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

Composition:

Active substance: ciprofloxacin;

One film-coated tablet contains 750 mg of ciprofloxacin as ciprofloxacin hydrochloride monohydrate;

Excipients: microcrystalline cellulose, sodium croscarmellose, sodium starch glycolate (type A), povidone, colloidal anhydrous silicon dioxide, magnesium stearate, talc, titanium dioxide (E 171), hypromellose, propylene glycol.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: oval, white, film-coated tablets with notches on both sides.

Pharmacotherapeutic group. Antibacterials for systemic use. Fluoroquinolones. 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 DNA life cycle processes such as replication, transcription, repair, and recombination.

Pharmacokinetic / pharmacodynamic relationships

Efficacy is primarily dependent 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 value of the area under the concentration-time curve (AUC) and MIC.

Mechanism of resistance

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

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

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

Spectrum of antibacterial activity

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

EUCAST recommendations

Microorganisms	Susceptible	Resistant
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
1 Staphylococcus spp. – breakpoints for ciprofloxacin apply to high-dose therapy. 2 Non-species-related breakpoints were primarily defined based on pharmacokinetic/pharmacodynamic data and are not dependent on MICs of individual species. They are used only for species lacking their own breakpoints, and not for species for which susceptibility testing is not recommended.

Susceptibility to ciprofloxacin in vitro

The prevalence of acquired resistance in isolated species may vary depending on the geographical location and time; therefore, local information on resistance patterns is required, especially when treating severe infections. When necessary, consultation with specialists should be sought if the local prevalence of resistance has reached a level at which the benefit of using the medicinal product is at least questionable for certain types of infections.

Generally susceptible bacterial genera and species to ciprofloxacin include

(for the genus Streptococcus, see section "Special precautions and warnings")

Susceptible (usually) microorganisms

Gram-positive aerobic microorganisms

Bacillus anthracis 1)

Gram-negative aerobic microorganisms

Aeromonas spp.

Brucella spp.

Citrobacter koseri

Francisella tularensis

Haemophilus ducreyi

Haemophilus influenzae 2)

Legionella spp.

Moraxella catarrhalis 2)

Neisseria meningitidis

Pasteurella spp.

Salmonella spp. 2)

Shigella spp. 2)

Vibrio spp.

Yersinia pestis

Anaerobic microorganisms

Mobiluncus

Other microorganisms

Chlamydia trachomatis 3)

Chlamydia pneumoniae 3)

Mycoplasma hominis 3)

Mycoplasma pneumoniae 3)

Microorganisms capable of developing acquired resistance

Gram-positive aerobic microorganisms

Enterococcus faecalis 3)

Staphylococcus spp. 1)4)

Gram-negative aerobic microorganisms

Acinetobacter baumannii 5)

Burkholderia cepacia 2) 5)

Campylobacter spp. 2) 5)

Citrobacter freundii 2)

Enterobacter aerogenes

Enterobacter cloacae 2)

Escherichia coli 2)

Klebsiella oxytoca

Klebsiella pneumoniae 2)

Morganella morganii 2)

Neisseria gonorrhoeae 2)

Proteus mirabilis 2)

Proteus vulgaris 2)

Providencia spp.

Pseudomonas aeruginosa 2)

Pseudomonas fluorescens

Serratia marcescens 2)

Anaerobic microorganisms

Peptostreptococcus spp.

Propionibacterium acnes

Microorganisms inherently resistant to ciprofloxacin

Gram-positive aerobic microorganisms

Actinomyces

Enterococcus faecium

Listeria monocytogenes

Gram-negative aerobic microorganisms

Stenotrophomonas maltophilia

Anaerobic microorganisms

Except those listed above

Other microorganisms

Mycoplasma genitalium

Ureaplasma urealyticum

It has been demonstrated that antibiotic administration immediately after exposure to Bacillus anthracis spores helps prevent disease, provided the spore burden can be reduced below the infectious dose. A two-month treatment with oral ciprofloxacin 500 mg twice daily is considered effective for prevention of anthrax in adults. The physician 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 also 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 EU countries.

Pharmacokinetics.

Absorption

After oral administration of 250 mg, 500 mg, and 750 mg ciprofloxacin tablets, ciprofloxacin is rapidly and well absorbed, primarily from the upper part of the small intestine. Maximum serum concentrations (Cmax) are reached within 1–2 hours.

Single doses of 100–750 mg resulted in dose-dependent Cmax values ranging between 0.56 mg/L and 3.7 mg/L. Serum concentrations increase proportionally with increasing doses up to 1000 mg.

The absolute bioavailability of the drug is 70–80%. An oral dose of ciprofloxacin 500 mg every 12 hours was associated with a total area under the concentration-time curve (AUC) equivalent to that after intravenous infusion of 400 mg ciprofloxacin administered over 60 minutes every 12 hours.

Distribution

The percentage of ciprofloxacin binding to plasma proteins is low (20–30%). Ciprofloxacin is present in blood plasma predominantly in the non-ionized form and has a large steady-state volume of distribution of 2–3 L/kg body weight. It achieves high concentrations in various tissues, such as lungs (epithelial lining fluid, alveolar macrophages, biopsy specimens), sinuses, inflamed and damaged tissues, and tissues of the genitourinary tract (urine, prostate, endometrium), where total concentrations exceed those in plasma.

Metabolism

Low concentrations of four metabolites have been detected: desethylciprofloxacin (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 known to be a moderate inhibitor of the CYP450 1A2 isoenzymes.

Elimination

Ciprofloxacin is eliminated predominantly unchanged both renally and via the gastrointestinal tract. The elimination half-life from plasma in individuals with normal renal function is approximately 4–7 hours.

Excretion of ciprofloxacin (% of dose) after oral administration
Name	Excretion routes
Name	in urine	in feces
Ciprofloxacin	44.7	25.0
Metabolites (M1-M4)	11.3	7.5

Renal clearance is 180–300 mL/kg/h, and total clearance is 480–600 mL/kg/h. Ciprofloxacin undergoes glomerular filtration and tubular secretion. In cases of severe renal impairment, the elimination half-life of ciprofloxacin may extend up to 12 hours.

Non-renal clearance of ciprofloxacin is primarily explained by transintestinal secretion and metabolism. One percent (1%) of the dose is excreted via the biliary tract. Ciprofloxacin is present in high concentrations in bile.

Children.

Pharmacokinetic data in children are limited.

In studies involving children, no age-dependent differences in Cmax or AUC were observed (in children aged 1 year and older). After multiple dosing (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) after a 1-hour intravenous infusion at a dose of 10 mg/kg. This value was 7.2 mg/L (range: 4.7–11.8 mg/L) in children aged 1 to 5 years. AUC values were 17.4 mg*h/L (range: 11.8–32.0 mg*h/L) and 16.5 mg*h/L (range: 11.0–23.8 mg*h/L), respectively, in the corresponding age groups. These values are within the range observed in adults receiving therapeutic doses. According to pharmacokinetic analyses in pediatric patients with various infections, the predicted mean elimination half-life in children is approximately 4–5 hours, and the bioavailability of the oral suspension ranges from 50% to 80%.

Clinical characteristics.

Indications.

Ciprofloxacin is indicated for the treatment of the following infections (see sections "Pharmacological properties", "Special warnings and precautions for use"). Before initiating therapy, careful consideration should be given to all available information regarding resistance to ciprofloxacin.

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

Adults

Lower respiratory tract infections caused by Gram-negative bacteria:
- Exacerbations of chronic obstructive pulmonary disease (in exacerbations of chronic obstructive pulmonary disease, ciprofloxacin should be used only when it is considered inappropriate to use other antibacterial agents usually recommended for the treatment of these infections);
- Bronchopulmonary infections in cystic fibrosis or bronchiectasis;
- Pneumonia.
Chronic suppurative otitis media.
Acute exacerbations of chronic sinusitis, particularly when caused by Gram-negative bacteria.
Severe external otitis.
Urinary tract infections:
- Uncomplicated acute cystitis (in uncomplicated acute cystitis, ciprofloxacin should be used only when it is considered inappropriate to use other antibacterial agents usually recommended for the treatment of these infections);
  - Acute pyelonephritis;
  - Complicated urinary tract infections;
  - Bacterial prostatitis.
Genital tract infections:
- Gonococcal urethritis and cervicitis caused by susceptible strains of Neisseria gonorrhoeae;
- Epididymo-orchitis caused by susceptible strains of Neisseria gonorrhoeae;
- Pelvic inflammatory disease, including that caused by susceptible strains of Neisseria gonorrhoeae.
- Gastrointestinal tract infections (e.g., traveler's diarrhea).
- Intra-abdominal infections.
- Skin and soft tissue infections caused by Gram-negative bacteria.
- Bone and joint infections.
- Prophylaxis of invasive infections caused by Neisseria meningitidis.
- Pulmonary form of anthrax (post-exposure prophylaxis and definitive treatment).

Ciprofloxacin may be used for the treatment of patients with neutropenia and fever when bacterial infection is suspected in this patient group.

Children and adolescents

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

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

Treatment should be initiated only by a physician experienced in the management of cystic fibrosis and/or severe infections in children and adolescents (see sections "Pharmacodynamics", "Special warnings and precautions for use").

Contraindications.

Ciprofloxacin must not be used in patients with hypersensitivity to the active substance, to other drugs of the fluoroquinolone group, or to any of the excipients of the medicinal product.

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

Interaction with other medicinal products and other forms of interaction.

Effect of other medicinal products on ciprofloxacin

Medicinal products 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 warnings and precautions for use").

Chelate complex formation

Concomitant administration of ciprofloxacin (orally) with medicinal products containing multivalent cations, mineral supplements (e.g., calcium, magnesium, aluminium, iron), phosphate-binding polymers (e.g., sevelamer or lanthanum carbonate), sucralfate, or antacids, as well as formulations with high buffering capacity (such as didanosine tablets) containing magnesium, aluminium, or calcium, reduces the absorption of ciprofloxacin. Therefore, ciprofloxacin should be taken 1–2 hours before or at least 4 hours after administration of these products.

This restriction does not apply to antacids belonging to the class of H2-receptor blockers.

Food and dairy products

Calcium contained in food has a minor effect on the absorption of ciprofloxacin (orally). Therefore, ciprofloxacin tablets may be taken 1–2 hours before or at least 4 hours after consumption of dairy products or mineral-fortified beverages, as recommended for calcium-containing products (see section "Posology and method of administration").

Probenecid

Probenecid affects the renal secretion of ciprofloxacin. Concomitant administration of medicinal products containing probenecid and ciprofloxacin leads to increased serum concentrations of ciprofloxacin.

Metoclopramide

Metoclopramide accelerates the absorption of ciprofloxacin, resulting in a faster achievement of Cmax. No effect on the bioavailability of ciprofloxacin has been observed.

Omeprazole

Concomitant administration of ciprofloxacin and medicinal products containing omeprazole results in a slight reduction in Cmax and AUC of ciprofloxacin.

Effect of ciprofloxacin on other medicinal products

Tizanidine

Tizanidine must not be administered concomitantly with ciprofloxacin (see section "Contraindications"). When ciprofloxacin and tizanidine are administered together, an increase in tizanidine plasma concentration has been observed (increase in Cmax by 7-fold, range 4–21-fold; increase in AUC by 10-fold, range 6–24-fold). Elevated tizanidine plasma concentration is associated with enhanced hypotensive and sedative effects.

Methotrexate

Concomitant administration of ciprofloxacin may slow tubular transport (renal metabolism) of methotrexate, potentially leading to increased methotrexate plasma concentrations and increased risk of methotrexate-induced toxic side effects. Concomitant use is not recommended (see section "Special warnings and precautions for use").

Theophylline

Concomitant administration of ciprofloxacin and medicinal products containing theophylline may lead to undesirable increases in theophylline plasma concentrations, which may result in adverse reactions. In isolated cases, such adverse reactions may be fatal. If concomitant use of these drugs cannot be avoided, theophylline plasma concentrations should be monitored and the dose adjusted accordingly (see section "Special warnings and precautions for use").

Other xanthine derivatives

After concomitant administration of ciprofloxacin and medicinal products containing caffeine or pentoxifylline (oxpentifylline), increased plasma concentrations of these xanthines have been reported.

Phenytoin

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

Cyclosporine

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

Vitamin K antagonists

Concomitant administration of ciprofloxacin and vitamin K antagonists may enhance their anticoagulant effect. Increased activity of oral anticoagulants has been reported in patients receiving antibacterial agents, including fluoroquinolones. The degree of risk may vary depending on the underlying type of infection, age, and general condition of the patient, making it difficult to precisely assess the impact of ciprofloxacin on the increase in International Normalized Ratio (INR). Frequent monitoring of INR is required during and immediately after concomitant administration of ciprofloxacin and vitamin K antagonists (e.g., warfarin, acenocoumarol, phenprocoumon, fluindione).

Duloxetine

Clinical studies have shown that concomitant administration of duloxetine with strong inhibitors of the CYP450 1A2 isoenzyme, such as fluvoxamine, may lead to increased AUC and Cmax of duloxetine. Despite the lack of clinical data on a possible interaction with ciprofloxacin, similar effects can be expected when these agents are used concomitantly (see section "Special warnings and precautions for use").

Ropinirole

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

Lidocaine

Reports indicate that concomitant administration of ciprofloxacin, a moderate inhibitor of CYP P450 1A2 isoenzymes, and medicinal products containing lidocaine reduces the clearance of intravenous lidocaine by 22%. Despite normal tolerability of lidocaine treatment, interaction with ciprofloxacin is possible, which may be associated with adverse reactions when these agents are used concomitantly.

Clozapine

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

Sildenafil

Cmax and AUC of sildenafil increased approximately two-fold in healthy volunteers after oral administration of 50 mg sildenafil and concomitant administration of 500 mg ciprofloxacin. Therefore, caution should be exercised when 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 a possible interaction with ciprofloxacin, a moderate inhibitor of CYP450 1A2, similar effects can be expected with concomitant use (see section "Special warnings and precautions for use").

Zolpidem

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

Special precautions for use.

The use of ciprofloxacin should be avoided in patients who have previously experienced serious adverse reactions to drugs containing quinolones or fluoroquinolones (see section "Adverse Reactions"). Treatment with ciprofloxacin in such patients should be initiated only when no alternative therapy is 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.

Genitourinary infections

Gonococcal urethritis, cervicitis, epididymitis, and pelvic inflammatory disease may be caused by fluoroquinolone-resistant strains of Neisseria gonorrhoeae.

Empirical therapy with ciprofloxacin for epididymitis and pelvic inflammatory disease may be used only in combination with other appropriate antibacterial agents (e.g., a cephalosporin), except in clinical situations where ciprofloxacin-resistant strains of Neisseria gonorrhoeae have been ruled out.

If no clinical improvement occurs within 3 days, therapy should be re-evaluated.

Urinary tract infections

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

A single dose of ciprofloxacin, which may be used in uncomplicated cystitis in premenopausal women, is expected to be less effective than longer-term therapy with the drug. This should be considered in light of the increasing resistance of Escherichia coli to quinolones.

Intra-abdominal infections

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

Traveler's diarrhea

When selecting a drug, information on resistance to ciprofloxacin 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

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

Children

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

Ciprofloxacin has caused arthropathy of weight-bearing joints in immature animals. Safety data from a randomized, double-blind study in children (ciprofloxacin: n=335, mean age = 6.3 years; comparator group: n=349, mean age = 6.2 years; age range 1–17 years) showed an incidence of arthropathy, likely related to drug use (distinct from clinical signs and symptoms directly related to joint involvement), of 7.2% and 4.6% in the treatment and comparator groups, respectively, on day 42 after initiation of treatment. The incidence of drug-related arthropathy at 1 year of follow-up was 9.0% and 5.7%, respectively. The increase in arthropathy cases related to drug use was statistically non-significant. However, treatment with ciprofloxacin in children and adolescents should be initiated only after careful assessment of the benefit-risk ratio due to the potential risk of adverse reactions affecting joints and/or surrounding tissues.

Bronchopulmonary infections in cystic fibrosis

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

Complicated urinary tract infections and pyelonephritis

Treatment of urinary tract infections with ciprofloxacin should be considered when no other treatment options are available. Therapy should be based on microbiological test results. Clinical studies have evaluated the use of ciprofloxacin in children and adolescents aged 1–17 years.

Other specific severe infections

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

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 to the drug

Hypersensitivity and allergic reactions, including anaphylaxis and anaphylactoid reactions, may occur after a single dose of ciprofloxacin (see section "Adverse Reactions") and may be life-threatening.

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

Prolonged, disabling, and potentially irreversible adverse reactions

In patients receiving quinolones and fluoroquinolones, very rare cases of prolonged (several months or years), disabling, and potentially irreversible serious adverse reactions affecting various body systems (musculoskeletal, nervous system, psychiatric, and sensory organs) have been reported, regardless of age or presence of risk factors. The use of ciprofloxacin should be discontinued immediately upon the first signs or symptoms of any serious adverse reaction, and medical advice should be sought.

Musculoskeletal system

Generally, ciprofloxacin should not be used in patients with tendon disorders or disorders related to previous quinolone use. However, in rare cases, after microbiological testing of the causative agent and 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 when microbiological test results justify the use of ciprofloxacin.

Tendinitis and tendon rupture

Generally, ciprofloxacin should not be used in patients with tendon disorders or disorders related to previous quinolone use. Nevertheless, in rare cases, after microbiological testing of the causative agent and 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 when microbiological test results justify the use of ciproflox游戏副本.

Tendinitis and tendon rupture (particularly, but not limited to, Achilles tendon), sometimes bilateral, may occur within 48 hours of starting treatment with quinolones and fluoroquinolones, and even several months after discontinuation of therapy. The risk of tendinitis and tendon rupture is increased in elderly patients, patients with renal impairment, organ transplant recipients, and patients receiving corticosteroid therapy (see section "Adverse Reactions"). If any signs of tendinitis (e.g., painful swelling, inflammation) occur, ciprofloxacin should be discontinued, and alternative therapy should be considered. The affected limb(s) should be rested and appropriately managed (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 "Special precautions for use").

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 patients. Rare cases of aortic aneurysm and aortic dissection, sometimes complicated by rupture (including fatal outcomes), and regurgitation/insufficiency of any heart valve have been reported in patients treated with fluoroquinolones (see section "Adverse Reactions").

Therefore, fluoroquinolones should be used only after careful benefit-risk assessment and consideration of alternative therapeutic options in patients with a family history of aortic aneurysm or congenital heart valve defects, patients with previously diagnosed 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 concurrently.

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

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

Visual disturbances

Patients should seek immediate medical advice if visual impairment or any noticeable effect on the eyes occurs.

Photosensitivity

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

Seizures

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

Peripheral neuropathy

Cases of sensory or sensorimotor polyneuropathy leading to paresthesia, hyposthesia, dysesthesia, or weakness have been reported in patients receiving quinolones and fluoroquinolones, including ciprofloxacin. 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 progression to 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 progress to suicidal thoughts and actions, including suicide or suicide attempts. In such cases, ciprofloxacin should be discontinued and appropriate measures taken.

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 imbalance (e.g., hypokalemia, hypomagnesemia);
Presence of cardiac disease (e.g., heart failure, myocardial infarction, bradycardia).

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

Dysglycemia

As with other quinolones, disturbances in blood glucose levels, including both hypoglycemia and hyperglycemia (see section "Adverse Reactions"), have been reported, particularly in elderly patients and diabetic patients receiving concomitant therapy with oral hypoglycemic agents (e.g., glyburide) or insulin. Cases of hypoglycemic coma have been reported. Diabetic patients are advised to closely monitor blood glucose levels.

Gastrointestinal tract

If severe and persistent diarrhea occurs during or after treatment (even several weeks after therapy), it may indicate the development of antibiotic-associated colitis (which may be 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 taking ciprofloxacin should maintain adequate fluid intake and avoid excessive alkalinization of urine.

Renal function impairment

Since ciprofloxacin is primarily excreted unchanged by the kidneys, dose adjustment is required in patients with impaired renal function according to the dosing 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 during ciprofloxacin use (see section "Adverse Reactions"). If any signs or symptoms of liver disease occur (such as anorexia, jaundice, dark urine, pruritus, or abdominal wall tension), treatment should be discontinued.

Glucose-6-phosphate dehydrogenase deficiency

Hemolytic reactions have been reported in patients with glucose-6-phosphate dehydrogenase deficiency during ciprofloxacin use. 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

Resistant bacteria may be isolated during or after ciprofloxacin treatment, with or without clinically evident superinfection. There is a certain 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 inhibits CYP450 1A2 and may therefore increase serum concentrations of concurrently administered substances metabolized by this enzyme (e.g., theophylline, clozapine, olanzapine, ropinirole, tizanidine, duloxetine, agomelatine). Therefore, patients receiving these substances concurrently 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 may in vitro affect culture results for Mycobacterium tuberculosis by inhibiting mycobacterial growth, potentially leading to false-negative culture results in patients taking ciprofloxacin.

Use during pregnancy or breastfeeding.

Pregnancy

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

Lactation period

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

Ability to affect reaction speed when driving vehicles or operating machinery.

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

Dosage and Administration.

The dosage is determined according to the indication, severity and site of infection, susceptibility of the causative organism(s) to ciprofloxacin, and the patient's renal function; in children, dosage also depends on body weight.

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

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

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

Dosage for adults

The available dosage forms of the drug Ciprinol® are 250 mg or 500 mg tablets.

Indications		Daily dose, mg	Duration of treatment (may include initial parenteral administration of ciprofloxacin)
Infections of the lower respiratory tract		from 500 mg* twice daily to 750 mg twice daily	7–14 days
Infections of the upper respiratory tract	exacerbation of chronic sinusitis	from 500 mg* twice daily to 750 mg twice daily	7–14 days
	chronic suppurative otitis media	from 500 mg* twice daily to 750 mg twice daily	7–14 days
	severe external otitis	750 mg twice daily	from 28 days to 3 months
Urinary tract infections (see section "Special instructions").	uncomplicated acute cystitis	from 250 mg* twice daily to 500 mg* twice daily	3 days
	uncomplicated acute cystitis	in premenopausal women a single dose of 500 mg* may be used
	complicated cystitis, acute pyelonephritis	500 mg* twice daily	7 days
	complicated pyelonephritis	from 500 mg* twice daily to 750 mg twice daily	at least 10 days; in certain special clinical cases (e.g. abscesses) treatment may be extended beyond 21 days
	bacterial prostatitis	from 500 mg* twice daily to 750 mg twice daily	2 to 4 weeks (acute) and 4 to 6 weeks (chronic)
Infections of the genital system	gonococcal urethritis and cervicitis caused by susceptible Neisseria gonorrhoeae	single dose 500 mg*	1 day (single dose)
Infections of the genital system	orchioepididymitis and pelvic inflammatory disease caused by susceptible Neisseria gonorrhoeae	from 500 mg* twice daily to 750 mg twice daily	at least 14 days
Infections of the gastrointestinal tract and intra-abdominal infections	diarrhea caused by bacterial pathogens, particularly Shigella spp., except Shigella dysenteriae type 1, empirical treatment of severe traveler's diarrhea	500 mg* twice daily	1 day
	diarrhea caused by Shigella dysenteriae, type 1	500 mg* twice daily	5 days
	diarrhea caused by Vibrio cholerae	500 mg* twice daily	3 days
	typhoid fever	500 mg* twice daily	7 days
	intra-abdominal infections caused by Gram-negative bacteria	from 500 mg* twice daily to 750 mg twice daily	5 to 14 days
Skin and soft tissue infections caused by Gram-negative bacteria		from 500 mg* twice daily to 750 mg twice daily	7 to 14 days
Bone and joint infections		from 500 mg* twice daily to 750 mg twice daily	up to 3 months
Patients with neutropenia and fever suspected of bacterial origin. Ciprofloxacin should be used concomitantly with appropriate antibacterial agents/agent according to official guidelines		from 500 mg* twice daily to 750 mg twice daily	treatment should continue throughout the period of neutropenia
Prophylaxis of invasive infections caused by Neisseria meningitidis		single dose 500 mg*	1 day (single dose)
Post-exposure prophylaxis and treatment of pulmonary anthrax in individuals who can receive oral therapy, if clinically indicated. Initiation of the medicinal product should begin as soon as possible after suspected or confirmed exposure.		500 mg* twice daily	60 days from the date of confirmed exposure to Bacillus anthracis

*The drug should be used at the appropriate dosage.

Children

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

Indications	Daily dose (mg)	Total duration of treatment (may include initial parenteral administration of ciprofloxacin)
Cystic fibrosis	20 mg/kg body weight twice daily, up to a maximum dose of 750 mg*	10 to 14 days
Complicated urinary tract infections and acute pyelonephritis	From 10 mg/kg body weight twice daily up to 20 mg/kg body weight twice daily, with a maximum dose of 750 mg*	10 to 21 days
Post-exposure prophylaxis and treatment of pulmonary anthrax in patients who can be treated orally, if clinically indicated. Treatment should be initiated as soon as possible after suspected or confirmed exposure.	From 10 mg/kg body weight twice daily up to 15 mg/kg body weight twice daily, with a maximum dose of 500 mg*	60 days from the date of confirmed exposure to Bacillus anthracis
Other severe infections	20 mg/kg body weight twice daily, up to a maximum dose of 750 mg*	Depending on the type of infection

*Administer the drug in the appropriate dosage.

Geriatric patients

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

Renal and hepatic impairment

Recommended initial and maintenance doses for patients with renal dysfunction

Creatinine clearance (ml/min/1.73 m2)	Serum creatinine (µmol/L)	Oral dose (mg)
> 60	< 124	See usual dosage
30–60	124–168	250–500 mg every 12 hours
< 30	> 169	250–500 mg every 24 hours
Patients on hemodialysis	> 169	250–500 mg every 24 hours (after dialysis)
Patients on peritoneal dialysis	> 169	250–500 mg every 24 hours

Patients with hepatic impairment do not require adjustment of ciprofloxacin dosage.

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

Method of administration

Tablets should be swallowed whole with a small amount of liquid without chewing. They may be taken independently of food intake. When taken on an empty stomach, the active ingredient is absorbed more rapidly. Ciprofloxacin tablets must not be taken with food containing dairy products (e.g., milk, yogurt) or fruit juices fortified with minerals (e.g., calcium-fortified orange juice). Ciprofloxacin tablets should be taken either 1–2 hours before or at least 4 hours after consuming dairy products or mineral-fortified beverages (see section "Interaction with other medicinal products and other forms of interactions").

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

If a dose is missed, it should be taken as soon as possible, but not later than 6 hours before the next scheduled dose.

If less than 6 hours remain before the next dose, the missed dose should not be taken; treatment should continue with the next scheduled dose. Double doses should not be taken to compensate for a missed dose.

Children.

Ciprofloxacin has caused arthropathy of weight-bearing joints in immature animals. Safety data in children indicate a frequency of arthropathy occurrence that is likely associated with ciprofloxacin use (distinct from clinical symptoms directly related to joint involvement). The increasing number of arthropathy cases associated with ciprofloxacin use is not statistically significant. However, ciprofloxacin treatment in children should only be initiated after careful benefit-risk assessment due to the risk of developing adverse reactions affecting joints and/or adjacent tissues.

Overdose.

Cases of moderate toxicity have been reported following ingestion of 12 g of the drug. Acute overdose with a dose of 16 g resulted in acute renal failure. Symptoms of overdose included dizziness, tremor, headache, increased fatigue, seizures, hallucinations, confusion, abdominal discomfort, renal and hepatic failure, as well as crystalluria and hematuria. Reversible nephrotoxicity has also been reported.

In addition to standard emergency measures such as gastric evacuation followed by administration of activated charcoal, monitoring of renal function is recommended, including determination of urine pH and, if necessary, acidification of urine to prevent crystalluria. Patients should receive adequate fluid intake and antacids containing magnesium and calcium, which reduce ciprofloxacin absorption.

Only a small amount of ciprofloxacin (< 10%) is removed by hemodialysis or peritoneal dialysis.

In case of overdose, symptomatic treatment should be administered. ECG monitoring should be performed due to the potential for QT interval prolongation.

Adverse reactions.

The most commonly reported adverse reactions were nausea and diarrhea.

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

When analyzing the frequency of occurrence, data from both oral and intravenous administration routes of ciprofloxacin are 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 precautions"), serum sickness-like reactions
Endocrine disorders					Syndrome of inappropriate antidiuretic hormone secretion (SIADH)
Metabolism and nutrition disorders		Decreased appetite	Hypoglycemia, hyperglycemia (see section "Special precautions")		Hypoglycemic coma (see section "Special precautions")
Psychiatric disorders*		Psychomotor agitation/ anxiety	Confusion and disorientation, restlessness, pathological dreams, depression (with possible suicidal ideation/thoughts or suicide attempts/acts) (see section "Special precautions"), hallucinations	Psychotic reactions (with possible suicidal ideation/thoughts or suicide attempts/acts) (see section "Special precautions")	Mania, hypomania
Nervous system disorders*		Headache, dizziness, sleep disorders, taste disturbances	Paraesthesia and dysaesthesia, hypoaesthesia, tremor, convulsions (including epileptic status, see section "Special precautions"), vertigo	Migraine, coordination disturbances, gait disturbances, smell disturbances, intracranial hypertension and pseudotumour cerebri	Peripheral neuropathy and polyneuropathy (see section "Special precautions")
Eye disorders*			Visual disturbances (e.g., diplopia)	Color vision disturbances
Ear and labyrinth disorders*			Tinnitus, hearing loss/hearing impairment
Cardiac disorders**			Tachycardia		Ventricular arrhythmia and torsades de pointes (mainly reported in patients with risk factors for QT interval prolongation), QT interval prolongation (see sections "Special precautions", "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 precautions")	Pancreatitis
Hepatobiliary disorders		Increased levels of transaminases and bilirubin	Liver function disturbances, cholestatic jaundice, hepatitis	Liver necrosis (rarely progressing to life-threatening hepatic failure) (see section "Special precautions")
Skin and subcutaneous tissue disorders		Rash, pruritus, urticaria	Photosensitivity reactions (see section "Special precautions")	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, tendinitis, tendon rupture (mainly Achilles tendons) (see section "Special precautions"), exacerbation of symptoms of myasthenia gravis (see section "Special precautions")
Renal and urinary disorders		Renal function impairment	Renal failure, hematuria, crystalluria (see section "Special precautions"), tubulointerstitial nephritis
General disorders and administration site conditions*	Injection and infusion site reactions (intravenous administration only)	Asthenia, fever	Edema, increased sweating (hyperhidrosis)
Investigations		Increased blood alkaline phosphatase activity	Increased amylase activity		Increased INR (in patients concomitantly receiving vitamin K antagonists)

*Cases of very rare, prolonged (several months or years), disabling and potentially irreversible serious adverse reactions affecting various organ systems have been reported (including such reactions as tendinitis, tendon rupture, arthralgia, pain in extremities, gait disturbance, neuropathies associated with paresthesia and neuralgia, fatigue, psychiatric symptoms (including sleep disorders, anxiety, panic attacks, depression, and suicidal thoughts), memory and concentration impairment, hearing impairment, visual, taste, and smell disturbances), associated with the use of quinolones and fluoroquinolones, regardless of the presence of risk factors (see section "Special precautions for use").

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

Use in children

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

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after authorization of the medicinal product is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance System at the following link: https://aisf.dec.gov.ua.

Shelf life. 5 years.

Storage conditions.

No special storage conditions are required for this medicinal product.

Keep out of the reach of children.

Packaging.

10 tablets in a blister; 1 or 2 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

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

Manufacturer's address and location of operations.

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