Ciprobelle®

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT CYPROBEL® (SIPROBEL®)

Composition:

Active substance: ciprofloxacin;

One tablet contains ciprofloxacin hydrochloride monohydrate equivalent to 500 mg of ciprofloxacin;

Excipients: maize starch, microcrystalline cellulose, povidone (K30), colloidal anhydrous silicon dioxide, magnesium stearate, sodium croscarmellose; coating Sepifilm LP 770: hypromellose, microcrystine cellulose, stearic acid, titanium dioxide (E 171).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white, prolonged-shaped, film-coated tablets with embossing "500" and "SIP" and a break line on one side, smooth on the other side.

Pharmacotherapeutic group.

Antibacterial agents for systemic use. Fluoroquinolone group.

ATC code J01MA02.

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 against 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 mutations in the target site occurring in topoisomerase IV and DNA gyrase through multiple-step mutations. The degree of cross-resistance between ciprofloxacin and other fluoroquinolones resulting from the above mechanisms may vary. Single mutations generally do not lead to clinical resistance; however, multiple mutations usually result in clinical resistance to several or all members of the fluoroquinolone class.

Resistance mechanisms such as impermeability or efflux pumps may exert varying effects on susceptibility to fluoroquinolones, depending on the physicochemical properties of different 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 (typical of Pseudomonas aeruginosa) and efflux mechanisms, may also affect 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

1Staphylococcus spp. – susceptibility breakpoints for ciprofloxacin apply to high-dose therapy.

*Non-species-related breakpoints were primarily established based on pharmacokinetic/pharmacodynamic (PK/PD) data and do not depend on the MICs of individual species. They are used only for species lacking their own specific breakpoints, and not for species for which susceptibility testing is not recommended.

The prevalence of acquired resistance among isolated species may vary 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 using the drug becomes 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").

Non-clinical safety data.

According to data from standard non-clinical studies of single-dose toxicity, repeated-dose toxicity, carcinogenic potential, and reproductive toxicity, no specific hazard for humans has been identified.

Pharmacokinetics.

Absorption.

After oral administration of ciprofloxacin tablets at doses of 250 mg, 500 mg, and 750 mg, 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 100–750 mg resulted in dose-dependent peak serum concentrations (Cmax) 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%. When administering an oral dose of ciprofloxacin 500 mg every 12 hours, the total area under the concentration-time curve (AUC) was equivalent to that observed after intravenous infusion of 400 mg ciprofloxacin administered over 60 minutes every 12 hours.

Distribution.

The percentage of ciprofloxacin binding to plasma proteins is low (20–30%). Ciprofloxacin is present in 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 or 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: desethylene-ciprofloxacin (M1), sulfociprofloxacin (M2), oxociprofloxacin (M3), and formylciprofloxacin (M4). These metabolites exhibit antimicrobial activity in vitro, although to a lesser extent than the parent compound.

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

Elimination.

Ciprofloxacin is primarily excreted unchanged by the kidneys, with a smaller portion eliminated via the intestine. The elimination half-life in plasma in subjects 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 attributed to transintestinal secretion and metabolism. One percent 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-related dependence of C_max and AUC was observed (in children aged 1 year and older). After repeated administration of the drug (10 mg/kg three times daily), no significant increase in C_max and AUC was observed. In 10 infants under 1 year of age with severe sepsis, C_max was 6.1 mg/L (range 4.6–8.3 mg/L) after a 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 11–23.8 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.

Ciprobay® 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 the appropriate use of antibacterial agents should be taken into account.

Adults

• Infections of the lower respiratory tract caused by Gram-negative bacteria:

• Exacerbations of chronic obstructive pulmonary disease (in exacerbations of chronic obstructive pulmonary disease, ciprofloxacin should be used only when it is considered inappropriate to use other antibacterial agents usually recommended for the treatment of these infections);

• 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 (in acute exacerbation of chronic sinusitis, ciprofloxacin should be used only when it is considered inappropriate to use other antibacterial agents usually recommended for the treatment of these infections);

• Urinary tract infections:

  • Uncomplicated acute cystitis (in uncomplicated acute cystitis, ciprofloxacin should be used only when it is considered inappropriate to use other antibacterial agents usually recommended for the treatment of these infections);
  • Acute pyelonephritis;
  • Complicated urinary tract infections;
  • Bacterial prostatitis.

• Genitourinary infections:

• Gonococcal urethritis and cervicitis caused by susceptible strains of Neisseria gonorrhoeae;

• Orchitis and epididymitis, particularly caused by susceptible strains of Neisseria gonorrhoeae;

• Pelvic inflammatory disease, including cases 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.

• Bone and joint infections.

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

Ciprofloxacin may be used in the management of febrile neutropenic patients suspected of having a bacterial cause of fever 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.
• Inhalational anthrax (post-exposure prophylaxis and definitive treatment).

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

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

Contraindications.

Hypersensitivity to ciprofloxacin, to other agents of the fluoroquinolone group, or to any of the excipients of the medicinal product.

Concomitant administration of ciprofloxacin and tizanidine is contraindicated (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Effect of other agents on ciprofloxacin.

Agents that prolong the QT interval.

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

Chelate complex formation.

Concomitant administration of oral ciprofloxacin with medicinal products containing multivalent cations and mineral supplements (e.g., calcium, magnesium, aluminum, iron), phosphate binders (e.g., sevelamer or lanthanum carbonate), sucralfate, or antacids, as well as buffered formulations (such as didanosine tablets) containing magnesium, aluminum, 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 agents. This restriction does not apply to antacids 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 products or mineral-enriched foods (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 maximum 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 used 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 (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.

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 reactions; therefore, concomitant use is not recommended (see section "Special precautions for use").

Theophylline.

Concomitant administration of ciprofloxacin and theophylline may lead to undesirable elevation of theophylline plasma concentrations, potentially causing adverse reactions. In isolated cases, such adverse reactions may be life-threatening or fatal. Therefore, when ciprofloxacin and theophylline are used concomitantly, theophylline plasma concentrations should be monitored and the dose adjusted if necessary (see section "Special precautions for use").

Other xanthine derivatives.

Increased plasma 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 phenytoin concentrations; 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 of serum creatinine (twice weekly) 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 during and immediately after concomitant use of ciprofloxacin and vitamin K antagonists (e.g., warfarin, acenocoumarol, phenprocoumon, fluindione) is recommended.

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 precautions for use").

Ropinirole.

Clinical studies have shown that concomitant administration of ropinirole with ciprofloxacin, a moderate inhibitor of CYP450 1A2, 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 concomitant use with ciprofloxacin (see section "Special precautions for use").

Lidocaine.

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

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 (see section "Special precautions for use").

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 risk/benefit ratio should be considered.

Agomelatine.

Clinical studies have shown that fluvoxamine, a strong inhibitor of CYP450 1A2 isoenzyme, markedly inhibits the metabolism of agomelatine, resulting in a 60-fold increase in agomelatine exposure. Although no clinical data are available on the potential interaction with ciprofloxacin, a moderate inhibitor of CYP450 1A2, similar effects may be expected upon concomitant use (see section "Special precautions for use. Cytochrome P450").

Zolpidem.

Concomitant administration of ciprofloxacin may increase zolpidem blood levels; therefore, concomitant use is not recommended.

Special precautions for use.

Ciprofloxacin should not be used in patients who have previously experienced serious adverse reactions to drugs containing quinolones or fluoroquinolones (see section "Adverse reactions"). Treatment of such patients with ciprofloxacin should only be initiated if no alternative treatment options are available and after careful benefit-risk assessment (see section "Contraindications").

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, orchitis-epididymitis, and pelvic inflammatory disease.

Therefore, ciprofloxacin should be used for the treatment of gonococcal urethritis or cervicitis only after confirmation of susceptibility of Neisseria gonorrhoeae to ciprofloxacin.

Empirical therapy with ciprofloxacin for orchitis-epididymitis 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 ruled out.

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

Urinary tract infections.

In European Union countries, varying resistance rates of Escherichia coli, the most common causative pathogen of urinary tract infections, to fluoroquinolones have been observed. Prescribers are advised to consider local resistance patterns of Escherichia coli to fluoroquinolones when selecting therapy.

Single-dose regimens of ciprofloxacin, which may be used for uncomplicated cystitis in premenopausal women, are considered less effective than longer treatment courses. This should be taken into account 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 therapy, information on resistance to ciprofloxacin of relevant microorganisms in the visited countries should be considered.

Bone and joint infections.

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

Inhalational anthrax.

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.

Ciprofloxacin use in children should be in accordance with current official recommendations. Treatment with ciprofloxacin should be initiated only by physicians experienced in treating children 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 1–17 years) indicate an incidence of arthropathy likely related to drug use (distinct from clinical signs and symptoms directly related to joint involvement) of 7.2% and 4.6% in the ciprofloxacin and comparator groups, respectively, on day 42 of treatment. The incidence of drug-related arthropathy after 1 year of follow-up was 9% and 5.7%, respectively. The increase in arthropathy cases related to drug use was not statistically significant. However, treatment of children and adolescents with ciprofloxacin should only be initiated after careful benefit-risk assessment due to the potential risk of adverse reactions affecting joints and/or adjacent tissues.

Respiratory tract infections in cystic fibrosis.

Clinical studies 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 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.

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

Ciprofloxacin use in specific severe infections other than those 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.

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

Prolonged, disabling, and potentially irreversible adverse reactions.

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

Ciprofloxacin should be discontinued immediately upon the first signs or symptoms of any serious adverse reaction, and patients should seek medical advice.

Musculoskeletal system.

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

Tendinitis and tendon rupture.

Tendinitis and tendon rupture (including Achilles tendon), sometimes bilateral, may occur within 48 hours of starting quinolone or fluoroquinolone therapy and even several months after discontinuation. The risk of tendinitis and tendon rupture is increased in elderly patients, patients with renal impairment, transplant recipients, and patients receiving corticosteroid therapy (see section "Adverse reactions"). Therefore, concomitant use of corticosteroids should be avoided.

If any signs of tendinitis (e.g., painful swelling, inflammation) occur, ciprofloxacin should be discontinued, and alternative therapy should be considered. Affected limbs should be managed appropriately (e.g., immobilization). 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 exacerbation of symptoms (see section "Adverse reactions").

Aortic aneurysm and aortic dissection, and cardiac valve regurgitation.

Epidemiological studies suggest an increased risk of aortic aneurysm and aortic dissection, particularly in elderly patients, and regurgitation of aortic and mitral valves following fluoroquinolone use. Cases of aortic aneurysm and dissection, sometimes complicated by aortic rupture (including fatal cases), and regurgitation/insufficiency of any cardiac valve have been reported in patients taking 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 family history of aortic aneurysm or congenital heart valve defects, or in patients diagnosed with aortic aneurysm and/or aortic dissection, or with cardiac valve disease, or in the presence of other risk factors or predisposing conditions, namely:

• for both aortic aneurysm and dissection, and cardiac valve regurgitation/insufficiency (e.g., connective tissue disorders such as Marfan syndrome, Ehlers-Danlos syndrome, Turner syndrome, Behçet’s disease, hypertension, rheumatoid arthritis), or additionally
• for aortic aneurysm or dissection (including vascular diseases such as Takayasu arteritis, giant cell arteritis, atherosclerosis, Sjögren’s syndrome), or additionally
• for cardiac valve regurgitation/insufficiency (e.g., infective endocarditis).

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

Patients should be advised to seek immediate medical attention in case of sudden abdominal, chest, or back pain.

Patients should be advised to seek immediate medical help if acute dyspnea, new onset of tachycardia, or development of abdominal or lower limb edema occurs.

Visual disturbances.

Patients should seek immediate medical advice if visual impairment or any ocular symptoms occur.

Photosensitivity.

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

Central nervous system.

Ciprofloxacin, like other quinolones, is known to cause seizures or lower the seizure threshold. Cases of status epilepticus have been reported. Ciprofloxacin should be used with caution in patients with central nervous system (CNS) disorders that may predispose to seizures. If seizures occur, ciprofloxacin should be discontinued (see section "Adverse reactions"). Psychotic reactions may occur even after the first dose of ciprofloxacin. In isolated cases, depression or psychosis may progress to suicidal ideation and behavior, including suicide attempts or completed suicide. In such cases, ciprofloxacin should be discontinued.

Peripheral neuropathy.

Cases of sensory or sensorimotor polyneuropathy, leading to paresthesia, hypoesthesia, dysesthesia, or weakness, have been reported in patients receiving ciprofloxacin. Patients should inform their physician immediately if symptoms of neuropathy such as pain, burning, tingling, numbness, or weakness develop during treatment to prevent progression to potentially irreversible conditions (see section "Adverse reactions").

Cardiac disorders.

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

• 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 QT-prolonging drugs. Therefore, fluoroquinolones, including ciprofloxacin, should be used with caution in these patient groups (see sections "Dosage and administration", "Interaction with other medicinal products and other forms of interaction", "Adverse reactions", "Overdose").

Dysglycemia.

Alterations in blood glucose levels, including both hypoglycemia and hyperglycemia (see section "Adverse reactions"), have been reported with quinolone use, typically in diabetic patients receiving concomitant therapy with oral hypoglycemic agents (e.g., glibenclamide) or insulin. Cases of hypoglycemic coma have been reported. Diabetic patients should be closely monitored for blood glucose levels.

Gastrointestinal tract.

The onset of severe and persistent diarrhea during or after treatment (even several weeks after therapy) may indicate antibiotic-associated colitis (which may be fatal) and requires urgent treatment (see section "Adverse reactions"). In such cases, ciprofloxacin should be discontinued and appropriate therapy initiated. Medicinal products that inhibit peristalsis are contraindicated in this clinical situation.

Kidneys and urinary system.

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

Renal function impairment.

Since ciprofloxacin is primarily excreted unchanged by the kidneys, dose adjustment is required in patients with impaired renal function as described in the section "Dosage and administration" 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 (see section "Adverse reactions"). If any signs or symptoms of liver disease (e.g., anorexia, jaundice, dark urine, pruritus, or abdominal distension) occur, treatment should be discontinued.

Glucose-6-phosphate dehydrogenase deficiency.

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

Resistance.

During or after a course of ciprofloxacin therapy, 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 nosocomial infections and/or infections caused by Staphylococcus and Pseudomonas species.

Cytochrome P450.

Ciprofloxacin inhibits CYP1A2 and may therefore increase serum concentrations of concomitantly administered drugs metabolized by this enzyme (e.g., theophylline, clozapine, olanzapine, ropinirole, tizanidine, duloxetine, agomelatine). 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 (see section "Interaction with other medicinal products and other forms of interaction").

Methotrexate.

Concomitant use 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 in vitro may affect culture results for Mycobacterium tuberculosis 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. Data do not indicate direct or indirect toxic effects on reproductive function; however, effects on immature cartilage tissue have been observed, and a potential harmful effect on joint cartilage of newborns/fetus cannot be excluded. Therefore, as a precaution, ciprofloxacin use during pregnancy should be avoided.

Breastfeeding period.

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

Ability to affect reaction speed when driving or operating machinery.

Fluoroquinolones, including ciprofloxacin, may affect a patient's ability to drive or operate machinery due to CNS-related reactions (see section "Adverse reactions"). Therefore, the ability to drive or operate machinery may be impaired.

Administration and Dosage

The dosage should be determined according to the indication, severity and site of infection, pathogen susceptibility to ciprofloxacin, and the patient's renal function; in children and adolescents, dosage should also be based on body weight.

The duration of treatment depends on the severity of the disease, specific features of the clinical presentation, and the type of causative pathogen.

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

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

Adults

Children and adolescents

Elderly patients

Elderly 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:

In patients with hepatic insufficiency, there is no need to modify the dosage of ciprofloxacin.

Studies on ciprofloxacin dosing in children with impaired renal and/or hepatic function have not been conducted.

Method of administration

Tablets should be swallowed whole and taken with liquid. 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, yoghurt) or fruit juices fortified with minerals (e.g., calcium-fortified orange juice) (see section "Interaction with other medicinal products and other forms of interaction").

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

Children.

Administration of ciprofloxacin in children and adolescents should be conducted according to current official guidelines. 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 been associated with arthropathy of weight-bearing joints. However, treatment with ciprofloxacin in children and adolescents should be initiated only after careful assessment of the benefit-risk ratio due to the risk of developing adverse reactions affecting joints and/or adjacent tissues.

Overdose.

Overdose following ingestion of 12 g of the drug has been reported to cause symptoms of moderate toxicity. Acute overdose of 16 g has 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 haematuria. Reversible nephrotoxicity 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 is required. Due to the potential for QT interval prolongation, ECG monitoring is also advisable.

Adverse Reactions

The most commonly reported adverse reactions to the medicinal product were nausea and diarrhea.

Data on adverse reactions associated with the medicinal product Ciprobay® are presented below.

Infections and infestations: Fungal superinfections, antibiotic-associated colitis with potentially fatal outcome (see section "Special Warnings and Precautions for Use").

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) (see section "Special Warnings and Precautions for Use"), serum sickness-like reactions.

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

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

Psychiatric disorders¹: Psychomotor agitation/anxiety, confusion and disorientation, restlessness, pathological dreams, hallucinations, depression (with possible suicidal ideation/thoughts or suicide attempts/perpetration), psychotic reactions (with possible suicidal ideation/thoughts or suicide attempts/perpetration), mania, hypomania (see section "Special Warnings and Precautions for Use").

Nervous system disorders¹: Headache, dizziness, sleep disorders, taste disturbances, paresthesia, dysesthesia, hypesthesia, tremor, convulsions (including epileptic status; see section "Special Warnings and Precautions for Use"), vertigo, migraine, coordination disturbances, gait disturbances, olfactory disturbances, intracranial hypertension and pseudotumor cerebri, peripheral neuropathy and polyneuropathy (see section "Special Warnings and Precautions for Use").

Eye disorders¹: Visual disturbances (e.g., diplopia), color vision disturbances.

Ear and labyrinth disorders¹: Tinnitus, hearing loss/hearing impairment.

Cardiac disorders²: Tachycardia, ventricular arrhythmia and torsades de pointes (mainly reported in patients with risk factors for QT interval prolongation), QT interval prolongation (see sections "Special Warnings and Precautions for Use", "Overdose").

Vascular disorders²: Vasodilation, hypotension, syncope, vasculitis.

Respiratory system disorders: Dyspnea (including asthmatic conditions).

Gastrointestinal disorders: Nausea, diarrhea, vomiting, stomach and intestinal pain, abdominal pain, dyspeptic disorders, flatulence, pancreatitis.

Hepatobiliary disorders: Increased levels of transaminases and bilirubin; liver function disturbances; cholestatic jaundice; hepatitis; hepatic necrosis progressing to life-threatening liver failure (see section "Special Warnings and Precautions for Use").

Skin and subcutaneous tissue disorders: Rash, pruritus, urticaria, photosensitivity reactions (see section "Special Warnings and Precautions for Use"), petechiae, erythema multiforme, nodular erythema, Stevens-Johnson syndrome (life-threatening), toxic epidermal necrolysis (life-threatening), acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS syndrome).

Musculoskeletal and connective tissue disorders¹: Musculoskeletal pain (e.g., limb, back, chest pain); arthralgia, myalgia, arthritis, increased muscle tone and muscle spasms, muscle weakness, tendinitis, tendon rupture (predominantly Achilles tendons) (see section "Special Warnings and Precautions for Use"); exacerbation of symptoms of myasthenia gravis (see section "Special Warnings and Precautions for Use").

Renal and urinary disorders: Disorders of kidney and urinary system, renal function impairment, renal failure, hematuria, crystalluria (see section "Special Warnings and Precautions for Use"), tubulointerstitial nephritis.

General disorders and administration site conditions¹: Asthenia, fever, edema, increased sweating (hyperhidrosis).

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

*These reactions were mainly observed in patients with additional risk factors for QT interval prolongation (see section "Special Warnings and Precautions for Use").

¹ Cases of very rare, prolonged (several months or years), disabling and potentially irreversible serious adverse reactions affecting various organ systems have been reported (including such reactions as tendinitis, tendon rupture, arthralgia, limb pain, gait disturbances, neuropathies associated with paresthesia, depression, fatigue, memory impairment, sleep disturbances, hearing impairment, visual disturbances, taste and smell disturbances) associated with quinolone and fluoroquinolone use, regardless of the presence or absence of risk factors.

² Cases of aortic aneurysm and aortic dissection (including fatal cases), as well as cases of regurgitation/insufficiency of any cardiac valve, have been reported in patients receiving fluoroquinolones.

Use in children

Arthropathy occurs more frequently in children (see section "Special Warnings and Precautions for Use").

Shelf life.

3 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in the original packaging.

Keep out of reach of children.

Packaging.

4 tablets in a blister, 1 blister in a cardboard pack.

7 tablets in a blister, 2 blisters in a cardboard pack.

14 tablets in a blister, 1 blister in a cardboard pack.

Prescription status.

Prescription only.

Manufacturer.

NOBEL ILAC SANAYI VE TICARET A.S.

Manufacturer's address and place of business:
Sankaklar District, Eskikarakoca Avenue No. 299, 81100 Duzce, Turkey.