Cytoral®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CITERAL® (CITERAL®)

Composition:

Active substance: ciprofloxacin;

1 tablet contains 250 mg or 500 mg of ciprofloxacin (as ciprofloxacin hydrochloride monohydrate 291.5 mg or 583 mg);

Excipients: gelatin, maize starch, colloidal anhydrous silicon dioxide, crospovidone, magnesium stearate, microcrystalline cellulose;

Coating: hypromellose, macrogol 4000, titanium dioxide (E 171).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

250 mg tablets: elongated, biconvex, film-coated tablets of white to slightly yellowish color;

500 mg tablets: elongated, biconvex, film-coated tablets of white to slightly yellowish color with a breakline on one side.

Pharmacotherapeutic group. Antibacterial agents for systemic use. Fluoroquinolones. ATC code J01M A02.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Ciprofloxacin exhibits high in vitro efficacy against a broad spectrum of Gram-negative and Gram-positive pathogens. The mechanism of antibacterial action is due to ciprofloxacin's ability to inhibit type II topoisomerases (DNA gyrase and topoisomerase IV), which are essential for various DNA life cycle processes such as replication, transcription, repair, and recombination.

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.

Resistance to ciprofloxacin in vitro is usually associated with mutations in the target site occurring in bacterial topoisomerases and DNA gyrase through multiple-step mutations. Single mutations are more likely to result in reduced susceptibility rather than clinical resistance. However, multiple mutations typically lead to clinical resistance to ciprofloxacin and cross-resistance to quinolones.

Resistance mechanisms that inactivate other antibiotics, such as decreased permeability of the bacterial outer membrane (inherent in Pseudomonas aeruginosa) and active drug efflux from the cell (efflux), may affect susceptibility to ciprofloxacin. Development of plasmid-mediated resistance encoded by the qnr antibiotic resistance 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

1 Staphylococcus spp. – the interpretive criteria for ciprofloxacin apply to high-dose therapy.

* Non-species-related interpretive criteria were established primarily based on pharmacokinetic/pharmacodynamic (PK/PD) data and are independent of the MIC values for individual species. They are intended for use only with species lacking their own specific interpretive criteria, and not for species for which susceptibility testing is not recommended.

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

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

* Clinical efficacy has been demonstrated for susceptible isolates in approved clinical indications.

• Resistance rate ≥ 50% in one or more EU countries.

($) Intrinsic intermediate susceptibility in the absence of acquired resistance mechanisms.

(1) Studies have been conducted in experimental animals infected via the airborne route with spores of Bacillus anthracis; these studies demonstrate that administration of antibiotics immediately after exposure to the pathogen helps prevent disease if the spore burden can be reduced below the infective dose. Recommendations for the use of ciprofloxacin are primarily based on in vitro susceptibility data in animals, together with limited data obtained in humans. A 2-month treatment course with oral ciprofloxacin 500 mg twice daily is considered effective for the prevention of anthrax infection in adults. Physicians should refer to national and/or international guidelines for the treatment of anthrax.

(2) Methicillin-resistant S. aureus is very frequently also resistant to fluoroquinolones. The resistance rate to methicillin among all staphylococcal isolates is approximately 20–50% and is usually high among hospital isolates.

Pharmacokinetics.

Absorption

After oral administration of 250 mg and 500 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.

The absolute bioavailability of the drug is 70–80%.

Distribution

The extent of plasma protein binding of ciprofloxacin is low (20–30%), and the drug is predominantly present in plasma in its non-ionized form. Ciprofloxacin freely diffuses into the extravascular space. The large volume of distribution at steady state, approximately 2–3 L/kg body weight, indicates that ciprofloxacin penetrates tissues achieving concentrations that may exceed plasma levels by several-fold. Ciprofloxacin reaches high concentrations in various tissues, such as lungs (epithelial lining fluid, alveolar macrophages, biopsy specimens), sinuses, inflamed and damaged tissues, and tissues of the urinary tract and genital organs (urine, prostate, endometrium).

Metabolism

Low concentrations of four metabolites have been detected: desethylciprofloxacin (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 the CYP450 1A2 isoenzymes.

Elimination

Ciprofloxacin is primarily excreted unchanged both renally and via the gastrointestinal tract. The elimination half-life in plasma of 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 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. No age-related dependence of Cmax or AUC values has been observed. After repeated administration of the drug (10 mg/kg three times daily), no significant increase in Cmax and AUC was observed.

In 10 infants under 1 year of age with severe sepsis, Cmax was 6.1 mg/L (range: 4.6–8.3 mg/L) after a 1-hour intravenous infusion at a dose of 10 mg/kg. In children aged 1 to 5 years, Cmax was 7.2 mg/L (range: 4.7–11.8 mg/L). AUC values were 17.4 mg*h/L (range: 11.8–32.0 mg*h/L) and 16.5 mg*h/L (range: 11–23.8 mg*h/L), 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 mean elimination half-life in children is approximately 4–5 hours, and the bioavailability of the oral suspension ranges from 50 to 80%.

Clinical characteristics.

Indications.

Ciprofloxacin is indicated for the treatment of the infections listed below (see sections "Special instructions" 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. In exacerbations of chronic obstructive pulmonary disease, Cytoral® should be used only when it is considered inappropriate to use other antibacterial agents typically recommended for the treatment of these infections.
  • Bronchopulmonary infections in cystic fibrosis or bronchiectasis;
  • Community-acquired pneumonia. In community-acquired pneumonia, Cytoral® should be used only when it is considered inappropriate to use other antibacterial agents typically recommended for the treatment of these infections.
• Chronic suppurative otitis media.
• Acute exacerbation of chronic sinusitis, particularly when caused by Gram-negative bacteria.
• Urinary tract infections:
  • Uncomplicated acute cystitis. In uncomplicated acute cystitis, Cytoral® should be used only when it is considered inappropriate to use other antibacterial agents typically recommended for the treatment of these infections.
  • Acute pyelonephritis.
  • Complicated urinary tract infections.
  • Bacterial prostatitis.
• Genital tract infections:
  • Gonococcal urethritis and cervicitis caused by susceptible Neisseria gonorrhoeae.
  • Epididymo-orchitis, particularly caused by Neisseria gonorrhoeae.
  • Pelvic inflammatory disease, particularly caused by Neisseria gonorrhoeae.
• Gastrointestinal tract infections (e.g., treatment of traveler's diarrhea).
• Intra-abdominal infections.
• Skin and soft tissue infections caused by Gram-negative bacteria.
• Malignant external otitis.
• Bone and joint infections.
• Prophylaxis of invasive infections caused by Neisseria meningitidis.
• Inhalational anthrax (post-exposure prophylaxis and definitive treatment).
• Ciprofloxacin may be used for therapy in neutropenic patients if there is suspicion that fever is caused by a bacterial infection.

Children and adolescents

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

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

Treatment should be initiated only by a physician experienced in the management of cystic fibrosis and/or severe infections in children and adolescents (see sections "Pharmacological properties" and "Special instructions").

Contraindications.

Hypersensitivity to ciprofloxacin or to any excipient of the medicinal product, as well as to other agents of the fluoroquinolone group.

Concomitant administration of ciprofloxacin and tizanidine due to clinically significant adverse effects (arterial hypotension, somnolence) associated with increased plasma concentration of tizanidine.

Interaction with other medicinal products and other types of interactions.

Effect of other agents on ciprofloxacin.

Agents that prolong the QT interval.

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

Chelate complex formation.

Concomitant administration of ciprofloxacin (orally) with medicinal products containing polyvalent cations, mineral supplements (e.g., calcium, magnesium, aluminum, iron), phosphate-binding polymers (e.g., sevelamer, lanthanum carbonate), sucralfate, or antacids, as well as formulations with high buffering capacity (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 products.

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 renal secretion of ciprofloxacin. Concomitant administration of medicinal products containing probenecid and ciprofloxacin leads to increased serum concentration of ciprofloxacin.

Metoclopramide.

Metoclopramide accelerates absorption of ciprofloxacin, resulting in faster achievement of Cmax. 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 prescribed concomitantly with ciprofloxacin (see section "Contraindications").

In a clinical study involving healthy volunteers, an increase in serum levels of tizanidine (increase in Cmax: 7-fold, range: 4–21-fold; increase in AUC: 10-fold, range: 6–24-fold) was observed when administered concomitantly with ciprofloxacin. Elevated serum concentrations of tizanidine are associated with potential hypotensive and sedative effects.

Methotrexate.

Concomitant administration of ciprofloxacin may slow tubular transport (renal metabolism) of methotrexate, potentially leading to increased plasma concentrations of methotrexate. This may increase the risk of adverse toxic reactions caused by methotrexate. Concomitant administration is not recommended (see section "Special instructions").

Theophylline.

Concomitant administration of ciprofloxacin and theophylline may lead to undesirable elevation of theophylline serum concentrations, which in turn may cause adverse reactions. In individual cases, such adverse reactions may be life-threatening or fatal. If concomitant administration of these agents cannot be avoided, serum concentrations of theophylline should be monitored and the dose appropriately reduced (see section "Special instructions").

Other xanthine derivatives.

Elevated serum concentrations of caffeine or pentoxifylline (oxpentifylline) have been reported following concomitant administration with ciprofloxacin.

Phenytoin.

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

Cyclosporine.

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

Vitamin K antagonists.

Concomitant administration of ciprofloxacin and vitamin K antagonists may enhance 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 increased International Normalized Ratio (INR). Frequent monitoring of INR is required during and immediately after concomitant administration of ciprofloxacin and vitamin K antagonists (e.g., warfarin, acenocoumarol, phenprocoumon, fluindione).

Duloxetine.

Concomitant administration of duloxetine with strong CYP450 1A2 inhibitors, such as fluvoxamine, may lead to increased AUC and Cmax of duloxetine. Despite the lack of clinical data on potential interaction with ciprofloxacin, similar effects may be expected when these agents are used concomitantly (see section "Special instructions").

Ropinirole.

Concomitant administration of ropinirole with ciprofloxacin, a moderate inhibitor of CYP450 1A2 isoenzyme, leads to a 60% and 84% increase in AUC and Cmax of ropinirole, respectively. Monitoring for adverse effects of ropinirole and appropriate dose adjustment are recommended during and immediately after co-administration with ciprofloxacin (see section "Special instructions").

Lidocaine.

It has been reported that in healthy subjects, concomitant administration of ciprofloxacin, a moderate inhibitor of cytochrome P450 1A2 isoenzymes, and medicinal products containing lidocaine reduces the clearance of intravenous lidocaine by 22%. Despite normal tolerance 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 administration with ciprofloxacin (see section "Special instructions").

Sildenafil.

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

Agomelatine.

Clinical studies have demonstrated that fluvoxamine, a potent inhibitor of CYP450 1A2 isoenzyme, markedly inhibits the metabolism of agomelatine, resulting in a 60-fold increase in agomelatine exposure. Although clinical data on potential interaction with ciprofloxacin, a moderate inhibitor of CYP450 1A2, are lacking, similar effects may be expected with concomitant use.

Zolpidem.

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

Special precautions for use.

The use of ciprofloxacin should be avoided in patients who have experienced serious adverse reactions in the past when using quinolones or products containing fluoroquinolones (see section "Adverse reactions"). Treatment of these 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 severe 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.

Infections of the genital tract.

Gonococcal urethritis, cervicitis, orchiepididymitis, and pelvic inflammatory disease may be caused by fluoroquinolone-resistant Neisseria gonorrhoeae. Therefore, ciprofloxacin should be used to treat gonococcal urethritis or cervicitis only if resistance of Neisseria gonorrhoeae to ciprofloxacin has been ruled out.

For orchiepididymitis and pelvic inflammatory disease, ciprofloxacin should only be considered in combination with another appropriate antibacterial agent (e.g., a cephalosporin) if resistance of Neisseria gonorrhoeae to ciprofloxacin cannot be excluded. If no clinical improvement occurs within 3 days, the therapy should be re-evaluated.

Urinary tract infections.

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

Single-dose regimens of ciprofloxacin, which may be used for uncomplicated cystitis in premenopausal women, are considered less effective than longer treatment courses. This fact should be taken into account, especially given 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 taken into account.

Bone and joint infections.

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

Pulmonary form of anthrax.

The use of the medicinal product in humans is based on in vitro susceptibility data, animal studies, and limited human data. The physician should act in accordance with national and/or international treatment guidelines for anthrax.

Children.

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

Ciprofloxacin has caused arthropathy of weight-bearing joints in immature animals. Safety data from a randomized, double-blind study of ciprofloxacin use 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 use (distinct from clinical signs and symptoms directly related to joint involvement) of 7.2% and 4.6% in the treatment and comparator groups, respectively, on day 42 after initiation 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 use was statistically non-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 surrounding tissues (see section "Adverse reactions").

Respiratory tract infections in cystic fibrosis.

Clinical trials included children and adolescents aged 5 to 17 years. Limited experience exists in treating children aged 1 to 5 years.

Complicated urinary tract infections and severe pyelonephritis.

Consideration should be given to treating urinary tract infections with ciprofloxacin when no other treatment is possible.

Treatment should be based on the results of microbiological testing.

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

Other specific severe infections.

The use of ciprofloxacin may be justified based on microbiological testing results for other infections according to official recommendations or after careful benefit-risk assessment when no other treatment is possible or when standard therapy has proven ineffective.

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.

Hypersensitivity to the drug.

In some cases, hypersensitivity and allergic reactions, including anaphylaxis and anaphylactoid reactions, which may occur after the first dose of ciprofloxacin and may be life-threatening, have been reported (see section "Adverse reactions").

In such cases, ciprofloxacin administration must be discontinued immediately, and appropriate medical treatment should be initiated without delay.

Prolonged, disabling, and potentially irreversible serious adverse drug reactions.

In patients receiving quinolones and fluoroquinolones, very rare cases of prolonged (lasting months or years), disabling, and potentially irreversible serious adverse reactions affecting various, sometimes multiple, body systems (musculoskeletal, nervous, psychiatric, and sensory organs) and risk factors have been reported, regardless of age. Ciprofloxacin should be discontinued immediately at the first signs or symptoms of any serious adverse reaction, and patients should be advised to consult a physician.

Tendinitis and tendon rupture.

Ciprofloxacin should not be used in patients with a history of tendon disorders related to quinolone therapy. Nevertheless, in very rare cases, after microbiological confirmation of the causative agent and risk/benefit assessment, ciprofloxacin may be prescribed to these patients for the treatment of certain severe infections, especially if standard therapy is ineffective or bacterial resistance exists, where microbiological data may justify the use of ciprofloxacin.

Tendinitis and tendon rupture (particularly, but not limited to, Achilles tendon), sometimes bilateral, may occur within the first 48 hours of treatment with quinolones and fluoroquinolones and, as reported, may even occur several months after discontinuation of treatment (see section "Adverse reactions"). The risk of tendinitis and tendon rupture may be increased in elderly patients, patients with impaired renal function, patients with solid organ transplants, and patients receiving concomitant corticosteroids. Therefore, the use of corticosteroids should be avoided.

If signs of tendinitis (such as painful swelling, inflammation) appear, ciprofloxacin treatment 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 if signs of tendinopathy occur.

Myasthenia.

Ciprofloxacin should be used with caution in patients with myasthenia, as symptoms may be exacerbated (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 only be used 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 an existing diagnosis of aneurysm and/or aortic dissection, or heart 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/dissection (e.g., vascular disorders such as Takayasu arteritis or giant cell arteritis, or known atherosclerosis, or Sjögren's syndrome), or additionally
• for cardiac valve regurgitation/insufficiency (e.g., infective endocarditis). The risk of aortic aneurysm and dissection and their rupture may be increased in patients receiving systemic corticosteroids concomitantly.

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.

Visual disturbances.

If visual impairment or any effect on the eyes occurs, medical consultation is required.

Photosensitivity.

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

Seizures.

Ciprofloxacin, like other fluoroquinolones, may cause seizures or lower the seizure threshold. Cases of epilepsy have been reported. Ciprofloxacin should be used with caution in patients with CNS disorders that may predispose to seizures or status epilepticus. If seizures occur, ciprofloxacin should be discontinued (see section "Special precautions for use").

Peripheral neuropathy.

Cases of sensory or sensorimotor polyneuropathy leading to paresthesia, hypoesthesia, dysesthesia, or weakness have been reported in patients taking quinolones and fluoroquinolones. Patients taking ciprofloxacin should be instructed to inform their physician if symptoms of neuropathy such as pain, burning, tingling, numbness, or weakness develop, to prevent potential worsening of symptoms (see section "Adverse reactions").

Psychiatric reactions.

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

Cardiac disorders.

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

• in patients with congenital long QT syndrome;
• when co-administered with drugs that may prolong the QT interval (e.g., class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, neuroleptics);
• in the presence of uncorrected electrolyte imbalance (e.g., hypokalemia, hypomagnesemia);
• in patients with cardiac conditions (e.g., heart failure, myocardial infarction, bradycardia).

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

Dysglycemia.

As with all 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 for patients with diabetes.

Gastrointestinal tract.

If severe and persistent diarrhea occurs during or after treatment (even several weeks after treatment), the physician should be informed, as this symptom may indicate antibiotic-associated colitis (a life-threatening condition that may be fatal), which requires immediate 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 case.

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 according to the instructions in the section "Method of administration and dosage" to avoid increased frequency of adverse reactions due to accumulation of ciprofloxacin.

Hepatobiliary system.

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

Glucose-6-phosphate dehydrogenase deficiency.

Hemolytic reactions have been reported in patients with glucose-6-phosphate dehydrogenase deficiency taking ciprofloxacin. The use of ciprofloxacin in such patients should be avoided 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 treatment, resistant bacteria may be isolated, with or without clinically defined superinfection. There may be a certain 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 moderately inhibits CYP1A2 and may therefore increase serum concentrations of concomitantly administered substances metabolized by this enzyme (e.g., theophylline, clozapine, olanzapine, ropinirole, tizanidine, duloxetine, agomelatine). Therefore, patients receiving these substances concomitantly with ciprofloxacin should be closely monitored for 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"). Concomitant administration of ciprofloxacin and tizanidine is contraindicated.

Methotrexate.

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

Effect on laboratory test results.

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

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, 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. Therefore, ciprofloxacin should preferably be avoided during pregnancy.

Lactation period.

Ciprofloxacin passes into 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 vehicles or operating machinery.

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

Method of administration and dosage.

The dose is determined according to the indication, severity and site of infection, susceptibility of the causative organism(s) 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, 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 administration 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

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:

Patients with hepatic insufficiency do not require dosage adjustment 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 with an adequate amount of fluid. 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 forms of interaction").

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

If a dose is missed, it should be taken as soon as possible, but not later than 6 hours before the next scheduled dose. If less than 6 hours remain before the next dose, the missed dose should be skipped, and treatment should continue as prescribed with the next scheduled dose. Double doses should not be taken to compensate for a missed dose.

Children.

Ciprofloxacin use in children should be carried out in accordance with current official recommendations. Treatment with ciprofloxacin should be administered only by a physician experienced in managing children with cystic fibrosis and/or severe infections.

Ciprofloxacin has been shown to cause arthropathy of weight-bearing joints in young animals. Treatment with ciprofloxacin in children should be initiated only after careful assessment of the benefit-risk ratio due to the potential risk of developing adverse reactions affecting joints and/or surrounding tissues.

Overdose.

Cases of moderate toxicity have been reported following ingestion of 12 g of the drug. Acute overdose of 16 g resulted in 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.

In addition to standard emergency measures taken in overdose cases, 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. In case of overdose, symptomatic treatment is required. ECG parameters should be monitored, as QT interval prolongation may occur.

Adverse reactions.

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

Data on adverse reactions to ciprofloxacin, obtained during clinical trials and post-marketing surveillance (oral, parenteral, and sequential administration routes), are presented below. In analyzing the frequency of occurrence, data from both oral and intravenous administration routes of ciprofloxacin are taken into account.

* Very rare cases of prolonged (up to months or years), disabling and potentially irreversible serious adverse reactions to medicinal products affecting multiple, sometimes several, organ systems and sensory organs (including such reactions as tendinitis, tendon rupture, arthralgia, limb pain, gait disturbance; in some cases, neuropathies associated with paresthesia, depression, fatigue, memory impairment, sleep disorders, hearing, vision, taste and smell disturbances) associated with the use of quinolones and fluoroquinolones, in some cases regardless of existing risk factors (see section "Special precautions for use").

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

Use in children

Arthropathy is observed more frequently in children (see section "Special precautions for use").

Shelf life.

3 years.

Storage conditions.

Store at a temperature not exceeding 25°C.

Keep out of reach of children.

Packaging.

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

Prescription status.

Prescription only.

Manufacturer.

ALKALOID AD Skopje.

Manufacturer's address and place of business.

Boulevard Alexander the Great, No. 12, Skopje, 1000, Republic of North Macedonia.