Flaproks

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

Composition:

Active substance: ciprofloxacin;

1 tablet contains 500 mg of ciprofloxacin (in the form of ciprofloxacin hydrochloride monohydrate);

Excipients: microcrystalline cellulose, corn starch, crospovidone, sodium croscarmellose, colloidal anhydrous silicon dioxide, magnesium stearate;

Film coating: Opadry White (hypromellose, polyethylene glycol, titanium dioxide (E 171)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white, round, biconvex film-coated tablets with a break line on one side.

Pharmacotherapeutic group.

Antibacterial agents for systemic use. Fluoroquinolone group. ATC code J01M A02.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action.

The bactericidal activity 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 primarily depends 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 curve (AUC) to MIC ratio.

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-mentioned mechanisms may vary. Single mutations generally do not lead to clinical resistance, whereas multiple mutations usually result in clinical resistance to several or all fluoroquinolone agents.

Resistance mechanisms such as impermeability 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 in vitro resistance mechanisms are generally observed in clinical isolates. Resistance mechanisms that inactivate other antibacterial agents, such as permeability barriers (characteristic of 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.

EUCAST recommendations

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

The following bacterial genera and species are generally susceptible to ciprofloxacin (for the genus Streptococcus, see section "Special instructions").

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 Cmax values between 0.56 and 3.7 mg/L. Serum concentrations increase proportionally at doses up to 1000 mg.

The absolute bioavailability of the drug is 70–80%. An oral dose of ciprofloxacin 500 mg every 12 hours results in an 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 is low (20–30%). Ciprofloxacin is present in blood plasma predominantly in the 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.

Metabolism.

Low concentrations of four metabolites have been observed: desethylene-ciprofloxacin (M1), sulfociprofloxacin (M2), oxociprofloxacin (M3), and formylciprofloxacin (M4). These 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.

Excretion.

Ciprofloxacin is excreted predominantly unchanged by the kidneys and to a lesser extent via the gastrointestinal tract. The elimination half-life in plasma in individuals with normal renal function is approximately 4–7 hours.

Renal clearance is 180–300 mL/kg/hr, and total clearance is 480–600 mL/kg/hr. 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 attributed 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 pediatric patients, no age-dependent differences in Cmax and AUC were observed (in children aged 1 year and older). Following 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*hr/L (range: 11.8–32.0 mg*hr/L) and 16.5 mg*hr/L (range: 11–23.8 mg*hr/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.

The drug is indicated for the treatment of the following infections (see sections "Special precautions for use" and "Pharmacological properties").

Before initiating therapy, particular attention should be paid to all available information regarding resistance to ciprofloxacin.

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

Adults.

• Lower respiratory tract infections caused by Gram-negative bacteria:

  • acute exacerbation of chronic obstructive pulmonary disease*;
  • bronchopulmonary infections in cystic fibrosis or bronchiectasis;
  • community-acquired pneumonia.

• Chronic suppurative otitis media.

• Acute exacerbation of chronic sinusitis, especially if 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;
  • epididymo-orchitis, particularly caused by susceptible strains of Neisseria gonorrhoeae;
  • pelvic inflammatory disease, particularly caused by susceptible strains of Neisseria gonorrhoeae.

• Gastrointestinal tract infections (e.g., traveler's diarrhea).

• Intra-abdominal infections.

• Skin and soft tissue infections caused by Gram-negative bacteria.

• Severe external otitis.

• Bone and joint infections.

• Prophylaxis of invasive infections caused by Neisseria meningitidis.

• Inhalational anthrax (post-exposure prophylaxis and definitive treatment).

Ciprofloxacin may be used for the management of febrile neutropenic patients with suspected bacterial etiology of fever in this patient group.

* Only when it has been determined that other antibacterial agents typically used for treatment of such infections are ineffective or inappropriate.

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 deemed necessary by the physician.

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

Contraindications.

• Hypersensitivity to the active substance, to other drugs of the fluoroquinolone group, 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.

QT-prolonging agents – concomitant use with ciprofloxacin may result in QT interval prolongation. Concomitant use with agents that prolong the QT interval (e.g., class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) should be undertaken with caution (see section "Special precautions for use").

Chelate formation – concomitant oral administration of ciprofloxacin with medicinal products containing multivalent cations and mineral supplements (e.g., calcium, magnesium, aluminium, iron), phosphate binders (e.g., sevelamer or lanthanum carbonate), sucralfate, antacids, or buffered medicinal products (such as didanosine tablets) containing magnesium, aluminium, or calcium reduces ciprofloxacin absorption. 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 H2-receptor antagonists.

Food and dairy products.

Calcium in food products slightly reduces ciprofloxacin absorption (oral). Therefore, the drug may be taken with dairy or mineral-fortified beverages. However, administration of ciprofloxacin together with dairy or mineral-fortified beverages (such as milk, yogurt, or calcium-enriched orange juice) consumed separately from food may reduce ciprofloxacin absorption. Therefore, the drug should be taken either 1–2 hours before or at least 4 hours after consumption of dairy or mineral-fortified beverages taken separately from food (see section "Dosage and administration").

Probenecid – concomitant administration with ciprofloxacin may increase plasma levels of the latter.

Metoclopramide – concomitant administration with ciprofloxacin may accelerate absorption (oral form), resulting in faster achievement of maximum plasma concentration. No effect on ciprofloxacin bioavailability has been observed.

Omeprazole – concomitant administration with ciprofloxacin may result in a slight reduction in Cmax and AUC of the latter.

Tizanidine – in a clinical study involving healthy volunteers, concomitant administration of ciprofloxacin and tizanidine resulted in increased plasma levels of tizanidine (7-fold increase in Cmax, range 4–21 times; 10-fold increase in AUC, range 6–24 times). Increased plasma concentrations of tizanidine are associated with hypotensive and sedative adverse reactions. Concomitant administration of these agents is contraindicated.

MTX (Methotrexate) – concomitant administration with ciprofloxacin may increase methotrexate plasma levels, increasing the risk of methotrexate-induced toxic adverse reactions. Concomitant use of these agents is not recommended (see section "Special precautions for use").

Theophylline – concomitant administration with ciprofloxacin may increase theophylline plasma levels, potentially leading to adverse reactions. In isolated cases, such adverse reactions may be life-threatening or fatal. When these agents are used concomitantly, monitoring of theophylline plasma levels is recommended, with dose adjustment if necessary (see section "Special precautions for use").

Other xanthine derivatives – increased plasma levels of xanthine derivatives (e.g., caffeine, pentoxifylline [oxpentifylline]) have been reported after concomitant administration with ciprofloxacin.

Cyclosporine – transient increases in plasma creatinine have been observed with concomitant administration of ciprofloxacin and cyclosporine-containing medicinal products. Frequent monitoring (twice weekly) of plasma creatinine levels is recommended when these agents are used concomitantly.

Phenytoin – concomitant administration with ciprofloxacin may increase phenytoin plasma levels. Monitoring of phenytoin plasma levels is recommended when these agents are used concomitantly.

Vitamin K antagonists – concomitant administration with ciprofloxacin may enhance anticoagulant effects. The degree of risk may vary depending on the type of infection, age, and general condition of the patient, making it difficult to precisely assess the impact of ciprofloxacin on International Normalized Ratio (INR) elevation. 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 – clinical studies have shown that concomitant administration of duloxetine with strong CYP450 1A2 inhibitors, such as fluvoxamine, may increase duloxetine AUC and Cmax. 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").

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

Lidocaine – in healthy subjects, concomitant administration of ciprofloxacin (a moderate inhibitor of cytochrome P450 1A2 isoenzymes) and lidocaine-containing medicinal products reduced intravenous lidocaine clearance by 22%. Despite normal tolerability of lidocaine treatment, interaction with ciprofloxacin associated with adverse reactions cannot be excluded when these agents are used concomitantly.

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

Sildenafil – after concomitant administration of 50 mg sildenafil and 500 mg ciprofloxacin, sildenafil Cmax and AUC increased approximately twofold in healthy volunteers. Caution should be exercised and the risk/benefit ratio considered when these agents are used concomitantly.

Zolpidem – concomitant administration with ciprofloxacin may increase zolpidem plasma levels. Concomitant use of these agents is not recommended.

Agomelatine – clinical studies have shown that fluvoxamine (a strong inhibitor of CYP450 1A2 isoenzyme) markedly inhibits agomelatine metabolism, increasing its exposure by 60-fold. Although there are no clinical data on potential interaction with ciprofloxacin (a moderate inhibitor of CYP450 1A2 isoenzyme), similar effects may be expected when these agents are used concomitantly (see section "Special precautions for use").

Special precautions for use.

The use of ciprofloxacin should be avoided in patients with serious adverse reactions to quinolones or fluoroquinolone-containing agents in their medical history (see section "Adverse reactions"). Treatment with ciprofloxacin should be initiated only if no alternative therapy is available and after careful benefit-risk assessment (see also section "Contraindications").

Use in 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.

Use in streptococcal infections (including Streptococcus pneumoniae).

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

Use in 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 the presence of ciprofloxacin-resistant strains of Neisseria gonorrhoeae has been excluded. If no clinical improvement is observed within 3 days, the therapy should be re-evaluated.

Use in urinary tract infections.

In European Union 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 Escherichia coli resistance to fluoroquinolones when prescribing therapy.

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

Use in intra-abdominal infections.

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

Use in travelers' diarrhea.

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

Use in bone and joint infections.

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

Use in pulmonary 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 anthrax treatment guidelines.

Use in bronchopulmonary 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.

Use in complicated urinary tract infections and pyelonephritis.

Treatment of urinary tract infections with ciprofloxacin should be considered only when alternative therapies 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.

The use of ciprofloxacin may be justified based on microbiological test results for other severe infections in accordance with official recommendations or after careful benefit-risk assessment when alternative treatments are not available or standard therapy has proven ineffective.

The use of ciprofloxacin in 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.

Risk of hypersensitivity reactions.

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, the drug should be discontinued immediately, and appropriate medical treatment should be initiated if necessary.

Prolonged, disabling, and potentially irreversible serious adverse reactions.

Very rarely, in patients receiving quinolones and fluoroquinolones, regardless of age or existing risk factors, prolonged (lasting months or years), disabling, and potentially irreversible adverse reactions affecting various, and sometimes multiple, organ systems (including musculoskeletal, nervous, psychiatric, and sensory systems) have been reported. The drug should be discontinued immediately upon the first signs or symptoms of any adverse reaction, and medical advice should be sought.

Risk of tendinitis and tendon rupture.

In general, the drug 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 to these patients for the treatment of specific severe infections—specifically, when standard therapy is ineffective or bacterial resistance exists, and microbiological test results justify the use of ciprofloxacin.

Tendinitis and tendon rupture (not limited to the Achilles tendon, sometimes bilateral) may occur within 48 hours of starting treatment with quinolones and fluoroquinolones, and have been reported even several months after discontinuation of therapy (see section "Adverse reactions"). The risk of tendinitis and tendon rupture is increased in elderly patients, patients with renal impairment, transplant recipients, and patients concurrently receiving corticosteroids. Therefore, concomitant use of corticosteroids should be avoided.

If signs of tendinitis (e.g., painful swelling, inflammation) occur, treatment with the drug should be discontinued, and alternative therapy should be considered. The affected limb(s) should be appropriately managed (e.g., immobilization). Corticosteroids should not be used in cases of tendonopathy.

Use in patients with myasthenia gravis.

The drug should be used with caution in patients with myasthenia gravis due to the potential for exacerbation of symptoms (see section "Adverse reactions").

Aortic aneurysm/dissection and cardiac valve regurgitation/insufficiency.

Epidemiological studies have reported an increased risk of aortic aneurysm and dissection, particularly in elderly patients, and regurgitation of aortic and mitral valves 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 therapeutic options in patients with a positive family history of aneurysm or congenital heart valve defects, or in patients with existing diagnosis of aneurysm and/or aortic dissection, or cardiac valve disease, or in the presence of other risk factors or predisposing conditions:

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

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

Patients should be advised to seek immediate medical help in case of acute dyspnea, new-onset palpitations, or development of abdominal or lower limb edema.

Risk of visual disturbances.

Visual disturbances have been reported with the use of ciprofloxacin. In case of visual deterioration or other visual effects, patients should seek medical advice immediately.

Risk of photosensitivity reactions.

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

Risk of seizures.

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

Risk of peripheral polyneuropathy.

Patients receiving ciprofloxacin have reported cases of polyneuropathy (based on neurological symptoms such as pain, burning, sensory disturbances, or muscle weakness, alone or in combination). The drug should be discontinued in patients who develop symptoms of neuropathy, including pain, burning, tingling, numbness, and/or weakness, to prevent the development of irreversible conditions (see section "Adverse reactions").

Risk of psychotic reactions.

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, the drug should be discontinued.

Risk of cardiac disturbances.

The drug should be used with caution in patients with known risk factors for QT interval prolongation, particularly:

• congenital long QT syndrome;
• concomitant use of agents 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 heart disease (e.g., heart failure, myocardial infarction, bradycardia).

Elderly patients and women may be more sensitive to QT-prolonging drugs. The drug should be used with caution in such patients (see sections: "Interaction with other medicinal products and other forms of interaction", "Posology and method of administration", "Adverse reactions").

Risk of dysglycemia.

Alterations in blood glucose levels (including both hyperglycemia and hypoglycemia) have been reported with quinolone use, particularly in diabetic patients receiving concomitant oral hypoglycemic agents (e.g., glyburide) or insulin (see section "Adverse reactions"). Cases of hypoglycemic coma have been documented. Diabetic patients should closely monitor plasma glucose levels.

Effects on the gastrointestinal tract.

The occurrence of severe and persistent diarrhea during or after ciprofloxacin treatment (even several weeks after treatment) may indicate the development of antibiotic-associated colitis (potentially life-threatening with possible fatal outcome) and requires immediate treatment (see section "Adverse reactions"). In such cases, the drug should be discontinued and appropriate therapy initiated. Medicinal products that inhibit peristalsis are contraindicated in this clinical situation.

Effects on kidneys and urinary system.

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

Effects on the hepatobiliary system.

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

Use in patients with renal impairment.

Since ciprofloxacin is primarily excreted unchanged by the kidneys, dose adjustment should be performed in patients with renal impairment according to the recommendations in the section "Posology and method of administration" to avoid increased frequency of adverse reactions due to accumulation of ciprofloxacin.

Use in patients with glucose-6-phosphate dehydrogenase deficiency.

Hemolytic reactions have been reported in such patients during ciprofloxacin use. The drug should be avoided in these patients unless the potential benefit outweighs the potential risk. In such cases, monitoring for possible hemolysis is recommended.

Risk of resistance development.

During or after a course of ciprofloxacin treatment, resistant bacteria may be isolated, with or without clinically evident superinfection. There may be an increased risk of isolation of ciprofloxacin-resistant bacteria during prolonged treatment courses and in the treatment of hospital-acquired infections and/or infections caused by Staphylococcus and Pseudomonas species.

Concomitant use with agents metabolized by cytochrome P450 enzyme.

Ciprofloxacin inhibits CYP1A2 and may therefore increase plasma levels of concomitantly administered agents metabolized by this enzyme (e.g., theophylline, clozapine, olanzapine, ropinirole, tizanidine, duloxetine). When these agents are used concomitantly with ciprofloxacin, patients should be closely monitored for possible signs of overdose. Plasma level monitoring (e.g., theophylline) may also be necessary (see section "Interaction with other medicinal products and other forms of interaction"). Concomitant use of ciprofloxacin and tizanidine is contraindicated.

Concomitant use with methotrexate.

Concomitant use of the drug with methotrexate is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Effect on laboratory test results.

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

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, in young 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 newborns/fetuses cannot be excluded. To prevent potential adverse effects on the fetus, ciprofloxacin use should be avoided during pregnancy.

Breastfeeding period.

Ciprofloxacin passes into breast milk. Due to the potential risk of damage to joint cartilage in newborns, the drug 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. Therefore, the ability to drive or operate machinery may be impaired.

Dosage and method of administration.

Method of administration.

The medication is intended for oral use.

Tablets should be swallowed whole without chewing and taken with liquid. They may be taken independently of food intake. Administration on an empty stomach results in faster absorption of the active substance.

The medicinal product may be taken during consumption of dairy or mineral-enriched beverages. However, it should not be administered simultaneously with dairy or mineral-enriched beverages (such as milk, yogurt, or calcium-fortified orange juice) consumed separately from meals, as this may reduce the absorption of ciprofloxacin. Therefore, the medicinal product should be taken either 1–2 hours before or at least 4 hours after consuming dairy or mineral-enriched beverages taken separately from meals, as recommended for medicinal products containing calcium (see section "Interaction with other medicinal products and other types of interactions", subsection "Food and dairy products").

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

If a dose is missed, it should be taken as soon as possible, but no later than 6 hours before the next scheduled dose. If less than 6 hours remain before the next dose, the missed dose should not be taken; treatment should continue as prescribed with the next scheduled dose. Double doses should not be taken to compensate for a missed dose.

Dosage.

The dosage is determined based on the indication, severity and site of infection, pathogen(s) susceptibility to ciprofloxacin, patient's renal function, and, in children and adolescents, body weight.

Duration of treatment depends on the severity of the disease, clinical presentation, and type of pathogen.

Treatment of infections caused by certain bacteria (e.g., Pseudomonas aeruginosa, Acinetobacter, or Staphylococci) may require 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 use of other necessary antibacterial agents depending on the type of pathogens identified.

Adults.

Children and adolescents.

Elderly patients.

These patients should receive a dose selected according to the severity of infection and creatinine clearance.

Patients with hepatic impairment.

These patients do not require dosage adjustment of ciprofloxacin.

Patients with renal impairment.

Recommended initial and maintenance doses for patients with renal impairment:

No studies have been conducted on the dosing of ciprofloxacin in children with impaired renal and/or hepatic function.

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 of weight-bearing joints in immature animals. According to data from a randomized, double-blind study of ciprofloxacin use in children (age range 1 to 17 years), the incidence of arthropathy likely related to drug administration (distinct from clinical signs and symptoms related to direct joint involvement) on day 42 of treatment was 7.2% and 4.6% in the treatment group and the comparator group, respectively. The incidence of drug-related arthropathy at 1 year of follow-up was 9% and 5.7%, respectively. The increase in the number of arthropathy cases associated with drug use was not statistically significant. However, treatment with ciprofloxacin in children and adolescents should only be initiated after careful assessment of the benefit-risk ratio due to the potential risk of developing adverse reactions involving joints and/or surrounding tissues.

Overdose.

Symptoms.

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

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

Treatment.

In case of overdose, symptomatic treatment should be initiated. Due to the possible prolongation of the QT interval, ECG monitoring is also advisable. In addition to standard emergency measures, 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 ciprofloxacin absorption in overdose. Only a small amount of ciprofloxacin (< 10%) is removed by hemodialysis or peritoneal dialysis.

Side effects.

The most commonly reported adverse reactions during ciprofloxacin use are nausea and diarrhoea.

Adverse reactions are classified by frequency of occurrence as follows: common (≥ 1/100 and < 1/10), uncommon (≥ 1/1,000 and < 1/100), rare (≥ 1/10,000 and < 1/1,000), very rare (< 1/10,000), and not known (frequency cannot be estimated from available data).

Infections and infestations:

uncommon – fungal superinfections.

Blood and lymphatic system disorders:

uncommon – eosinophilia; rare – leucopenia, anaemia, neutropenia, leucocytosis, thrombocytopenia, thrombocytosis; very rare – haemolytic anaemia, agranulocytosis, pancytopenia (life-threatening), bone marrow 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:

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"); not known – hypoglycaemic coma (see section "Special precautions for use").

Psychiatric disorders*:

uncommon – psychomotor agitation/anxiety; rare – confusion, disorientation, restlessness, abnormal dreams, depression (with possible suicidal thoughts/ideation or attempts/perpetration of suicide) (see section "Special precautions for use"), hallucinations; very rare – psychotic reactions (with possible suicidal thoughts/ideation or attempts/perpetration of suicide) (see section "Special precautions for use"); not known – mania, including hypomania.

Nervous system disorders*:

uncommon – headache, dizziness, sleep disturbances, taste disturbances; rare – paraesthesia, dysaesthesia, hypoaesthesia, tremor, convulsions (including epileptic status) (see section "Special precautions for use"), vertigo; very rare – migraine, coordination disorders, gait disturbances, smell disturbances, intracranial hypertension, pseudotumour cerebri; not known – peripheral neuropathy, polyneuropathy (see section "Special precautions for use").

Eye disorders*:

rare – visual disturbances (e.g. diplopia); very rare – colour vision disturbances.

Ear and labyrinth disorders*:

rare – tinnitus, hearing loss/hearing disturbances.

Cardiac disorders**:

rare – tachycardia; not known – ventricular arrhythmia, torsades de pointes (mainly reported in patients with risk factors for QT interval prolongation), QT interval prolongation (see sections: "Special precautions for use", "Overdose").

Vascular disorders**:

rare – vasodilatation, arterial hypotension, syncope; very rare – vasculitis.

Respiratory, thoracic and mediastinal disorders:

rare – dyspnoea (including asthmatic conditions).

Gastrointestinal disorders:

common – nausea, diarrhoea; uncommon – vomiting, stomach and intestinal pain, abdominal pain, dyspepsia, flatulence; rare – antibiotic-associated colitis (very rare – potentially fatal) (see section "Special precautions for use"); very rare – pancreatitis.

Hepatobiliary disorders:

uncommon – increased plasma levels of transaminases and bilirubin; rare – liver function disorders, cholestatic jaundice, hepatitis; very rare – hepatic necrosis (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); not known – acute generalized exanthematous pustulosis, 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, muscle spasms; very rare – muscle weakness, tendinitis, tendon rupture (predominantly Achilles tendons), exacerbation of symptoms of myasthenia gravis (see section "Special precautions for use").

Renal and urinary disorders:

uncommon – renal function disorders; rare – renal failure, haematuria, crystalluria (see section "Special precautions for use"), tubulointerstitial nephritis.

General disorders and administration site conditions*:

uncommon – asthenia, fever; rare – oedema, increased sweating (hyperhidrosis).

Investigations:

uncommon – increased plasma alkaline phosphatase activity; rare – increased plasma amylase activity; not known – increased INR (in patients concomitantly taking vitamin K antagonists).

* Very rare cases of long-term (months or years), disabling and potentially irreversible serious adverse reactions involving various, sometimes multiple organ systems (tendinitis, tendon rupture, arthralgia, limb pain, gait disturbances, anxiety, suicidal thoughts, panic attacks, neuralgia, difficulty concentrating, neuropathies with paraesthesia, depression, fatigue, memory impairment, sleep disturbances, and disturbances of hearing, vision, smell and taste), associated with quinolone and fluoroquinolone use, have been reported, sometimes occurring independently of pre-existing risk factors (see section "Special precautions for use").

** 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 "Special precautions for use").

Use in children.

The frequency of arthropathy mentioned above is based on data obtained from studies in adult patients. Arthropathy occurs more frequently in children (see section "Special precautions for use").

Reporting of suspected adverse reactions

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

Shelf life. 5 years.

Storage conditions.

Store at temperatures not exceeding 25 °C, in a place inaccessible to children.

Packaging.

10 tablets in a blister; 1 blister in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

UORLД MEDICIN ILAC SAN. VE TIC. A.S., Turkey /
WORLD MEDICINE ILAC SAN. VE TIC. A.S., Turkey.

Manufacturer's address and location of its business operations.

15 Temmuz Mahallesi Cami Yolu Caddesi No:50 Gunesli Bagcilar/Istanbul, Turkey.

Marketing Authorisation Holder.

LLC "WORLD MEDICINE", Ukraine /
WORLD MEDICINE, LLC, Ukraine.