontinued.

Cases of sensory or sensorimotor polyneuropathy, leading to paresthesia, hypoesthesia, dysesthesia, or weakness, have been reported in patients receiving ciprofloxacin. Patients should be instructed to inform their physician immediately if symptoms of neuropathy develop (e.g., pain, burning, tingling, numbness, or weakness) during treatment to prevent progression to irreversible conditions.

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

• congenital long QT syndrome;
• concomitant use of drugs that may prolong the QT interval (e.g., class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, neuroleptics);
• uncorrected electrolyte imbalances (e.g., hypokalemia, hypomagnesemia);
• presence of cardiac conditions (e.g., heart failure, myocardial infarction, bradycardia).

Elderly patients and women may be more sensitive to drugs that prolong the QTc interval. Therefore, fluoroquinolones, including ciprofloxacin, should be used with caution in these patient groups.

Dysglycemia. As with other quinolones, disturbances in blood glucose levels, including both hypoglycemia and hyperglycemia (see section "Adverse reactions"), have been reported, usually in diabetic patients receiving concomitant therapy with oral hypoglycemic agents (e.g., glyburide) or insulin. Cases of hypoglycemic coma have been reported. Close monitoring of blood glucose levels is recommended in all diabetic patients.

Gastrointestinal tract. The occurrence of severe and persistent diarrhea during or after treatment (even weeks after therapy) may indicate antibiotic-associated colitis (a potentially life-threatening condition with possible fatal outcome) and requires immediate treatment. In such cases, ciprofloxacin should be discontinued and appropriate therapy initiated. Antiperistaltic agents are contraindicated in this clinical situation.

Kidneys and urinary system. Crystalluria associated with ciprofloxacin use has been reported. Patients taking ciprofloxacin should maintain 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 required in patients with impaired renal function according to the recommendations in the "Dosage and administration" section to avoid increased frequency of adverse reactions due to ciprofloxacin accumulation.

Hepatobiliary system. Cases of hepatic necrosis and life-threatening liver failure have been reported with ciprofloxacin use. If any signs or symptoms of liver disease occur (e.g., anorexia, jaundice, dark urine, pruritus, or abdominal distension), treatment should be discontinued.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency. Hemolytic reactions have been reported in patients with G6PD deficiency receiving ciprofloxacin. Ciprofloxacin should be avoided in such patients unless the potential benefit outweighs the potential risk. In such cases, patients should be monitored for possible hemolysis.

Resistance. Resistant bacteria may be isolated during or after ciprofloxacin therapy, with or without clinically evident superinfection. There may be an increased risk of isolating ciprofloxacin-resistant bacteria during prolonged treatment courses and in the treatment of nosocomial infections and/or infections caused by Staphylococcus and Pseudomonas species.

Cytochrome P450. Ciprofloxacin inhibits CYP1A2 and may therefore increase serum concentrations of concurrently administered drugs metabolized by this enzyme (e.g., theophylline, clozapine, olanzapine, ropinirole, tizanidine, duloxetine). Concomitant use of ciprofloxacin and tizanidine is contraindicated. Therefore, patients receiving these drugs concomitantly with ciprofloxacin should be closely monitored for possible signs of overdose. Serum concentration monitoring (e.g., theophylline) may also be necessary.

Methotrexate. Concomitant use of ciprofloxacin and methotrexate is not recommended.

Effect on laboratory test results. In vitro, ciprofloxacin may affect results of Mycobacterium tuberculosis culture by inhibiting mycobacterial growth, potentially leading to false-negative culture results in patients taking ciprofloxacin.

Prolonged, disabling, and potentially irreversible serious adverse reactions. Very rare cases of prolonged (months or years), disabling, and potentially irreversible serious adverse reactions affecting various, sometimes multiple organ systems (musculoskeletal, nervous system, psychiatric, and sensory organs) have been reported in patients receiving quinolones and fluoroquinolones, regardless of age or risk factors.

Ciprofloxacin should be discontinued immediately at the first signs or symptoms of any serious adverse reaction. Patients should consult their physician.

Use during pregnancy or breastfeeding.

Pregnancy. Data on the use of ciprofloxacin 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 have been observed in young animals exposed to quinolones before birth, so the possibility that the drug may be harmful to the joint cartilage of newborns/fetus cannot be excluded. Therefore, to prevent potential adverse effects on the fetus, ciprofloxacin should be avoided during pregnancy.

Lactation. Ciprofloxacin is excreted in breast milk. Due to the potential 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 affect a patient's ability to drive or operate machinery due to nervous system reactions (see section "Adverse reactions"). Therefore, the ability to drive or operate machinery may be impaired.

Method of administration and dosage.

The dosage should be determined according to the indication, severity and site of infection, pathogen (pathogens) susceptibility to ciprofloxacin, patient's renal function, and in children and adolescents — according to body weight.

Duration of treatment depends on the severity of the disease, specific features of the clinical picture, and the type of pathogen.

Treatment of infections caused by certain bacteria (e.g., Pseudomonas aeruginosa, Acinetobacter, or Staphylococci) may require administration of higher doses of ciprofloxacin and concomitant use of other necessary antibacterial agents.

Treatment of certain infections (e.g., pelvic inflammatory disease, intra-abdominal infections, infections in neutropenic patients, bone and joint infections) may require concomitant administration of other necessary antibacterial agents depending on the type of identified pathogens.

Adults

Children and adolescents

Geriatric patients. Geriatric patients should receive a dose selected according to the severity of infection and the patient's creatinine clearance.

Renal and hepatic impairment. Recommended initial and maintenance doses for patients with impaired renal function:

For patients with hepatic insufficiency, there is no need to adjust the dosage of ciprofloxacin.

Dosage studies of ciprofloxacin in children with impaired renal and/or hepatic function have not been conducted.

Method of administration. Tablets should be swallowed whole with liquid without chewing. They may be taken independently of food intake. When administered on an empty stomach, the active substance is absorbed more rapidly. Ciprofloxacin tablets must not be taken together with dairy products (e.g., milk, yogurt) or fruit juices fortified with minerals (e.g., calcium-fortified orange juice) (see section "Interaction with other medicinal products and other types of interactions").

In severe cases or when the patient is unable to take tablets (e.g., during enteral nutrition), initiation of therapy with intravenous ciprofloxacin is recommended until oral administration becomes feasible.

Children. The use of ciprofloxacin in children and adolescents should be carried out in accordance with current official recommendations. Treatment with ciprofloxacin should be administered 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. Safety data from a randomized, double-blind study in children (ciprofloxacin: n = 335, mean age = 6.3 years; comparator group: n = 349, mean age = 6.2 years; age range: 1 to 17 years) showed an incidence of arthropathy likely related to drug exposure (differing from clinical signs and symptoms directly related to joint involvement) of 7.2% and 4.6% in the ciprofloxacin and comparator groups, respectively, by day 42 of treatment. The incidence of drug-related arthropathy at 1 year of follow-up was 9% and 5.7%, respectively. The increase in arthropathy cases related to drug exposure was not statistically significant. However, treatment of children and adolescents with ciprofloxacin should only be initiated after careful assessment of the benefit-risk ratio due to the risk of developing adverse reactions affecting joints and/or surrounding tissues.

Overdose.

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

Symptoms of overdose include dizziness, tremor, headache, increased fatigue, seizures, hallucinations, confusion, abdominal discomfort, renal and hepatic failure, as well as crystalluria and hematuria. Reversible renal toxicity has also been reported.

In addition to standard emergency measures for overdose, 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 absorption of ciprofloxacin in overdose.

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

In cases of overdose, symptomatic treatment should be administered. Due to the potential for QT interval prolongation, ECG monitoring is also advisable.

Adverse Reactions

The most commonly reported adverse reactions were nausea and diarrhea. Data on adverse reactions to ciprofloxacin from clinical trials and post-marketing surveillance (oral, intravenous, and sequential administration) are listed below.

Infections and infestations: Fungal superinfections, antibiotic-associated colitis (very rare – with potentially fatal outcome).

Blood and lymphatic system disorders: Eosinophilia, leukopenia, anemia, neutropenia, leukocytosis, thrombocytopenia, thrombocytosis, hemolytic anemia, agranulocytosis, pancytopenia (life-threatening), bone marrow suppression (life-threatening).

Immune system disorders: Allergic reactions, allergic/angioneurotic edema, anaphylactic reactions, anaphylactic shock (life-threatening), serum sickness-like reactions.

Endocrine system disorders: Syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Metabolism and nutrition disorders: Decreased appetite, hyperglycemia, hypoglycemia, hypoglycemic coma (see section "Special Warnings and Precautions for Use").

Psychiatric disorders*: Psychomotor agitation/anxiety, confusion and disorientation, restlessness, abnormal dreams, depression (with possible suicidal thoughts/ideation or suicide attempts/acts), hallucinations, psychotic reactions (with possible suicidal thoughts/ideation or suicide attempts/acts).

Nervous system disorders*: Headache, dizziness, sleep disturbances, taste disturbances, paresthesia and dysesthesia, hypoesthesia, tremor, convulsions (including epileptic status), migraine, coordination disturbances, gait disturbances, smell disturbances, intracranial hypertension and pseudotumor cerebri, peripheral neuropathy and polyneuropathy.

Eye disorders*: Visual disturbances (e.g., diplopia), color vision disturbances.

Ear and labyrinth disorders*: Tinnitus, hearing loss/hearing impairment.

Cardiac disorders**: Tachycardia, ventricular arrhythmia and torsades de pointes (observed predominantly in patients with risk factors for QT interval prolongation), QT interval prolongation.

Vascular disorders**: Vasodilation, hypotension, syncope, vasculitis.

Respiratory, thoracic and mediastinal disorders: Dyspnea (including asthmatic conditions).

Gastrointestinal disorders: Nausea, diarrhea, vomiting, epigastric and intestinal pain, abdominal pain, dyspepsia, flatulence, pancreatitis.

Hepatobiliary disorders: Increased levels of transaminases and bilirubin, liver function abnormalities, cholestatic jaundice, hepatitis, hepatic necrosis (rarely progressing to life-threatening liver failure).

Skin and subcutaneous tissue disorders: Rash, pruritus, urticaria, photosensitivity reactions, petechiae, erythema multiforme, nodular erythema, Stevens-Johnson syndrome (potentially life-threatening), toxic epidermal necrolysis (potentially life-threatening), acute generalized exanthematous pustulosis (AGEP).

Musculoskeletal and connective tissue disorders*: Musculoskeletal pain (e.g., limb pain, back pain, chest pain), arthralgia, myalgia, arthritis, increased muscle tone and muscle spasms, muscle weakness, tendinitis, tendon rupture (predominantly Achilles tendons), exacerbation of symptoms of myasthenia gravis.

Renal and urinary disorders: Renal function abnormalities, renal failure, hematuria, crystalluria, tubulointerstitial nephritis.

General disorders*: Asthenia, fever, edema, increased sweating (hyperhidrosis).

Investigations: Increased alkaline phosphatase activity in blood, increased amylase activity, increased INR (in patients concurrently taking vitamin K antagonists).

* With quinolone and fluoroquinolone use, very rare cases of long-term (lasting several months or years) disability and potentially irreversible serious adverse reactions affecting various organ systems, sometimes multiple systems, have been observed regardless of the presence of risk factors (including such reactions as tendinitis, tendon rupture, arthralgia, limb pain, gait disturbances, neuropathies associated with paresthesia and neuralgia, depression, fatigue, anxiety, panic attacks, suicidal thoughts, memory and concentration disturbances, sleep disturbances, hearing, vision, taste, and smell disturbances).

** Cases of aneurysm and aortic dissection, sometimes complicated by rupture (including fatal cases), and regurgitation/insufficiency of any cardiac valve have been reported in patients receiving fluoroquinolones (see section "Special Warnings and Precautions for Use").

Reporting suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals should report any suspected adverse reactions.

Shelf life. 3 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging. 10 tablets in a blister pack, 1 blister pack per carton.

Prescription status. Prescription only.

Manufacturer.

Limited Liability Company "Experimental Plant 'GNCLS'".

LIMITED LIABILITY COMPANY "CORPORATION 'ZDOROVIYA'".

Address of the manufacturer and location of business activity.

Ukraine, 61057, Kharkiv region, city of Kharkiv, Vorobiova Street, 8.

(Limited Liability Company "Experimental Plant 'GNCLS')

Ukraine, 61013, Kharkiv region, city of Kharkiv, Shevchenka Street, 22.

(LIMITED LIABILITY COMPANY "CORPORATION 'ZDOROVIYA')