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

Composition:

Active ingredient: ciprofloxacin;

1 ml of solution contains 2 mg of ciprofloxacin in the form of lactate;

Excipients: sodium lactate, sodium chloride, hydrochloric acid, water for injections.

Pharmaceutical form. Infusion solution.

Main physicochemical properties: transparent solution of yellowish-green color, practically free from mechanical particles.

Pharmacotherapeutic group. Antibacterials for systemic use. Fluoroquinolones. Ciprofloxacin. ATC code J01M A02.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

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

Pharmacokinetic / pharmacodynamic relationships

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

Mechanism of resistance

Resistance to ciprofloxacin in vitro is usually associated with target-site mutations occurring in topoisomerase IV and DNA gyrase through multiple-step mutations. As a result, the extent of cross-resistance among ciprofloxacin and other fluoroquinolones may vary. Single mutations usually do not lead to clinical resistance; however, multiple mutations typically result in clinical resistance to several or all members of the fluoroquinolone class.

Mechanisms of resistance such as impermeability and/or efflux pumps may differentially affect susceptibility to fluoroquinolones, depending on the physicochemical properties of individual agents within this class and the affinity of transport systems for each active substance. All resistance mechanisms observed in vitro are generally found in clinical isolates. Resistance mechanisms that inactivate other antibacterial agents, such as permeability barriers (inherent in Pseudomonas aeruginosa) and efflux mechanisms, may also influence susceptibility to ciprofloxacin.

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

Spectrum of antibacterial activity

Breakpoints distinguish susceptible strains from those with intermediate susceptibility, and the latter from resistant strains.

EUCAST recommendations

Microorganisms	Susceptible (S)	Resistant (R)
Enterobacteriaceae	≤ 0.25 mg/L	> 0.5 mg/L
Salmonella spp.	≤ 0.06 mg/L	> 0.06 mg/L
Pseudomonas spp.	≤ 0.5 mg/L	> 0.5 mg/L
Acinetobacter spp.	≤ 1 mg/L	> 1 mg/L
Staphylococcus spp.1	≤ 1 mg/L	> 1 mg/L
Haemophilus influenzae	≤ 0.06 mg/L	> 0.06 mg/L
Moraxella catarrhalis	≤ 0.125 mg/L	> 0.125 mg/L
Neisseria gonorrhoeae	≤ 0.03 mg/L	> 0.06 mg/L
Neisseria meningitidis	≤ 0.03 mg/L	> 0.03 mg/L
Non-species-related breakpoints2	≤ 0.25 mg/L	> 0.5 mg/L
1Staphylococcus spp. – breakpoints for ciprofloxacin apply to high-dose therapy. 2Non-species-related breakpoints were primarily determined based on pharmacokinetic/pharmacodynamic data and are not dependent on 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 in isolated species may vary depending on the region 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 at which the benefit of using the drug is questionable, at least for certain types of infections.

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

Susceptible (usually) microorganisms

Aerobic gram-positive microorganisms

Bacillus anthracis¹⁾

Aerobic gram-negative microorganisms

Aeromonas spp.

Brucella spp.

Citrobacter koseri

Francisella tularensis

Haemophilus ducreyi

Haemophilus influenzae²⁾

Legionella spp.

Moraxella catarrhalis²⁾

Neisseria meningitidis

Pasteurella spp.

Salmonella spp.²⁾

Shigella spp.²⁾

Vibrio spp.

Yersinia pestis

Anaerobic microorganisms

Mobiluncus

Other microorganisms

Chlamydia trachomatis³⁾

Chlamydia pneumoniae³⁾

Mycoplasma hominis³⁾

Mycoplasma pneumoniae³⁾

Microorganisms capable of developing acquired resistance

Aerobic gram-positive microorganisms

Enterococcus faecalis³⁾

Staphylococcus spp.^{2), 4)}

Aerobic gram-negative microorganisms

Acinetobacter baumannii⁵⁾

Burkholderia cepacia^{2), 5)}

Campylobacter spp.^{2), 5)}

Citrobacter freundii²⁾

Enterobacter aerogenes

Enterobacter cloacae²⁾

Escherichia coli²⁾

Klebsiella oxytoca

Klebsiella pneumoniae²⁾

Morganella morganii²⁾

Neisseria gonorrhoeae²⁾

Proteus mirabilis²⁾

Proteus vulgaris²⁾

Providencia spp.

Pseudomonas aeruginosa²⁾

Pseudomonas fluorescens

Serratia marcescens²⁾

Anaerobic microorganisms

Peptostreptococcus spp.

Propionibacterium acnes

Microorganisms inherently resistant to ciprofloxacin

Aerobic gram-positive microorganisms

Actinomyces

Enterococcus faecium

Listeria monocytogenes

Aerobic gram-negative microorganisms

Stenotrophomonas maltophilia

Anaerobic microorganisms

With the exception of those specified above

Other microorganisms

Mycoplasma genitalium

Ureaplasma urealyticum

Studies have been conducted in experimental animals infected via the airborne route with spores of Bacillus anthracis; these studies demonstrate that antibiotic administration immediately after exposure to the pathogen helps prevent disease, provided the spore burden can be reduced below the infectious 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 course of oral ciprofloxacin 500 mg twice daily is considered effective for prevention of anthrax infection in adults. Physicians should refer to national and/or international anthrax treatment guidelines.
Clinical efficacy has been demonstrated for susceptible isolates in approved clinical indications.
Natural intermediate susceptibility in the absence of acquired resistance mechanisms.
Methicillin-resistant S. aureus is very frequently cross-resistant to fluoroquinolones.

The methicillin resistance rate among all staphylococcal species is approximately 20–50% and is usually high among hospital isolates.

Resistance rate ≥ 50% in one or more European Union countries.

Pharmacokinetics.

Absorption

With intravenous infusion, the mean maximum concentration of ciprofloxacin is achieved at the end of the infusion. The pharmacokinetics of ciprofloxacin after intravenous administration are linear within the dose range up to 400 mg.

When comparing pharmacokinetic parameters after intravenous administration twice versus three times daily, no accumulation of ciprofloxacin or its metabolites was observed.

An intravenous infusion of 200 mg ciprofloxacin administered over 60 minutes every 12 hours is characterized by an AUC equivalent to that after an oral dose of 250 mg ciprofloxacin every 12 hours.

An intravenous infusion of 400 mg ciprofloxacin administered over 60 minutes every 12 hours is bioequivalent in terms of AUC to an oral dose of 500 mg ciprofloxacin every 12 hours.

Cmax values after intravenous infusion of 400 mg ciprofloxacin administered over 60 minutes every 12 hours are similar to those after an oral dose of 750 mg ciprofloxacin every 12 hours.

An intravenous infusion of 400 mg ciprofloxacin administered over 60 minutes every 8 hours is equivalent in terms of AUC to an oral dose of 750 mg ciprofloxacin 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 volume of distribution at steady state, ranging from 2 to 3 L/kg body weight. Ciprofloxacin achieves high concentrations in various tissues, such as lungs (epithelial lining fluid, alveolar macrophages, biopsy specimens), sinuses, inflamed and damaged tissues (bulla fluid), and genitourinary tissues (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, but to a lesser extent than the parent compound.

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

Elimination

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

Excretion of ciprofloxacin (% of dose) after oral administration.

Name	Excretion pathways
Name	In urine	In feces
Ciprofloxacin	61.5	15.2
Metabolites (M1–M4)	9.5	2.6

Renal clearance ranges from 180 to 300 mL/kg/h, and total clearance ranges from 480 to 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. Approximately 1% of the dose is excreted via the biliary tract. Ciprofloxacin is present in high concentrations in bile.

Children

Pharmacokinetic data in children are limited.

In studies involving children aged 1 year and older, no age-dependent differences in Cmax or AUC were observed. After repeated administration of the drug (10 mg/kg three times daily), no significant increase in Cmax or 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) following a one-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) 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.

Ciprinol®, infusion solution, is indicated for the treatment of the following infections (see sections “Pharmacodynamics” and “Special instructions”). Before initiating therapy, particular attention should be paid to all available information regarding resistance to ciprofloxacin.

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

Adults.

Lower respiratory tract infections caused by Gram-negative bacteria:
- 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 treatment of these infections);
- bronchopulmonary infections in cystic fibrosis or bronchiectasis;
- pneumonia.
Chronic suppurative otitis media.
Acute exacerbations of chronic sinusitis, particularly when caused by Gram-negative bacteria.
Urinary tract infections:
- acute pyelonephritis;
- complicated urinary tract infections;
- bacterial prostatitis.
Genital system infections:
- orchitis and epididymitis, including those caused by Neisseria gonorrhoeae strains;
- pelvic inflammatory disease, including that caused by Neisseria gonorrhoeae strains.
Gastrointestinal tract infections (e.g., traveler’s diarrhea).
Intra-abdominal infections.
Skin and soft tissue infections caused by Gram-negative bacteria.
Severe external otitis.
Bone and joint infections.
Inhalational anthrax (post-exposure prophylaxis and radical treatment).

Ciprofloxacin may be used in neutropenic patients if fever is suspected to be due to 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 radical 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 managing cystic fibrosis and/or severe infections in children and adolescents (see sections “Pharmacodynamics” and “Special instructions”).

Contraindications.

Hypersensitivity to ciprofloxacin or to any other component of the medicinal product, as well as to other fluoroquinolones.

Concomitant administration of ciprofloxacin and tizanidine (see section “Interaction with other medicinal products and other types of interactions”).

Interaction with other medicinal products and other types of interactions.

Effects 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 instructions”).

Probenecid

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

Effects of ciprofloxacin on other medicinal products

Tizanidine

Tizanidine must not be administered 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 (increase in Cmax by 7-fold, range: 4–21 times; increase in AUC by 10-fold, range: 6–24 times). Elevated tizanidine plasma concentrations are associated with enhanced 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 use is not recommended (see section “Special instructions”).

Theophylline

Concomitant administration of ciprofloxacin and theophylline may lead to undesirable increases in theophylline plasma concentrations, which may result in adverse reactions. In isolated cases, such adverse reactions may be life-threatening or fatal. If concomitant use of these agents cannot be avoided, theophylline plasma concentrations should be monitored and the dose reduced as necessary (see section “Special instructions”).

Other xanthine derivatives

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

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 (twice weekly) of serum creatinine concentrations is necessary in such 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 infection, age, and general condition of the patient, making it difficult to precisely assess the impact of ciprofloxacin on the increase in International Normalized Ratio (INR). Frequent monitoring of INR is required during and immediately after concomitant administration of ciprofloxacin and vitamin K antagonists (e.g., warfarin, acenocoumarol, phenprocoumon, or fluindione).

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 instructions”).

Ropinirole

Clinical studies have shown that concomitant administration of ropinirole with ciprofloxacin, a moderate inhibitor of the CYP450 1A2 isoenzyme, increases the Cmax and AUC of ropinirole by 60% and 84%, respectively. Monitoring for ropinirole adverse reactions and appropriate dose adjustment are recommended during and immediately after concomitant use with ciprofloxacin (see section “Special instructions”).

Lidocaine

In healthy volunteers, concomitant administration of ciprofloxacin, a moderate inhibitor of cytochrome P450 1A2 isoenzymes, and lidocaine-containing medicinal products has been reported to reduce the clearance of intravenous lidocaine by 22%. Despite normal tolerability of lidocaine treatment, interaction with ciprofloxacin may be associated with adverse reactions upon concomitant administration of these agents.

Clozapine

Concomitant administration of 250 mg ciprofloxacin with clozapine for 7 days increased serum concentrations of clozapine and N-desmethylclozapine 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 instructions”).

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 ciprofloxacin is used concomitantly with sildenafil, considering the risk/benefit ratio.

Agomelatine

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

Zolpidem

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

Special precautions for use.

The use of ciprofloxacin should be avoided in patients who have previously experienced serious adverse reactions to drugs containing quinolones or fluoroquinolones (see section "Adverse reactions"). Treatment with ciprofloxacin in such patients should only be initiated if no alternative treatment options are available and after careful assessment of the benefit-risk ratio (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.

Infections of the genital system

Fluoroquinolone-resistant strains of Neisseria gonorrhoeae may cause epididymo-orchitis and pelvic inflammatory disease. Empirical therapy with ciprofloxacin for epididymo-orchitis and pelvic inflammatory disease may only be used in combination with other appropriate antibacterial agents (e.g., cephalosporins), except in clinical situations where resistant strains of Neisseria gonorrhoeae to ciprofloxacin have been ruled out. If no clinical improvement occurs within 3 days, therapy should be re-evaluated.

Urinary tract infections

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

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 ciprofloxacin resistance of relevant microorganisms in countries visited by the patient should be taken into account.

Bone and joint infections

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

Pulmonary form of anthrax

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

Children

The use of ciprofloxacin in children and adolescents should be conducted in accordance with current official recommendations. Treatment with ciprofloxacin should only be administered by physicians experienced in treating children and adolescents 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 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, by day 42 of treatment. The incidence of drug-related arthropathy at 1 year of follow-up was 9.0% and 5.7%, respectively. The increase in arthropathy cases related to drug use was not statistically significant. However, treatment with ciprofloxacin in children and adolescents should only be initiated after careful assessment of the benefit-risk ratio due to the potential risk of adverse reactions affecting joints and/or surrounding tissues (see section "Adverse reactions").

Respiratory tract infections in cystic fibrosis

Clinical studies included children and adolescents aged 5–17 years. Experience in treating children aged 1 to 5 years is more limited.

Complicated urinary tract infections and pyelonephritis

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

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

Other specific severe infections

The use of ciprofloxacin may be justified based on microbiological test results for other severe infections according to official recommendations or after careful benefit-risk assessment when alternative treatments are not possible or 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

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.

Long-lasting, disabling, and potentially irreversible adverse reactions

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

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

Tendinitis and tendon rupture

Ciprofloxacin should generally not be used in patients with tendon disorders or injuries related to prior quinolone use. However, in very rare cases, after microbiological testing and careful benefit-risk assessment, ciprofloxacin may be prescribed to such patients for the treatment of certain severe infections, particularly when standard therapy is ineffective or bacterial resistance is present, and microbiological data justify its use.

Tendinitis and tendon rupture (especially of the Achilles tendon), sometimes bilateral, may occur within the first 48 hours of treatment with quinolones and fluoroquinolones and have been reported even several months after discontinuation of therapy. The risk of tendinitis and tendon rupture is increased in elderly patients, patients with renal impairment, patients with solid organ transplants, and those receiving concomitant corticosteroids. Therefore, concomitant use of corticosteroids should be avoided.

Treatment with ciprofloxacin should be discontinued at the first signs of tendinitis (e.g., painful swelling, inflammation), and alternative therapy should be considered. The affected limb should be managed 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, as symptoms may worsen (see section "Adverse reactions").

Aneurysm and aortic dissection, valvular regurgitation/insufficiency

Epidemiological studies have shown an increased risk of aortic aneurysm and dissection, as well as aortic and mitral valve regurgitation, following fluoroquinolone use, particularly in elderly individuals. Cases of aortic aneurysm and dissection, sometimes complicated by rupture (including fatal cases), and valvular 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 therapeutic options in patients with a family history of aortic aneurysm or congenital heart valve defects, patients previously diagnosed with aortic aneurysm and/or aortic dissection, patients with heart valve disease, and in the presence of other risk factors:

Risk factors for aortic aneurysm and/or dissection and valvular regurgitation/insufficiency: connective tissue disorders such as Marfan syndrome, Ehlers-Danlos syndrome, Turner syndrome, Behçet’s disease, hypertension, rheumatoid arthritis;
Risk factors for aortic aneurysm and dissection: vascular disorders such as Takayasu arteritis or giant cell arteritis, atherosclerosis, Sjögren’s syndrome;
Risk factors for valvular regurgitation/insufficiency: infective endocarditis.

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

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

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

Visual disturbances

In case of visual impairment or any noticeable effect on the eyes, patients should immediately consult a physician.

Photosensitivity

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

Seizures

Ciprofloxacin, like other quinolones, is known to cause seizures or lower the seizure threshold. Cases of epileptic status have been reported. Ciprofloxacin should be used with caution in patients with CNS disorders predisposing to seizures. If seizures occur, ciprofloxacin should be discontinued (see section "Adverse reactions").

Peripheral neuropathy

Cases of sensory or sensorimotor polyneuropathy leading to paresthesia, hypoaesthesia, dysesthesia, or weakness have been observed in patients receiving quinolones or fluoroquinolones. Patients taking ciprofloxacin should inform their physician before continuing treatment if symptoms of neuropathy such as pain, burning, tingling, numbness, or weakness develop, to prevent potentially irreversible conditions (see section "Adverse reactions").

Psychotic reactions

Psychotic reactions may occur even after the first dose of ciprofloxacin. In very rare cases, depression or psychosis may progress to suicidal thoughts and behaviors, including suicide or suicide attempts. If depression, psychotic reactions, or suicidal thoughts or behaviors occur, ciprofloxacin should be discontinued.

Cardiac disorders

Fluoroquinolones, including ciprofloxacin, should be used with caution in patients with known 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);
Unresolved electrolyte imbalances (e.g., hypokalemia, hypomagnesemia);
Presence of cardiac diseases (e.g., heart failure, myocardial infarction, bradycardia).

Women and elderly patients may be more sensitive to drugs that prolong the QTc interval. Therefore, fluoroquinolones, including ciprofloxacin, should be used cautiously in these patient groups (see sections "Interaction with other medicinal products and other forms of interaction", "Method of administration and dosage" (Elderly patients), "Overdose", "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 receiving concomitant oral hypoglycemic agents (e.g., glibenclamide) or insulin. Cases of hypoglycemic coma have been reported. Diabetic patients are advised to closely monitor blood glucose levels.

Gastrointestinal tract

The occurrence of severe and persistent diarrhea during or after treatment, even several weeks after therapy, may indicate the development of antibiotic-associated colitis (potentially life-threatening with possible fatal outcome) and requires immediate treatment (see section "Adverse reactions"). In such cases, 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 receiving 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 necessary in patients with impaired renal function according to the recommendations in the section "Method of administration and dosage" to avoid increased frequency of adverse reactions due to ciprofloxacin accumulation.

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

Cytochrome P450

Ciprofloxacin moderately 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). 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"). 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

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

Injection site reactions

Reactions at the infusion site have been observed with intravenous ciprofloxacin, occurring more frequently when the infusion duration is 30 minutes or less. These may manifest as transient local skin reactions resolving quickly after infusion completion. Further intravenous administration is not contraindicated unless reactions recur or worsen.

Special warnings regarding inactive ingredients

1 ml of ciprofloxacin infusion solution contains 0.1571 mmol (or 3.61 mg) of sodium. Therefore, additional sodium load should be considered for patients on a low-sodium diet (patients with congestive heart failure, renal failure, nephrotic syndrome).

Use during pregnancy or breastfeeding.

Pregnancy

Data on ciprofloxacin use in pregnant women show no evidence of malformations or fetal/neonatal toxicity. Animal studies do not indicate direct or indirect toxic effects on reproductive function. However, effects on immature cartilage have been observed in young animals and animals exposed to quinolones before birth; therefore, the possibility that ciprofloxacin may be harmful to the joint cartilage of newborns/fetus cannot be excluded. Therefore, during pregnancy, ciprofloxacin use should be avoided to prevent potential adverse effects on the fetus.

Period of breastfeeding

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.

Ciprofloxacin may affect a patient's ability to drive or operate machinery due to nervous system reactions. Therefore, the ability to drive or operate machinery may be impaired.

Dosage and Administration.

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

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

If clinically indicated and according to physician's judgment, initial intravenous administration may be switched to tablets or suspension. Such transition from intravenous to oral therapy should be performed as early as possible. In severe cases or when the patient is unable to take tablets (e.g., a patient receiving enteral nutrition), therapy should be initiated with intravenous ciprofloxacin until oral administration becomes feasible.

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

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

Adults

Indications		Daily dose, mg	Total duration (may include initial parenteral administration of ciprofloxacin)
Infections of the lower respiratory tract		From 400 mg twice daily to 400 mg three times daily	7–14 days
Infections of the upper respiratory tract	Exacerbation of chronic sinusitis	From 400 mg twice daily to 400 mg three times daily	7–14 days
	Chronic suppurative otitis media	From 400 mg twice daily to 400 mg three times daily	7–14 days
	Severe external otitis	400 mg three times daily	From 28 days to 3 months
Urinary tract infections (see section "Special precautions")	Acute and complicated pyelonephritis	From 400 mg twice daily to 400 mg three times daily	From 7 to 21 days; in certain special clinical cases (such as abscesses), treatment may be extended beyond 21 days
	Bacterial prostatitis	From 400 mg twice daily to 400 mg three times daily	2 to 4 weeks (acute)
Infections of the genital organs	Orchiepididymitis and pelvic inflammatory disease caused by susceptible Neisseria gonorrhoeae	From 400 mg twice daily to 400 mg three times daily	At least 14 days
Gastrointestinal and intra-abdominal infections	Diarrhea caused by bacterial pathogens, including Shigella spp., except Shigella dysenteriae type 1, and empirical treatment of severe traveler's diarrhea	From 400 mg twice daily	1 day
	Diarrhea caused by Shigella dysenteriae, type 1	From 400 mg twice daily	5 days
	Diarrhea caused by Vibrio cholerae	From 400 mg twice daily to 400 mg three times daily	3 days
	Typhoid fever	From 400 mg twice daily to 400 mg three times daily	7 days
	Intra-abdominal infections caused by Gram-negative bacteria	From 400 mg twice daily to 400 mg three times daily	5 to 14 days
Skin and soft tissue infections caused by Gram-negative bacteria		From 400 mg twice daily to 400 mg three times daily	7 to 14 days
Bone and joint infections		From 400 mg twice daily to 400 mg three times daily	Up to 3 months
Neutropenic patients with fever when there is suspicion that the elevated body temperature is due to bacterial infection. Ciprofloxacin should be used in combination with other appropriate antibacterial agents according to official guidelines		From 400 mg twice daily to 400 mg three times daily	Treatment should continue throughout the period of neutropenia
Post-exposure prophylaxis and treatment of pulmonary anthrax in individuals who can receive oral therapy, if clinically necessary. Administration should be initiated as soon as possible after suspected or confirmed exposure.		From 400 mg twice daily	60 days from the date of confirmed exposure to Bacillus anthracis

Children and adolescents

Indications	Daily dose, mg	Total duration (may include initial parenteral administration of ciprofloxacin)
Cystic fibrosis	10 mg/kg body weight 3 times daily, with a maximum single dose of 400 mg	10 to 14 days
Complicated urinary tract infections and acute pyelonephritis	From 6 mg/kg body weight 3 times daily up to 10 mg/kg body weight 3 times daily, with a maximum single dose of 400 mg	10 to 21 days
Post-exposure prophylaxis and treatment of pulmonary anthrax in patients who can be treated orally, if clinically indicated. Initiation of the drug should begin as soon as possible after suspected or confirmed exposure	From 10 mg/kg body weight 2 times daily up to 15 mg/kg body weight 2 times daily, with a maximum single dose of 400 mg	60 days from the date of confirmed exposure to Bacillus anthracis
Other severe forms of infections	10 mg/kg body weight 3 times daily, with a maximum single dose of 400 mg	Depending on the type of infection

Geriatric patients

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

Patients with renal impairment

Recommended initial and maintenance doses for patients with impaired renal function:

Creatinine clearance, mL/min/1.73 m2	Serum creatinine, µmol/L	Oral dose, mg
> 60	< 124	See usual dosage
30‑60	124–168	200–400 mg every 12 hours
< 30	>169	200–400 mg every 24 hours
Patients on hemodialysis	>169	200–400 mg every 24 hours (after dialysis)
Patients on peritoneal dialysis	>169	200–400 mg every 24 hours

Hepatic impairment

In patients with hepatic insufficiency, no dosage adjustment of ciprofloxacin is required.

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

Method of administration

The ciprofloxacin infusion solution should be visually inspected before use. The solution must not be used if cloudiness or particulate matter is observed.

Ciprofloxacin should be administered by intravenous infusion. In children, the infusion duration is 60 minutes.

In adult patients, the infusion duration is 60 minutes for the 400 mg (200 mL) ciprofloxacin infusion solution and 30 minutes for the 200 mg (100 mL) ciprofloxacin infusion solution. Slow infusion into a large vein minimizes patient discomfort and reduces the risk of venous irritation.

The solution may be administered undiluted or after addition to compatible infusion solutions (see section "Incompatibility").

For single use only. The smallest volume is 100 mL.

Any unused solution must be discarded.

Compatibility with other solutions

The ciprofloxacin infusion solution is compatible with 0.9% sodium chloride solution, Ringer's solution, Ringer's lactate solution, 5% and 10% glucose solutions, 10% fructose solution, and 5% glucose with 0.225% NaCl or 0.45% NaCl. The mixed solution of ciprofloxacin with compatible infusion solutions should be used as soon as possible due to the risk of microbial contamination and the light sensitivity of the drug (therefore, the vial should be removed from the carton only immediately before use). When protected from direct sunlight, the solution is guaranteed to remain stable for 3 days.

If compatibility with another infusion solution has not been confirmed, the ciprofloxacin infusion solution should be administered separately. Visible signs of incompatibility include precipitation, cloudiness, or discoloration of the solution.

Storage of the ciprofloxacin infusion solution at low temperatures may result in precipitation, which dissolves at room temperature. Therefore, storage of the infusion solution in the refrigerator is not recommended.

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 precautions"). Ciprofloxacin is not recommended for use in children for the treatment of infectious diseases other than those specified in the section "Indications".

Overdose

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

Symptoms of overdose included dizziness, tremor, headache, 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 supportive measures for overdose management, monitoring of renal function is recommended, including determination of urine pH, and, if necessary, alkalinization of urine to prevent crystalluria. Patients should maintain adequate fluid intake.

Antacids containing calcium or magnesium may theoretically reduce ciprofloxacin absorption in overdose.

Hemodialysis or peritoneal dialysis removes only a small amount of ciprofloxacin (< 10%).

In case of overdose, symptomatic treatment should be administered. ECG monitoring is necessary, as QT interval prolongation may occur.

Adverse reactions

The most commonly reported adverse reactions were nausea, diarrhea, vomiting, transient elevations in transaminase levels, rash, and injection site reactions.

Data on adverse reactions to ciprofloxacin obtained during clinical trials and post-marketing surveillance (oral, parenteral, and sequential routes of administration) are presented below.

When analyzing the frequency of occurrence, data from both oral and intravenous routes of ciprofloxacin administration should be considered.

System Organ Class	Common ≥1/100 to <1/10	Uncommon ≥1/1,000 to <1/100	Rare ≥1/10,000 to <1/1,000	Very rare <1/10,000	Frequency not known (cannot be estimated from the available data)
Infections and infestations		Fungal superinfections
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 (potentially life-threatening) (see section "Special warnings and precautions for use"), serum sickness-like reactions
Endocrine disorders					Syndrome of inappropriate secretion of antidiuretic hormone (SIADH)
Metabolism and nutrition disorders		Decreased appetite	Hypoglycemia, hyperglycemia (see section "Special warnings and precautions for use")		Hypoglycemic coma (see section "Special warnings and precautions for use")
Psychiatric disorders*		Psychomotor hyperactivity/anxiety	Confusion and disorientation, restlessness, pathological dreams, depression (with possible suicidal thoughts/ideation or suicide attempts/acts) (see section "Special warnings and precautions for use"), hallucinations	Psychotic reactions (with possible suicidal thoughts/ideation or suicide attempts/acts) (see section "Special warnings and precautions for use")	Mania, hypomania
Nervous system disorders*		Headache, dizziness, sleep disorders, taste disturbances	Paresthesia and dysesthesia, hypoesthesia, tremor, convulsions (including status epilepticus, see section "Special warnings and precautions for use"), vertigo	Migraine, coordination disorders, gait disturbances, olfactory disturbances, intracranial hypertension and pseudotumor cerebri	Peripheral neuropathy and polyneuropathy (see section "Special warnings and precautions for use")
Eye disorders*			Visual disturbances (e.g., diplopia)	Color vision abnormalities
Ear and labyrinth disorders*			Tinnitus, hearing loss/hearing impairment
Cardiac disorders**			Tachycardia		Ventricular arrhythmia and torsades de pointes (observed predominantly in patients with risk factors for QT interval prolongation), QT interval prolongation (see sections "Special warnings and precautions for use", "Overdose")
Vascular disorders**			Vasodilation, arterial hypotension, syncope	Vasculitis
Respiratory, thoracic and mediastinal disorders			Dyspnea (including asthmatic conditions)
Gastrointestinal disorders	Nausea, diarrhea	Vomiting, stomach and intestinal pain, abdominal pain, dyspepsia, flatulence	Antibiotic-associated colitis (very rare with possible fatal outcome) (see section "Special warnings and precautions for use")	Pancreatitis
Hepatobiliary disorders		Elevated levels of transaminases and bilirubin	Liver function abnormalities, cholestatic jaundice, hepatitis	Liver necrosis (rarely 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 (potentially life-threatening), toxic epidermal necrolysis (potentially life-threatening)	Acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS syndrome)
Musculoskeletal and connective tissue disorders*		Musculoskeletal pain (e.g., limb pain, back pain, chest pain), arthralgia	Myalgia, arthritis, increased muscle tone and muscle spasms	Muscle weakness, tendonitis, 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		Renal function impairment	Renal failure, hematuria, crystalluria (see section "Special warnings and precautions for use"), tubulointerstitial nephritis
General disorders and administration site conditions*	Injection and infusion site reactions (intravenous administration only)	Asthenia, fever	Edema, increased sweating (hyperhidrosis)
Investigations		Elevated blood alkaline phosphatase activity	Elevated amylase activity		Increased INR (in patients concomitantly receiving vitamin K antagonists)

*Very rare cases of prolonged (for months or years), disabling and potentially irreversible serious adverse reactions affecting various, sometimes multiple, organ systems and sensory organs have been reported with the use of quinolones and fluoroquinolones in some cases, regardless of existing risk factors (see section "Special precautions for use"). These reactions include tendinitis, tendon rupture, arthralgia, pain in extremities, gait disturbance, neuropathy associated with paresthesia and neuralgia, fatigue, psychiatric symptoms (including sleep disorders, anxiety, panic attacks, depression, and suicidal thoughts), memory and concentration impairment, sleep disorders, and disturbances of hearing, vision, taste, and smell.

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

The adverse reactions listed below occur at a higher frequency category in subgroups of patients who received intravenous or step-down (switch from intravenous to oral) therapy:

Common	Vomiting, transient increase in transaminases, rash
Uncommon	Thrombocytopenia, thrombocytosis, confusion and disorientation, hallucinations, paresthesia and dysesthesia, seizures, dizziness, visual, hearing disturbances, tachycardia, vasodilation, hypotension, transient liver failure, cholestatic jaundice, renal failure, edema
Rare	Pancytopenia, bone marrow depression, anaphylactic shock, psychotic reactions, migraine, olfactory nerve disorders, hearing impairment, vasculitis, pancreatitis, liver necrosis, petechiae, tendon rupture

Use in children

The frequency of arthropathy (arthralgia, arthritis) mentioned above is based on data obtained from studies conducted in adult patients. Arthropathy occurs more frequently in children (see section "Special instructions").

Reporting suspected adverse reactions

Reporting adverse reactions after drug registration is of great importance. It allows continuous monitoring of the benefit-risk balance of the drug. Medical and pharmaceutical personnel, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of drug efficacy via the Automated Pharmacovigilance System at the following link: https://aisf.dec.gov.ua.

Shelf life. 5 years.

Storage conditions.

Store in a place protected from light. The medicinal product does not require special storage temperature conditions. Keep out of reach of children.

Incompatibility.

The drug should not be mixed with other medicinal products in the same container, except as specified in the section "Method of administration and dosage".

If compatibility with other infusion solutions/products has not been confirmed, the ciprofloxacin infusion solution should be administered separately. Visible signs of incompatibility include precipitation, turbidity, or change in solution color.

Incompatibility occurs when used with all infusion solutions/products that are physically or chemically unstable at pH levels between 3 and 4 (e.g., penicillins, heparin solutions), particularly in combination with solutions whose pH has been adjusted to alkaline (pH of ciprofloxacin solutions: 3.9–4.5).

Packaging.

Infusion solution 100 ml (200 mg); 1 vial in a cardboard box.

Infusion solution 200 ml (400 mg); 1 vial in a cardboard box.

Prescription category. By prescription only.

Manufacturer.

KRKA, d.d., Novo mesto, Slovenia/KRKA, d.d., Novo mesto, Slovenia.

Manufacturer's address and location of operations.

Smarjeska cesta 6, 8501 Novo mesto, Slovenia/Smarjeska cesta 6, 8501 Novo mesto, Slovenia.