Ciflosin

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT CYFLOSIN (CIFLOSIN)

Composition:
Active substance: ciprofloxacin;
100 ml of solution contains 200 mg of ciprofloxacin.

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

Pharmaceutical form:
Infusion solution.

Basic physicochemical properties:
Clear, colorless or slightly yellowish liquid. Theoretical osmolarity: 321 mosmol/L.

Pharmacotherapeutic group:
Antibacterials for systemic use. Fluoroquinolones. Ciprofloxacin.
ATC code: J01MA02.

Pharmacological properties

Pharmacodynamics:
The bactericidal activity of ciprofloxacin, an antibacterial agent of the fluoroquinolone class, is due to its ability to inhibit DNA gyrase (topoisomerase II) and topoisomerase IV. Both enzymes are essential for bacterial replication, transcription, recombination, and DNA repair.

Pharmacokinetics/Pharmacodynamics:
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 ratio between the area under the concentration-time curve (AUC) and MIC.

Mechanism of resistance:
Resistance to ciprofloxacin in vitro may develop gradually due to mutations in DNA gyrase and topoisomerase IV. The degree of cross-resistance between ciprofloxacin and other fluoroquinolones may vary. Single mutations usually do not lead to clinical resistance, whereas multiple mutations typically result in clinical resistance to several or all active substances within this class.

Impermeability of the bacterial cell wall and/or efflux pump-mediated resistance may differentially affect the level of susceptibility to fluoroquinolones. This depends on the physicochemical properties of the various active substances within the class and the affinity of transport systems for each active substance. All in vitro resistance mechanisms are frequently observed in clinical isolates.

Resistance mechanisms that inactivate other antibacterial agents, such as reduced permeability of the bacterial cell wall (inherent in Pseudomonas aeruginosa) and efflux mechanisms, may also affect susceptibility to ciprofloxacin. Plasmid-mediated resistance encoded by the qnr gene has been reported.

Antibacterial spectrum:
Breakpoints distinguishing 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 geographical location and time; therefore, local information on resistance is necessary, especially when treating severe infections. When necessary, consultation with specialists should be sought if local resistance prevalence has reached a level where the benefit of using the medicinal product is questionable, at least for certain types of infections. Susceptibility of major pathogens to ciprofloxacin (for Streptococcus, see section "Special precautions for use").

Pharmacokinetics. Absorption After intravenous infusion of ciprofloxacin, the mean maximum serum concentration is achieved at the end of the infusion. For doses up to 400 mg administered intravenously, the pharmacokinetics of ciprofloxacin are linear. When comparing pharmacokinetic parameters following intravenous administration twice daily or three times daily, no accumulation of ciprofloxacin or its metabolites was observed. Intravenous infusion of 200 mg ciprofloxacin over 60 minutes and oral administration of 250 mg ciprofloxacin every 12 hours were characterized by equivalent AUC. Intravenous infusion of 400 mg ciprofloxacin over 60 minutes every 12 hours was bioequivalent to the oral dose of 500 mg every 12 hours according to AUC. Intravenous infusion of 400 mg ciprofloxacin over 60 minutes every 12 hours showed a Cmax similar to the oral dose of 750 mg. Intravenous infusion of 400 mg ciprofloxacin over 60 minutes every 8 hours was equivalent to oral administration of 750 mg every 12 hours in terms of AUC.

Distribution
Plasma protein binding of ciprofloxacin is low (20–30%). Ciprofloxacin in blood plasma is predominantly in the non-ionized form and has a large volume of distribution at steady state, ranging from 2 to 3 L/kg body weight. Ciprofloxacin concentrations reach high levels in various tissues, such as lungs (epithelial lining fluid, alveolar macrophages, biopsies), sinuses, sites of inflammation (bulla fluid), and genitourinary organs (urine, prostate, endometrium), where concentrations exceed those in plasma.

Metabolism
Low concentrations of four metabolites have been detected: desethylene-ciprofloxacin (M1), sulfociprofloxacin (M2), oxociprofloxacin (M3), and formylciprofloxacin (M4). The metabolites exhibit antimicrobial activity in vitro, but to a lesser extent than the parent compound. Ciprofloxacin is a known moderate inhibitor of CYP450 1A2.

Excretion
Ciprofloxacin is excreted predominantly in unchanged form via the kidneys, and to a lesser extent through the gastrointestinal tract.

Renal clearance is 180–300 mL/kg/h, and total clearance is 480–600 mL/kg/h. Ciprofloxacin undergoes glomerular filtration and tubular secretion. Severe renal impairment leads to an increase in the elimination half-life of ciprofloxacin to 12 hours. Extrarenal clearance of ciprofloxacin is primarily achieved through active secretion in the intestine and metabolism. 1% of the dose is excreted in bile. Ciprofloxacin is present in bile at high concentrations.

Children
Pharmacokinetic data in children are limited. In a study involving children aged 1 year and older, no age-dependent differences in Cmax and AUC were observed. No significant increase in Cmax and AUC was observed after multiple dosing (10 mg/kg three times daily). In 10 infants under 1 year of age with severe sepsis, after a one-hour intravenous infusion of 10 mg/kg, Cmax was 6.1 mg/L (range 4.6–8.3 mg/L), while in children aged 1 to 5 years, Cmax was 7.2 mg/L (range 4.7–11.8 mg/L). AUC values in the respective age groups were 17.4 mg*h/L (range 11.8–32.0 mg*h/L) and 16.5 mg*h/L (range 11.0–23.8 mg*h/L). These values are within the range observed in adults receiving therapeutic doses. Based on pharmacokinetic analyses in pediatric patients with various infections, the elimination half-life was estimated to be approximately 4–5 hours, and the bioavailability of the oral suspension is 50–80%.

Preclinical Safety Data
Preclinical data reveal no specific risks for humans based on standard studies of acute toxicity, repeated-dose toxicity, carcinogenic potential, and reproductive toxicity. Like other quinolones, ciprofloxacin is phototoxic in animals at clinically relevant exposure levels. Data on photomutagenicity/photocarcinogenicity indicate a weak photomutagenic or photocarcinogenic effect of ciprofloxacin in vitro and in animal studies. This effect was comparable to that of other DNA gyrase inhibitors.

Effect on Joints
Like other DNA gyrase inhibitors, ciprofloxacin causes damage to weight-bearing joints in young animals. The degree of cartilage damage depends on the animal species, age, and dose; reducing joint load decreases cartilage damage. Studies in adult animals (rats, dogs) did not reveal cartilage damage. In a study in young beagle dogs, a two-week treatment with therapeutic doses of ciprofloxacin caused severe joint damage, detectable even 5 months later.

Clinical Characteristics. Indications.
Ciprofloxacin is indicated for the treatment of the following infections (see sections "Pharmacological Properties" and "Special Warnings and Precautions for Use"). Before initiating therapy, particular attention should be paid to available information on resistance to ciprofloxacin. Official recommendations on the appropriate use of antibacterial agents should be considered.

Adults

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

− exacerbation of chronic obstructive pulmonary disease. In exacerbations of chronic obstructive pulmonary disease, ciprofloxacin should be used only when other antibacterial agents typically recommended for the treatment of these infections are considered inappropriate;

− bronchopulmonary infections in cystic fibrosis or bronchiectasis;
− community-acquired pneumonia.

• Chronic suppurative otitis media.
• Acute exacerbation of chronic sinusitis, particularly if caused by Gram-negative bacteria.
• Urinary tract infections:

− acute pyelonephritis;

− complicated urinary tract infections;
− bacterial prostatitis.

• Genital tract infections:

− epididymo-orchitis, including cases caused by susceptible Neisseria gonorrhoeae;

− pelvic inflammatory disease, including cases caused by susceptible Neisseria gonorrhoeae.

• Gastrointestinal tract infections (e.g., traveler's diarrhea).
• Intra-abdominal infections.
• Skin and soft tissue infections caused by Gram-negative bacteria.
• Malignant external otitis.
• Bone and joint infections.
• Pulmonary form of anthrax (post-exposure prophylaxis and treatment).

Ciprofloxacin may be used for the treatment of patients with neutropenia and fever when there is suspicion that the fever is caused by a bacterial infection.

Children

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

Ciprofloxacin may also be used for the treatment of severe infections in children when considered necessary. Treatment should be initiated only by a physician experienced in the treatment of cystic fibrosis and severe infections in children (see sections "Pharmacological Properties" and "Special Warnings and Precautions for Use").

Contraindications.

• Hypersensitivity to the active substance, other quinolones, or to any of the excipients of the medicinal product.
• Concomitant use 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.
Effect of Other Medicinal Products on Ciprofloxacin

Medicinal Products that Prolong the QT Interval
Ciprofloxacin, like other fluoroquinolones, should be used with caution in patients receiving medicinal products that prolong the QT interval (e.g., class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, neuroleptics) (see section "Special Warnings and Precautions for Use").

Probenecid
Probenecid interferes with the renal secretion of ciprofloxacin. Concomitant administration of probenecid and ciprofloxacin increases the serum concentration 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 in healthy volunteers, concomitant administration of ciprofloxacin and tizanidine resulted in increased serum concentrations of tizanidine (increase in Cmax: 7-fold, range: 4–21-fold; increase in AUC: 10-fold, range: 6–24-fold). Increased serum concentrations of tizanidine are associated with hypotensive and sedative adverse reactions.

Methotrexate
Concomitant administration of ciprofloxacin may inhibit the renal tubular transport of methotrexate, leading to increased plasma concentrations of methotrexate and potentially increasing the risk of methotrexate-related toxic reactions. Concomitant use is not recommended (see section "Special Warnings and Precautions for Use").

Theophylline
Concomitant administration of ciprofloxacin and theophylline may lead to an undesirable increase in the serum concentration of theophylline. This may result in theophylline-related adverse reactions, which in isolated cases may be life-threatening or fatal. Serum theophylline concentrations should be monitored and the dose reduced if necessary when used concomitantly (see section "Special Warnings and Precautions for Use").

Other Xanthine Derivatives
Increased serum concentrations of caffeine or pentoxifylline (oxpentifylline) have been reported with concomitant administration of ciprofloxacin.

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

Cyclosporine
Transient increases in serum creatinine levels have been observed with concomitant administration of ciprofloxacin and cyclosporine. Therefore, serum creatinine levels should be monitored regularly (twice weekly) in such patients.

Vitamin K Antagonists
Concomitant administration of ciprofloxacin with a vitamin K antagonist may potentiate its anticoagulant effect. 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 the increase in the international normalized ratio (INR). INR should be monitored regularly in patients receiving vitamin K antagonists (e.g., warfarin, acenocoumarol, phenprocoumon, fluindione) during and shortly after completion of ciprofloxacin therapy.

Duloxetine
Clinical studies have shown that concomitant administration of duloxetine with strong CYP450 1A2 inhibitors, such as fluvoxamine, may lead to increased AUC and Cmax of duloxetine. Although clinical data on a potential interaction with ciprofloxacin are lacking, similar effects may be expected with concomitant use (see section "Special Warnings and Precautions for Use").

Ropinirole
A clinical study demonstrated that concomitant administration of ropinirole with ciprofloxacin, a moderate CYP450 1A2 inhibitor, resulted in a 60% increase in Cmax and an 84% increase in AUC of ropinirole. Monitoring and appropriate dose adjustment of ropinirole are recommended during and shortly after ciprofloxacin therapy (see section "Special Warnings and Precautions for Use").

Lidocaine
It is known that concomitant administration of lidocaine-containing products with ciprofloxacin, a moderate CYP450 1A2 inhibitor, reduces the clearance of intravenous lidocaine by 22% in healthy subjects. Despite normal tolerance of lidocaine, an interaction with ciprofloxacin may occur, associated with adverse reactions.

Clozapine
Concomitant administration of 250 mg ciprofloxacin with clozapine for 7 days increased the serum concentration of clozapine by 29% and N-desmethylclozapine by 31%. Clinical monitoring and appropriate dose adjustment of clozapine are recommended during and shortly after ciprofloxacin therapy (see section "Special Warnings and 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, ciprofloxacin should be prescribed cautiously concomitantly with sildenafil, and the benefit-risk balance should be carefully weighed.

Agomelatine
Clinical studies have shown that fluvoxamine, a strong CYP450 1A2 inhibitor, significantly inhibits the metabolism of agomelatine. This leads to a 60-fold increase in agomelatine exposure. Although there are no clinical data on interaction with ciprofloxacin, a moderate CYP450 1A2 inhibitor, similar effects may be expected with concomitant use (see section "Special Warnings and Precautions for Use").

Zolpidem
Concomitant administration of ciprofloxacin and zolpidem may lead to increased blood levels of zolpidem. Therefore, concomitant use is not recommended.

Safety Precautions.
The ciprofloxacin infusion solution is compatible with Ringer's solution, Ringer's lactate solution, 0.9% sodium chloride solution, 5% and 10% glucose solutions, and 5% and 10% fructose solutions. If the ciprofloxacin solution is mixed with other compatible infusion solutions, the resulting solution should be used immediately after preparation for microbiological and light sensitivity reasons. As the infusion solution is light-sensitive, the bottle should be removed from the packaging immediately before use. Full efficacy of the solution is guaranteed for 3 days under daylight conditions. For single use only. A precipitate may form at low temperatures, which dissolves at room temperature (15–25°C). For ease of use, the stopper should be punctured in the area of the central ring. Puncturing outside the central ring may damage the stopper. Unused solution should be discarded.

Special Warnings and Precautions for Use.
Ciprofloxacin should be avoided in patients who have previously experienced serious adverse reactions to quinolones or fluoroquinolones (see section "Adverse Reactions"). Treatment of such patients with ciprofloxacin should only be initiated if no alternative therapy is available and after careful benefit-risk assessment (see section "Contraindications").

Severe Infections and Mixed Infections Caused by Gram-Positive or Anaerobic Pathogens
Ciprofloxacin should not be used as monotherapy for the treatment of severe infections and infections caused by Gram-positive or anaerobic pathogens. In such cases, ciprofloxacin should be combined with other appropriate antibacterial agents.

Streptococcal Infections (including Streptococcus pneumoniae)
Ciprofloxacin is not recommended for the treatment of streptococcal infections due to insufficient efficacy.

Genital Tract Infections
Epididymo-orchitis and pelvic inflammatory disease may be caused by fluoroquinolone-resistant strains of Neisseria gonorrhoeae. Therefore, for empirical treatment of epididymo-orchitis and pelvic inflammatory disease, ciprofloxacin should only be used in combination with another appropriate antibiotic (e.g., cephalosporins), except in situations where resistance of Neisseria gonorrhoeae strains to ciprofloxacin can be excluded. If no clinical improvement occurs within 3 days, therapy should be re-evaluated.

Urinary Tract Infections
In European Union countries, there is variable resistance to fluoroquinolones among Escherichia coli, the most common cause of urinary tract infections. Local prevalence of E. coli resistance to fluoroquinolones should be considered when prescribing therapy.

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

Traveler's Diarrhea
When selecting ciprofloxacin, information on resistance to ciprofloxacin of relevant pathogens in the countries visited should be considered.

Bone and Joint Infections
Ciprofloxacin should be used in combination with other antimicrobial agents according to the results of microbiological testing.

Pulmonary Form of Anthrax
Recommendations for use in humans are based on in vitro susceptibility data, animal studies, and limited human use data. The physician should act according to national and/or international anthrax treatment protocols.

Children
When using ciprofloxacin in children, official recommendations should be followed. Treatment with ciprofloxacin should only be initiated by a physician experienced in the treatment of cystic fibrosis and severe infections in children. Animal studies have shown that ciprofloxacin causes arthropathy in weight-bearing joints in immature animals. In a clinical study, the increased frequency of arthropathy associated with ciprofloxacin use in children was not statistically significant. Due to the potential adverse effect on joints and/or periarticular tissues, ciprofloxacin should only be used in children after careful benefit-risk assessment (see section "Adverse Reactions").

Bronchopulmonary Infections in Cystic Fibrosis
Children aged 5–17 years were included in clinical trials. 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 only be considered when other treatments are not possible and justified by microbiological test results. Children aged 1–17 years participated in clinical trials.

Other Specific Severe Infections
In cases of other specific severe infections, ciprofloxacin is used according to official recommendations or after careful benefit-risk assessment when alternative treatment is not possible, standard therapy is ineffective, and the use of ciprofloxacin is based on microbiological test results. The use of ciprofloxacin for specific severe infections other than those 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
Hypersensitivity and allergic reactions, including anaphylactic and anaphylactoid reactions, may occur after the first dose of the drug (see section "Adverse Reactions") and may be life-threatening. In such cases, ciprofloxacin should be discontinued immediately, and appropriate medical treatment should be initiated.

Prolonged, Disabling, and Potentially Irreversible Serious Adverse Reactions
In very rare cases, patients receiving quinolones and fluoroquinolones, regardless of age and existing risk factors, have reported prolonged (lasting several months or years), disabling, and potentially irreversible serious adverse reactions affecting various (sometimes multiple simultaneously) body systems, including the musculoskeletal, nervous, and sensory systems, and the psyche. Upon the first signs or symptoms of any serious adverse reaction, ciprofloxacin should be discontinued immediately, and medical advice should be sought.

Tendinitis and Tendon Rupture
Generally, ciprofloxacin should not be used in patients with tendon disorders or injuries related to previous quinolone use. However, in very rare cases, after microbiological testing of the pathogen and careful benefit-risk assessment, ciprofloxacin may be prescribed to these patients for the treatment of certain severe infections, particularly in cases of ineffective standard therapy or bacterial resistance, when microbiological data justify the use of ciprofloxacin. Tendinitis and tendon rupture (particularly of the Achilles tendon), sometimes bilateral, may occur within 48 hours of starting treatment with quinolones and fluoroquinolones and, as reported, even several months after discontinuation of treatment. The risk of tendinitis and tendon rupture is increased in elderly patients, patients with renal impairment, patients with transplanted organs, and patients receiving concomitant corticosteroids. Therefore, concomitant use of corticosteroids should be avoided. Upon first signs of tendinitis (e.g., painful swelling, inflammation), treatment should be discontinued, and alternative therapy should be considered. The affected limb should be treated appropriately (e.g., immobilization). Corticosteroids should not be used if signs of tendinopathy occur.

Patients with Myasthenia Gravis
Ciprofloxacin should be used with caution in patients with myasthenia gravis due to the potential for exacerbation of symptoms (see section "Adverse Reactions").

Aneurysm or Aortic Dissection, Valve Regurgitation/Insufficiency
Epidemiological studies suggest an increased risk of aneurysm and aortic dissection, particularly in the elderly, and regurgitation of aortic and mitral valves after fluoroquinolone use. Cases of aneurysm and aortic dissection, sometimes complicated by rupture (including fatal cases), and regurgitation/insufficiency of any heart 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 treatment options in patients with a family history of aneurysm or congenital heart valve defect, or in patients with an existing diagnosis of aortic aneurysm, aortic dissection, heart valve disease, or predisposition and other risk factors:

• in aortic aneurysm, aortic dissection, valve regurgitation/insufficiency (e.g., connective tissue disorders such as Marfan syndrome, Ehlers-Danlos syndrome, Turner syndrome, Behçet's disease, hypertension, rheumatoid arthritis);
• in aortic aneurysm and dissection (e.g., vascular disorders such as Takayasu arteritis, giant cell arteritis, known atherosclerosis, Sjögren's syndrome);
• in heart valve regurgitation/insufficiency (e.g., infective endocarditis).

The risk of aneurysm or aortic dissection and rupture may be increased in patients concurrently taking systemic corticosteroids. In case of sudden abdominal, chest, or back pain, patients should seek immediate medical attention. Patients should be advised to seek immediate medical help if acute shortness of breath, sudden palpitations, or development of abdominal or lower limb edema occurs.

Visual Disturbances
In case of visual disturbances or other ocular disorders, an ophthalmologist should be consulted urgently.

Photosensitization
It is known that ciprofloxacin causes photosensitization. Patients are advised to avoid direct sunlight and ultraviolet radiation during ciprofloxacin therapy (see section "Adverse Reactions").

Seizures
It is known that ciprofloxacin, like other quinolones, may cause seizures or lower the seizure threshold. Cases of epileptic status have been reported. Therefore, ciprofloxacin should be used with caution in patients with CNS disorders that may predispose to seizures. In case of seizures, ciprofloxacin should be discontinued immediately (see section "Adverse Reactions").

Peripheral Neuropathy
Cases of sensory or sensorimotor polyneuropathy leading to paresthesia, hypoesthesia, dysesthesia, or weakness have been reported in patients taking quinolones or fluoroquinolones. Patients taking ciprofloxacin who experience symptoms of neuropathy such as pain, burning, tingling, numbness, or weakness should inform their physician to prevent potentially irreversible conditions (see section "Adverse Reactions").

Psychotic Reactions
Psychotic reactions may occur even after the first dose of ciprofloxacin. In rare cases, depression or psychosis may be accompanied by suicidal thoughts/ideation, which may lead to suicide or suicide attempts. In such cases, ciprofloxacin should be discontinued immediately.

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

• congenital long QT syndrome;
• concomitant use of medicinal products known to prolong the QT interval (e.g., class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, neuroleptics);
• uncorrected electrolyte imbalance (e.g., hypokalemia, hypomagnesemia);
• heart disease (e.g., heart failure, myocardial infarction, bradycardia).

Elderly patients and women are 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", "Dosage and Administration", "Overdose", and "Adverse Reactions").

Dysglycemia
As with other quinolones, disturbances in blood glucose levels, including both hypoglycemia and hyperglycemia (see section "Adverse Reactions"), have been reported, usually in elderly patients with diabetes mellitus who are concomitantly taking oral hypoglycemic agents (e.g., glyburide) or insulin. Cases of hypoglycemic coma have been documented. Careful monitoring of blood glucose levels is recommended in diabetic patients.

Gastrointestinal Tract
The occurrence of severe and persistent diarrhea during or after treatment (even weeks after treatment) may indicate pseudomembranous colitis (life-threatening, potentially fatal), which requires immediate treatment (see section "Adverse Reactions"). In such cases, ciprofloxacin should be discontinued and appropriate treatment initiated. In this situation, drugs that inhibit peristalsis are contraindicated.

Kidneys and Urinary Tract
Crystalluria has been reported during ciprofloxacin use (see section "Adverse Reactions"). Patients receiving ciprofloxacin should receive adequate fluid intake and avoid excessive urine alkalinity.

Renal Impairment
Since ciprofloxacin is primarily excreted unchanged by the kidneys, dose adjustment is necessary in patients with renal impairment as specified in the "Dosage and Administration" section to avoid increased frequency of adverse reactions due to ciprofloxacin accumulation.

Hepatobiliary System
Cases of liver necrosis and development of life-threatening liver failure have been reported with ciprofloxacin use (see section "Adverse Reactions"). If any signs or symptoms of liver disease occur (anorexia, jaundice, dark urine, pruritus, or abdominal distension), 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 use should be avoided in these patients, except when the expected benefit outweighs the potential risk. In such cases, monitoring for possible hemolysis is necessary.

Resistance
Resistant pathogens may be isolated during or after a course of ciprofloxacin treatment, both in clinically defined superinfections and without them. There is a risk of selection of ciprofloxacin-resistant pathogens during prolonged treatment courses and/or nosocomial infections and/or infections caused by Staphylococcus and Pseudomonas species.

Cytochrome P450
Ciprofloxacin inhibits CYP 1A2 and may therefore cause increased serum concentrations of concomitantly administered substances metabolized by this enzyme system (e.g., theophylline, clozapine, olanzapine, ropinirole, tizanidine, duloxetine, agomelatine). Therefore, patients receiving these substances concomitantly with ciprofloxacin should be closely monitored for possible clinical signs of overdose. Serum concentration determination (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.

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
The in vitro activity of ciprofloxacin against Mycobacterium tuberculosis may lead to false-negative culture results in patients currently taking ciprofloxacin.

Injection Site Reactions
Venous irritation has been reported with intravenous administration of ciprofloxacin. Such reactions are more common when the infusion lasts 30 minutes or less. They may manifest as local skin reactions that quickly resolve after completion of the infusion. Repeated intravenous administration is contraindicated only if such reactions recur or worsen.

Sodium Content
This medicinal product contains 15.43 mmol (or 354.7 mg) of sodium in 100 mL. Caution is advised when administering to patients on a sodium-controlled diet.

Use During Pregnancy or Breastfeeding.

Pregnancy
Data on the use of ciprofloxacin in pregnant women indicate no development of malformations or fetotoxic/neonatal toxicity. Animal studies did not reveal direct or indirect toxic effects on reproductive function. In young and prenatal animals exposed to quinolones, effects on immature cartilage tissue were observed. Therefore, the possibility that the drug may be harmful to the joint cartilage of the newborn/fetus cannot be excluded (see section "Pharmacological Properties"). Therefore, it is preferable to avoid the use of ciprofloxacin during pregnancy.

Breastfeeding 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 or Operating Machinery.
Due to neurological effects, ciprofloxacin may affect reaction speed; therefore, the ability to drive or operate machinery may be impaired.

Dosage and Administration.
The dose depends on the indication, severity and site of infection, pathogen susceptibility to ciprofloxacin, patient renal function, and body weight in the case of children. The duration of treatment depends on the severity of the disease and the clinical and bacteriological picture. If clinically indicated and according to the physician's judgment, initial intravenous administration may be switched to tablet or suspension use. Such a switch from intravenous to oral therapy should be made as early as possible. In severe cases or if the patient is unable to take tablets (e.g., in case of enteral feeding), intravenous therapy should be used until oral ciprofloxacin administration becomes possible. Treatment of infections caused by certain pathogens (e.g., Pseudomonas aeruginosa, Acinetobacter, or staphylococci) may require higher doses of ciprofloxacin and concomitant use of other appropriate antibacterial agents. Treatment of some infections (e.g., pelvic inflammatory disease, intra-abdominal infections, infections in patients with neutropenia, and bone and joint infections), depending on the pathogen, may require additional use of other antimicrobial agents.

Adults

Children

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

Patients with renal and hepatic impairment Recommended initial and maintenance doses for patients with renal function impairment:

For patients with hepatic impairment, no dose adjustment is required. Doses for children with renal and/or hepatic impairment have not been studied.

Route of Administration

The medicinal product should be visually inspected before administration. Do not use cloudy infusion solutions. Ciprofloxacin should be administered by intravenous infusion. For children, the infusion duration is 60 minutes. For adults, the infusion duration is 60 minutes for 400 mg and 30 minutes for 200 mg of Ciflosin. Slow administration into a large vein reduces the potential for patient discomfort and decreases the risk of venous irritation. The infusion solution may be administered either separately or after prior mixing with compatible infusion solutions (see section "Special precautions for safety").

Children

Due to the potential adverse effects on joints and periarticular tissues, ciprofloxacin should be used in children only after careful benefit-risk assessment (see section "Special considerations"). Ciprofloxacin is not recommended for use in children for the treatment of other infectious diseases except those specified in the section "Indications", as stated in the section "Dosage and administration".

Overdose

Moderate toxicity symptoms have been reported following overdoses of 12 g of the drug. Acute overdose of 16 g has been reported to cause acute renal failure. Symptoms of overdose include dizziness, tremor, headache, increased fatigue, seizures, hallucinations, confusion, abdominal discomfort, renal and hepatic dysfunction, as well as crystalluria and hematuria. Reversible nephrotoxicity has also been observed. In addition to standard emergency measures such as gastric lavage and activated charcoal administration, renal function should be monitored, including urine pH, and urine acidity should be increased if necessary to prevent crystalluria. Patients should receive adequate fluid intake. Antacids containing calcium or magnesium may theoretically reduce ciprofloxacin absorption in cases of overdose. Only a small amount of ciprofloxacin (<10%) is removed by hemodialysis or peritoneal dialysis. In cases of overdose, symptomatic treatment should be administered. Due to the potential for QT interval prolongation, ECG monitoring is required.

Adverse Reactions

The most frequently reported adverse reactions include nausea, diarrhea, vomiting, transient elevation of transaminase levels, rash, and injection site reactions. Data on adverse reactions obtained from clinical trials and post-marketing surveillance of ciprofloxacin (oral, intravenous, and sequential therapy) are listed below according to their frequency of occurrence. The frequency analysis includes data from both oral and intravenous administration of ciprofloxacin. Frequency is defined as follows: common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10000 to <1/1000), very rare (<1/10000), frequency not known (cannot be estimated from available data).

Infections and infestations

Uncommon: fungal superinfections.

Blood and lymphatic system disorders

Uncommon: eosinophilia.
Rare: leukopenia, anemia, neutropenia, leukocytosis, thrombocytopenia, thrombocytosis.
Very rare: hemolytic anemia, agranulocytosis, pancytopenia (life-threatening), bone marrow function suppression (life-threatening).

Immune system disorders

Rare: allergic reactions, allergic/angioneurotic edema.
Very rare: anaphylactic reactions, anaphylactic shock (life-threatening) (see section "Special considerations"), serum sickness-like reactions.

Metabolism and nutrition disorders

Uncommon: decreased appetite.
Rare: hyperglycemia, hypoglycemia (see section "Special considerations").
Frequency not known: hypoglycemic coma (see section "Special considerations").

Psychiatric disorders*

Uncommon: psychomotor hyperactivity/anxiety.
Rare: confusion and disorientation, restlessness, pathological dreams, depression (with possible suicidal thoughts/ideation or suicide attempts/acts) (see section "Special considerations"), hallucinations.
Very rare: psychotic reactions (with possible suicidal thoughts/ideation or suicide attempts/acts) (see section "Special considerations").
Frequency not known: mania, including hypomania.

Nervous system disorders*

Uncommon: headache, dizziness, sleep disorders, taste disturbances.
Rare: paresthesia and dysesthesia, hypesthesia, tremor, seizures (including epileptic status, see section "Special considerations"), vertigo.
Very rare: migraine, coordination disorders, gait disturbances, olfactory disturbances, intracranial hypertension.
Frequency not known: peripheral neuropathy and polyneuropathy (see section "Special considerations").

Eye disorders*

Rare: visual disturbances (e.g., diplopia).
Very rare: color vision disturbances.

Ear and labyrinth disorders*

Rare: tinnitus, hearing loss/impairment.

Cardiac disorders**

Rare: tachycardia.
Frequency not known: ventricular arrhythmia, torsades de pointes (predominantly in patients with risk factors for QT interval prolongation), QT interval prolongation on ECG (see sections "Special considerations" and "Overdose").

Vascular disorders**

Rare: vasodilation, hypotension, syncope.
Very rare: vasculitis.

Respiratory, thoracic and mediastinal disorders

Rare: dyspnea (including asthmatic conditions).

Gastrointestinal disorders

Common: nausea, diarrhea.
Uncommon: vomiting, gastrointestinal pain, abdominal pain, dyspepsia, flatulence.
Rare: pseudomembranous colitis (very rarely with potentially fatal outcome) (see section "Special considerations").
Very rare: pancreatitis.

Hepatobiliary disorders

Uncommon: increased levels of transaminases and bilirubin.
Rare: hepatic dysfunction, cholestatic jaundice, hepatitis.
Very rare: hepatic necrosis (very rarely progressing to life-threatening liver failure) (see section "Special considerations").

Endocrine disorders

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

Skin and subcutaneous tissue disorders

Uncommon: rash, pruritus, urticaria.
Rare: photosensitization (see section "Special considerations").
Very rare: petechiae, erythema multiforme, nodular erythema, Stevens-Johnson syndrome (potentially life-threatening), toxic epidermal necrolysis (potentially life-threatening).
Frequency not known: acute generalized exanthematous pustulosis (AGEP), 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, cramps.
Very rare: muscle weakness, tendinitis, tendon ruptures (predominantly Achilles tendons) (see section "Special considerations"), exacerbation of symptoms of myasthenia gravis (see section "Special considerations").

Renal and urinary disorders

Uncommon: renal dysfunction.
Rare: renal failure, hematuria, crystalluria (see section "Special considerations"), tubulointerstitial nephritis.

General disorders and administration site conditions*

Common: infusion site reactions (only with intravenous administration).
Uncommon: asthenia, fever.
Rare: edema, increased sweating (hyperhidrosis).

Investigations

Uncommon: increased alkaline phosphatase levels in blood.
Rare: increased amylase levels.
Frequency not known: increased INR (in patients taking vitamin K antagonists).

* In very rare cases, patients receiving quinolones and fluoroquinolones, regardless of age and existing risk factors, have reported long-term (lasting months or years), disabling, and potentially irreversible serious adverse reactions affecting various systems and sensory organs, sometimes multiple simultaneously (including reactions such as tendinitis, tendon rupture, arthralgia, limb pain, gait disturbances, neuropathy-related paresthesias, depression, fatigue, memory impairment, sleep disturbances, hearing, vision, taste, and smell disturbances) (see section "Special considerations").

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

The following adverse reactions occur more frequently in patients receiving intravenous or sequential (intravenous followed by oral) treatment:

• Common: vomiting, transient elevation of transaminase levels, rash.
• Uncommon: thrombocytopenia, thrombocytosis, confusion and disorientation, hallucinations, paresthesias and dysesthesias, seizures, vertigo, visual disturbances, hearing loss, tachycardia, vasodilation, arterial hypotension, transient hepatic dysfunction, cholestatic jaundice, renal failure, edema.
• Rare: pancytopenia, bone marrow suppression, anaphylactic shock, psychotic reactions, migraine, olfactory disturbances, hearing disturbances, vasculitis, pancreatitis, hepatic necrosis, petechiae, tendon rupture.

Children

The above-mentioned frequency of arthropathy (arthralgia, arthritis) is based on data from studies in adults. In children, arthropathy is reported to occur more frequently (see section "Special considerations").

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after drug authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions through the national reporting system.

Shelf life

3 years.

Storage conditions

Store in the original packaging at a temperature not exceeding 25°C, in a place inaccessible to children. Do not refrigerate. Do not freeze.

Incompatibilities

The medicinal product must not be used simultaneously with other medicinal products except those specified in the section "Special precautions for safety". Infusion solutions, if compatibility with other solutions or medicinal products has not been confirmed, must be administered separately. Visual signs of incompatibility include, for example, precipitation, cloudiness, or color change. The medicinal product is incompatible with all infusion solutions or medicinal products that are physically or chemically unstable at the pH of the ciprofloxacin solution (e.g., penicillin, heparin solutions), especially when combined with alkaline solutions (pH of ciprofloxacin solution is 3.9–4.5).

Packaging

100 ml in a vial, 1 vial in a carton.

Prescription status

Prescription only.

Manufacturer

Private Joint-Stock Company "Infuziya".

Manufacturer's address and location of operations

84A Nemirivske Highway, Vinnytski Khotory, Vinnytsia district, Vinnytsia region, 23219, Ukraine.