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

Composition:

Active substance: ciprofloxacin;

One film-coated tablet contains 250 mg or 500 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:

250 mg tablets: round, white, film-coated tablets with a score line on one side;

500 mg tablets: oval, white, film-coated tablets with a score line on one side.

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 in several DNA life cycle processes such as replication, transcription, repair, and recombination.

Pharmacokinetic / pharmacodynamic relationships

Efficacy primarily depends on the ratio between the maximum serum concentration (Cmax) and the minimum inhibitory concentration (MIC) of ciprofloxacin for 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 target-site mutations 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.

Mechanisms of resistance such as impermeability and/or efflux pumps may cause varying effects on susceptibility to fluoroquinolones, depending on the physicochemical properties of different agents within this class and the affinity of transport systems for each active substance. All resistance mechanisms observed in vitro are generally found in clinical isolates. Resistance mechanisms that inactivate other antibacterial agents, such as permeability barriers (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. – susceptibility breakpoints for ciprofloxacin apply to high-dose therapy. 2 Non-species related breakpoints were established primarily based on pharmacokinetic/pharmacodynamic data and are not dependent on MICs for individual species. They are used only for species without their own specific 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 geographical location and time; therefore, local information on resistance patterns 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 medicinal product is questionable, at least 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) microbial species

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)

Species in which acquired resistance may develop

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 specified above

Other microorganisms

Mycoplasma genitalium

Ureaplasma urealyticum

It has been demonstrated that antibiotic administration immediately after exposure to Bacillus anthracis spores can prevent disease if the spore burden is 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. Physicians should refer to national and/or international treatment guidelines for anthrax.
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 often simultaneously resistant to fluoroquinolones. The methicillin resistance rate among all Staphylococcus species is approximately 20–50%, and is usually high among hospital isolates.

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 between 0.56 mg/L and 3.7 mg/L. Serum concentrations increase proportionally with increasing dose up to 1000 mg.

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

Distribution

The percentage of ciprofloxacin protein binding in blood is low (20–30%). Ciprofloxacin is predominantly present in blood plasma in its non-ionized form and has a large steady-state volume of distribution of 2–3 L/kg body weight. It reaches high concentrations in various tissues, such as lungs (epithelial lining fluid, alveolar macrophages, biopsy specimens), sinuses, inflamed and damaged tissues, and tissues of the 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, although to a lesser extent than the parent compound.

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

Elimination

Ciprofloxacin is primarily excreted unchanged both renally and via the gastrointestinal tract. The elimination half-life from plasma in individuals 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	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 C_max and AUC were observed (in children aged 1 year and older). After repeated administration of the drug (10 mg/kg three times daily), no significant increase in C_max and AUC was observed. In 10 infants under 1 year of age with severe sepsis, C_max was 6.1 mg/L (range: 4.6–8.3 mg/L) after a one-hour intravenous infusion 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: 11–23.8 mg*h/L), respectively, in the corresponding age groups. These values are within the range observed in adults receiving therapeutic doses. According to pharmacokinetic analyses in pediatric patients with various infections, the predicted mean elimination half-life in children is approximately 4–5 hours, and the bioavailability of the oral suspension ranges from 50% to 80%.

Clinical characteristics.

Indications.

Ciprofloxacin is indicated for the treatment of the infections listed below (see sections "Pharmacological properties", "Special instructions"). Before initiating therapy, particular attention should be paid to all available information regarding resistance to ciprofloxacin.

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

Adults

Lower respiratory tract infections caused by Gram-negative bacteria:
- Exacerbation of chronic obstructive pulmonary disease (in exacerbations of chronic obstructive pulmonary disease, ciprofloxacin should be used only when 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 exacerbation of chronic sinusitis, particularly if 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 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.
Inhalational anthrax (post-exposure prophylaxis and treatment).

Ciprofloxacin may be used for therapy in neutropenic patients with 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.
Inhalational anthrax (post-exposure prophylaxis and 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 instructions").

Contraindications.

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

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

Interaction with other medicinal products and other forms of interaction.

Effects 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 instructions").

Chelate complex formation

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

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 "Dosage and 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 was observed.

Omeprazole

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

Effects 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 concentrations are associated with enhanced hypotensive and sedative effects.

Methotrexate

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

Theophylline

Concomitant administration of ciprofloxacin and medicinal products containing theophylline may lead to an undesirable increase in theophylline serum concentration, which in turn may cause adverse reactions. In isolated cases, such adverse reactions may be fatal. If concomitant administration of these drugs cannot be avoided, serum theophylline concentrations should be monitored and the dose appropriately reduced (see section "Special instructions").

Other xanthine derivatives

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

Phenytoin

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

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 recommended during and immediately after concomitant administration of ciprofloxacin and vitamin K antagonists (e.g., warfarin, acenocoumarol, phenprocoumon, fluindione).

Ropinirole

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

Clozapine

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

Lidocaine

It has been reported that concomitant use of ciprofloxacin, a moderate inhibitor of cytochrome CYP450 1A2 isoenzymes, and medicinal products containing lidocaine reduces the clearance of intravenous lidocaine by 22%. Despite normal tolerance of lidocaine treatment, interaction with ciprofloxacin is possible, which may be associated with adverse reactions and may develop when these agents are used concomitantly.

Sildenafil

Cmax and AUC of sildenafil increased approximately two-fold in healthy volunteers after oral administration of 50 mg sildenafil concomitantly with 500 mg ciprofloxacin. Therefore, caution should be exercised when ciprofloxacin is used concomitantly with sildenafil, considering the risk/benefit ratio.

Duloxetine

Clinical studies have shown that concomitant administration of duloxetine with potent inhibitors of CYP450 1A2 isoenzyme, such as fluvoxamine, may lead to increased Cmax and AUC of duloxetine. Although there are no clinical data on possible interaction with ciprofloxacin, similar effects can be expected when these agents are used concomitantly (see section "Special instructions").

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 such patients.

Agomelatine

Clinical studies have shown that fluvoxamine, a strong inhibitor of 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 possible interaction with ciprofloxacin, a moderate inhibitor of CYP450 1A2, similar effects can be expected with concomitant use (see section "Special instructions").

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 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 if no alternative therapy is available and after careful benefit-risk assessment (see section "Contraindications").

Severe and/or mixed infections caused by gram-positive or anaerobic bacteria

Ciprofloxacin should not be used as monotherapy for the treatment of severe infections or infections caused by gram-positive or anaerobic bacteria.

For treatment of such infections, ciprofloxacin should be used in combination with appropriate antibacterial agents.

Streptococcal infections (including Streptococcus pneumoniae)

Ciprofloxacin is not recommended for the treatment of streptococcal infections due to insufficient efficacy.

Genitourinary infections

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 to fluoroquinolones among Escherichia coli, the most common pathogen causing urinary tract infections, has been observed. When prescribing therapy, 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 treatment with the drug. This fact 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 therapy, 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 anthrax

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

Ciprofloxacin should be used in children 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 in weight-bearing joints in immature animals. Safety data from a randomized, double-blind study in children (ciprofloxacin: n=335, mean age = 6.3 years; comparator group: n=349, mean age = 6.2 years; age range 1–17 years) showed an incidence of arthropathy likely related to drug use (differing 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 not statistically significant. However, treatment of children and adolescents with ciprofloxacin should be initiated only after careful benefit-risk assessment due to the potential risk of adverse reactions affecting joints and/or surrounding tissues.

Respiratory tract infections in cystic fibrosis

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

Complicated urinary tract infections and pyelonephritis

Treatment of urinary tract infections with ciprofloxacin should be considered only when other treatments are not feasible. Therapy should be based on microbiological test results. Clinical studies have evaluated the use of ciprofloxacin in children and adolescents aged 1–17 years.

Other specific severe infections

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

Ciprofloxacin use for specific severe infections other than those mentioned above has not been evaluated in clinical trials, and clinical experience is limited. Therefore, treatment of patients with such infections should be approached with caution.

Hypersensitivity to the drug

Hypersensitivity and allergic reactions, including 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 administration must be discontinued immediately and appropriate medical treatment initiated promptly.

Prolonged, disabling, and potentially irreversible adverse reactions

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

Ciprofloxacin use 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 prior quinolone use. However, in rare cases, after microbiological testing and benefit-risk assessment, ciprofloxacin may be prescribed for treatment of specific severe infections, particularly when standard therapy is ineffective or bacterial resistance is present, and when microbiological test results justify ciprofloxacin use.

Tendinitis and tendon rupture

Generally, ciprofloxacin should not be used in patients with a history of tendon disorders related to quinolone use. Nevertheless, in rare cases, after microbiological testing of the causative agent and benefit-risk assessment, ciprofloxacin may be prescribed for treatment of specific severe infections, particularly when standard therapy is ineffective or bacterial resistance is present, and when microbiological test results justify ciprofloxacin use.

Tendinitis and tendon rupture (particularly, but not limited to, Achilles tendon), sometimes bilateral, may occur within 48 hours of starting fluoroquinolone or fluoroquinolone therapy and even several months after discontinuation of treatment. 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 use should be discontinued, and alternative therapy considered. The affected limb(s) should be appropriately managed (e.g., immobilization) and kept at rest. Corticosteroids should not be used if signs of tendinopathy occur.

Patients with myasthenia

Ciprofloxacin should be used with caution in patients with myasthenia gravis, as symptoms may be exacerbated (see section "Special precautions for use").

Aortic aneurysm and 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 wall dissection, sometimes complicated by rupture (including fatal cases), and regurgitation/insufficiency of any heart valve have been reported in patients receiving fluoroquinolones (see section "Adverse reactions").

Therefore, fluoroquinolones should 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/or 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 concurrently receiving systemic corticosteroids.

In case of sudden abdominal, chest, or back pain, patients should seek immediate medical attention at an emergency department.

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

Visual disturbances

If vision deteriorates or any noticeable effect on the eyes occurs, patients should seek immediate medical advice.

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, hypoesthesia, 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 develop, such as pain, burning, tingling, numbness, or weakness, to prevent development of 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, including:

congenital long QT syndrome;
concomitant use of drugs that may prolong the QT interval (e.g., class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, neuroleptics);
uncorrected electrolyte imbalances (e.g., hypokalemia, hypomagnesemia);
presence of cardiac conditions (e.g., heart failure, myocardial infarction, bradycardia).

Elderly patients and women may be more sensitive to 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 treatment), it may indicate 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 taking ciprofloxacin should receive adequate fluid intake and avoid excessive urine alkalinization.

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 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 wall tension), treatment should be discontinued.

Glucose-6-phosphate dehydrogenase deficiency

Hemolytic reactions have been reported in patients with glucose-6-phosphate dehydrogenase deficiency receiving ciprofloxacin. Ciprofloxacin use should be avoided in such patients, except when potential benefit outweighs 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 defined superinfection. There is a certain risk of emergence 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 drugs metabolized by this enzyme (e.g., theophylline, clozapine, olanzapine, ropinirole, tizanidine, duloxetine, agomelatine). Therefore, patients receiving these drugs 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 results of Mycobacterium tuberculosis culture 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 fetotoxic/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 the drug may be harmful to the joint cartilage of newborns/fetus cannot be excluded. Therefore, to prevent undesirable effects on the fetus, ciprofloxacin use during pregnancy should be avoided.

Breastfeeding period

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

Ability to affect reaction speed when driving or operating machinery.

Fluoroquinolones, including ciprofloxacin, may affect a patient's ability to drive or operate machinery due to nervous system reactions (see section "Adverse 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, susceptibility of the causative pathogen(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 clinical features, 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 use of other necessary antibacterial agents.

Treatment of certain infections (e.g., inflammatory pelvic diseases, 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

Ciprinol® is available as 750 mg tablets.

Indications		Daily dose, mg	Total 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 precautions")	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 (such as 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)
Genital infections	gonococcal urethritis and cervicitis caused by susceptible Neisseria gonorrhoeae	single dose 500 mg	1 day (single dose)
Genital infections	orchioepididymitis and inflammatory diseases of the pelvic organs caused by susceptible Neisseria gonorrhoeae	from 500 mg twice daily to 750 mg twice 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	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	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
Neutropenic patients with fever suspected of having a bacterial origin. Ciprofloxacin should be used in combination with appropriate antibacterial agents/agent according to official guidelines		from 500 mg twice daily to 750 mg twice daily	treatment should be continued throughout the neutropenic period
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 be treated orally, if clinically indicated. Treatment should be initiated as soon as possible after suspected or confirmed exposure.		500 mg twice daily	60 days from the date of confirmed exposure to Bacillus anthracis

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 with a maximum single 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 single 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 to Bacillus anthracis	from 10 mg/kg body weight twice daily up to 15 mg/kg body weight twice daily with a maximum single 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 with a maximum single dose of 750 mg* per dose	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 function impairment:

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 impaired renal and/or hepatic function 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 administered on an empty stomach, the active substance is absorbed more rapidly. Ciprofloxacin tablets must not be taken simultaneously 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 patients are unable to take tablets (e.g., during enteral nutrition), initiation of therapy with intravenous ciprofloxacin is recommended 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 must not be taken to compensate for a missed dose.

Children.

Ciprofloxacin has been shown to cause arthropathy of weight-bearing joints in immature animals. Safety data in children indicate a frequency of arthropathy 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. Nevertheless, ciprofloxacin therapy in children should only be initiated after careful assessment of the benefit-risk ratio 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 include 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 lavage 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 cases 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 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 ideation/thoughts or suicide attempts/perpetration) (see section "Special warnings and precautions for use"), hallucinations	Psychotic reactions (with possible suicidal ideation/thoughts or suicide attempts/perpetration) (see section "Special warnings and precautions for use")	Mania, hypomania
Nervous system disorders*		Headache, dizziness, sleep disorders, taste disturbances	Paresthesia and dysesthesia, hypesthesia, tremor, seizures (including epileptic status, see section "Special warnings and precautions for use"), vertigo	Migraine, coordination disorders, gait disturbances, smell disturbances, intracranial hypertension and pseudotumour cerebri	Peripheral neuropathy and polyneuropathy (see section "Special warnings and precautions for use")
Eye disorders*			Visual disturbances (e.g., diplopia)	Color vision disturbances
Ear and labyrinth disorders*			Tinnitus, hearing loss/hearing disturbances
Cardiac disorders**			Tachycardia		Ventricular arrhythmia and torsades de pointes (mainly observed 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		Increased levels of transaminases and bilirubin	Liver function disorders, cholestatic jaundice, hepatitis	Liver necrosis (rarely progressing to life-threatening hepatic failure) (see section "Special warnings and precautions for use")
Skin and subcutaneous tissue disorders		Skin rashes, 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, back, chest pain), arthralgia	Myalgia, arthritis, increased muscle tone and muscle spasms	Muscle weakness, tendinitis, tendon ruptures (mainly Achilles tendons) (see section "Special warnings and precautions for use"), exacerbation of myasthenia gravis symptoms (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		Increased blood alkaline phosphatase activity	Increased amylase activity		Increased INR (in patients concomitantly receiving vitamin K antagonists)

*Very rare, prolonged (several months or years), disabling and potentially irreversible serious adverse reactions affecting various organ systems have been reported (including such reactions as tendinitis, tendon rupture, arthralgia, limb pain, gait 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 disturbances, visual disturbances, disturbances of taste and smell), associated with the use of quinolones and fluoroquinolones, regardless of the presence of risk factors (see section "Special warnings and 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 warnings and precautions for use").

Use in children

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

Reporting suspected adverse reactions

Reporting suspected adverse reactions after a medicine has been authorized is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals and patients are encouraged to report any 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 blister in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

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

Manufacturer's address and place of business.

Smarjeska cesta 6, 8501 Novo mesto, Slovenia.