Ciprofloxacin-astrafarm

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CYPROFLOXACIN-ASTRAFARM (CIPROFLOXACIN-ASTRAFARM)

Composition:

Active substance: ciprofloxacin;

One film-coated tablet contains 500 mg of ciprofloxacin;

Excipients: microcrystalline cellulose, corn starch, crospovidone, anhydrous colloidal silicon dioxide, magnesium stearate; coating: hypromellose; polyethylene glycol 6000; titanium dioxide (E 171).

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics: oval-shaped, biconvex tablets coated with a white film coating, with a score line on one side.

Pharmacotherapeutic group.

Antibacterial agents for systemic use. Fluoroquinolone group.
ATC code J01M A02.

Pharmacological properties.

Pharmacodynamics.

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

Pharmacokinetic/pharmacodynamic relationships

Efficacy primarily depends on the ratio between the maximum serum concentration (Cmax) and the minimum inhibitory concentration (MIC) of ciprofloxacin against the bacterial pathogen, as well as on the area under the concentration-time curve (AUC) relative to the 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 extent of cross-resistance between ciprofloxacin and other fluoroquinolones resulting from the above mechanisms may vary. Single mutations generally do not lead to clinical resistance; however, multiple mutations typically 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 individual agents within this class and the affinity of transport systems for each active substance. All in vitro resistance mechanisms have generally been observed in clinical isolates. Resistance mechanisms that inactivate other antibacterial agents, such as permeability barriers (inherent in Pseudomonas aeruginosa) and efflux mechanisms, may also influence susceptibility to ciprofloxacin.

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

Spectrum of antibacterial activity

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

EUCAST recommendations

Table 1

Microorganisms	Susceptible	Resistant
Enterobacteriaceae	≤ 0.5 mg/l	> 1 mg/l
Pseudomonas spp.	≤ 0.5 mg/l	> 1 mg/l
Acinetobacter spp.	≤ 1 mg/l	> 1 mg/l
Staphylococcus spp.1	≤ 1 mg/l	> 1 mg/l
Haemophilus influenzae and Moraxella catarrhalis	≤ 0.5 mg/l	> 0.5 mg/l
Neisseria gonorrhoeae	≤ 0.03 mg/l	> 0.06 mg/l
Neisseria meningitidis	≤ 0.03 mg/l	> 0.06 mg/l
Non-species related breakpoints *	≤ 0.5 mg/l	> 1 mg/l

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

* Non-species-related breakpoints were primarily defined based on pharmacokinetic/pharmacodynamic (PK/PD) data and are not dependent on the MICs of individual species. They are used only for species lacking their own specific breakpoints, and not for species for which susceptibility testing is not recommended.

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

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

Susceptible (usually) microbial species

Aerobic Gram-positive microorganisms Bacillus anthracis (1)

Aerobic Gram-negative microorganisms Aeromonas spp. Brucella spp. Citrobacter koseri Francisella tularensis Haemophilus ducreyi Haemophilus influenzae* Legionella spp. Moraxella catarrhalis* Neisseria meningitidis Pasteurella spp. Salmonella spp.* Shigella spp. * Vibrio spp. Yersinia pestis

Anaerobic microorganisms Mobiluncus

Other microorganisms Chlamydia trachomatis ($) Chlamydia pneumoniae ($) Mycoplasma hominis ($) Mycoplasma pneumoniae ($)

Species in which development of acquired resistance may occur

Aerobic Gram-positive microorganisms Enterococcus faecalis ($) Staphylococcus spp .* (2)

Aerobic Gram-negative microorganisms Acinetobacter baumannii+ Burkholderia cepacia+* Campylobacter spp.+* Citrobacter freundii* Enterobacter aerogenes Enterobacter cloacae* Escherichia coli* Klebsiella oxytoca Klebsiella pneumoniae* Morganella morganii* Neisseria gonorrhoeae* Proteus mirabilis* Proteus vulgaris* Providencia spp. Pseudomonas aeruginosa* Pseudomonas fluorescens Serratia marcescens*

Anaerobic microorganisms Peptostreptococcus spp. Propionibacterium acnes

Microorganisms inherently resistant to ciprofloxacin

Aerobic Gram-positive microorganisms Actinomyces Enterococcus faecium Listeria monocytogenes

Aerobic Gram-negative microorganisms Stenotrophomonas maltophilia

Anaerobic microorganisms With the exception of those listed above

Other microorganisms Mycoplasma genitalium Ureaplasma urealyticum

* Clinical efficacy has been demonstrated for susceptible isolates according to approved clinical indications + Resistance rate ≥ 50% in one or more EU countries. ($) Natural intermediate susceptibility in the absence of acquired resistance mechanisms (1) Studies have been conducted in experimental animals infected via the airborne route with spores of Bacillus anthracis; these studies show that administration of antibiotics immediately after exposure to the pathogen helps prevent disease if the spore burden can be reduced below the infective dose. Recommendations for the use of ciprofloxacin are primarily based on in vitro susceptibility data in animals together with limited human data. A 2-month course of oral ciprofloxacin 500 mg twice daily is considered effective for post-exposure prophylaxis of anthrax in adults. Physicians should refer to national and/or international anthrax treatment guidelines. (2) Methicillin-resistant S. aureus is very frequently also resistant to fluoroquinolones. The methicillin resistance rate among all Staphylococcus species is approximately 20–50% and is usually high among hospital isolates.

Non-clinical safety data.

Non-clinical data reveal no special hazard to humans based on conventional studies of single-dose toxicity, repeated-dose toxicity, carcinogenic potential, or reproductive toxicity.

Pharmacokinetics.

Absorption.

After oral administration of 250 mg, 500 mg, or 750 mg ciprofloxacin tablets, ciprofloxacin is rapidly and well absorbed, primarily from the upper part of the small intestine. Peak serum concentration is reached within 1–2 hours.

Single doses ranging from 100 to 750 mg resulted in dose-dependent peak serum concentrations in the range of 0.56–3.7 mg/L. Serum concentration increases proportionally with doses up to 1000 mg.

The absolute bioavailability of the drug is 70–80%. When administered orally as 500 mg ciprofloxacin every 12 hours, the total area under the concentration-time curve is equivalent to that achieved after intravenous infusion of 400 mg ciprofloxacin administered over 60 minutes every 12 hours.

Distribution.

The extent of plasma protein binding of ciprofloxacin is low (20–30%). Ciprofloxacin is present in plasma predominantly in the 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 samples), sinuses, inflamed and damaged tissues, and tissues of the genitourinary tract (urine, prostate, endometrium), where total concentrations exceed those in plasma.

Biotransformation.

Low concentrations of four metabolites have been detected: desethylene-ciprofloxacin (M1), sulfociprofloxacin (M2), oxociprofloxacin (M3), and formylciprofloxacin (M4). These metabolites exhibit antimicrobial activity in vitro, but to a lesser extent than the parent compound.

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

Elimination.

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

Table 2

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

Renal clearance amounts to 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 attributed to transintestinal secretion and metabolism. One percent (1%) of the dose is excreted via the biliary tract. Ciprofloxacin is present in high concentrations in bile.

Children.

Pharmacokinetic data in children are limited. Studies involving children have not revealed age-dependent differences in C_max and AUC (in children aged 1 year and older). After repeated dosing (10 mg/kg three times daily), no significant increase in C_max and AUC was observed. In children 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) in the respective age groups. These values are within the range observed in adults receiving therapeutic doses. According to pharmacokinetic analyses in pediatric patients with various infections, the predicted mean elimination half-life in children is approximately 4–5 hours, and the bioavailability of the oral suspension ranges from 50 to 80%.

Clinical characteristics.

Indications.

For the treatment of the following lower-mentioned infections (see sections "Pharmacological properties" and "Special precautions"). Before initiating therapy, particular attention should be paid to all available information regarding resistance to ciprofloxacin. Official recommendations on appropriate use of antibacterial agents should be taken into account.

Adults

Lower respiratory tract infections caused by Gram-negative bacteria:

• Exacerbations of chronic obstructive pulmonary disease (COPD) (ciprofloxacin should be used in exacerbations of COPD 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;
• Community-acquired pneumonia.

Chronic suppurative otitis media.

Severe external otitis.

Acute exacerbation of chronic sinusitis, especially if caused by Gram-negative bacteria.

Urinary tract infections:

• Uncomplicated acute cystitis.

Ciprofloxacin should be used in uncomplicated acute cystitis only when it is considered inappropriate to use other antibacterial agents usually recommended for treatment of such 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, particularly caused by susceptible strains of Neisseria gonorrhoeae;
• Pelvic inflammatory disease, particularly 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 definitive treatment).

Ciprofloxacin may be used for the treatment of febrile neutropenia when bacterial infection is suspected.

Children and adolescents

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

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

Treatment should be initiated by a physician experienced in managing cystic fibrosis and/or severe infections in children and adolescents (see sections "Pharmacodynamics" and "Special precautions").

Contraindications.

Hypersensitivity to ciprofloxacin or to other quinolone antibiotics, or to any of the excipients of the medicinal product.

Concomitant administration of ciprofloxacin and tizanidine is contraindicated due to clinically significant adverse effects (hypotension, somnolence) associated with increased plasma concentrations of tizanidine (see section "Special precautions").

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 precautions").

Chelate complex formation.

Concomitant administration of ciprofloxacin (oral) with medicinal products containing multivalent cations and mineral supplements (e.g. calcium, magnesium, aluminium, iron), phosphate-binding polymers (e.g. sevelamer or lanthanum carbonate), sucralfate, or antacids, as well as medicinal products with high buffer capacity (such as didanosine tablets) containing magnesium, aluminium, or calcium, reduces the absorption of ciprofloxacin. Therefore, ciprofloxacin should be taken either 1–2 hours before or at least 4 hours after administration of these products. This restriction does not apply to antacids belonging to the class of H2-receptor blockers.

Food, including dairy products.

Calcium in food has a minor effect on absorption. However, simultaneous intake of ciprofloxacin with dairy or mineral-enriched products (such as milk, yogurt, or calcium-fortified orange juice) should be avoided, as it may reduce ciprofloxacin absorption.

Probenecid.

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

Metoclopramide.

Metoclopramide accelerates the absorption of orally administered ciprofloxacin, resulting in a faster achievement of maximum plasma concentration. 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.

Effects of ciprofloxacin on other medicinal products.

Tizanidine.

Tizanidine must not be used concomitantly with ciprofloxacin (see section "Contraindications"). It is known that concomitant administration of ciprofloxacin and tizanidine increases plasma concentrations of tizanidine (increase in Cmax by 7-fold, range: 4–21-fold; increase in AUC by 10-fold, range: 6–24-fold). Increased plasma concentrations of tizanidine are associated with hypotensive and sedative adverse reactions.

Methotrexate.

Concomitant administration of ciprofloxacin may slow tubular transport of methotrexate, potentially leading to increased plasma concentrations of methotrexate. This may increase the risk of methotrexate-induced toxic adverse reactions; therefore, concomitant use is not recommended (see section "Special precautions").

Theophylline.

Concomitant administration of ciprofloxacin and theophylline may lead to undesirable increases in theophylline plasma concentrations, which in turn may cause adverse reactions. In isolated cases, such adverse reactions may be life-threatening or even fatal. Therefore, when ciprofloxacin and theophylline are used concomitantly, serum theophylline concentrations should be monitored and the dose reduced if necessary (see section "Special precautions").

Other xanthine derivatives.

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

Phenytoin.

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

Cyclosporine.

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

Vitamin K antagonists.

Concomitant administration of ciprofloxacin and vitamin K antagonists may enhance their anticoagulant effect. The degree of risk may vary depending on the underlying type of infection, age, and general condition of the patient, making it difficult to accurately 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.

It has been reported that concomitant administration of duloxetine with strong CYP450 1A2 inhibitors, such as fluvoxamine, may increase AUC and Cmax of duloxetine. Despite the lack of clinical data on potential interaction with ciprofloxacin, similar effects may be expected when these agents are used concomitantly (see section "Special precautions").

Ropinirole.

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

Lidocaine.

It has been shown in healthy volunteers that concomitant administration of ciprofloxacin, a moderate inhibitor of cytochrome P450 1A2 isoenzymes, and medicinal products containing lidocaine reduces the clearance of intravenous lidocaine by 22%. Despite normal tolerability of lidocaine treatment, interaction with ciprofloxacin associated with adverse reactions may occur when these agents are used concomitantly.

Clozapine.

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

Sildenafil.

Cmax and AUC of sildenafil increased approximately 2-fold in healthy volunteers after concomitant oral administration of 50 mg sildenafil and 500 mg ciprofloxacin. Therefore, caution should be exercised when co-prescribing ciprofloxacin with sildenafil, and the risk/benefit ratio should be considered.

Agomelatine

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

Zolpidem

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

Special precautions for use.

Before initiating therapy, particular attention should be paid to all available information regarding resistance to ciprofloxacin.

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

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

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.

Fluoroquinolone-resistant strains of Neisseria gonorrhoeae may cause gonococcal urethritis, cervicitis, orchioepididymitis, and pelvic inflammatory disease.

Ciprofloxacin should be used for the treatment of gonococcal urethritis or cervicitis only if resistance of Neisseria gonorrhoeae to ciprofloxacin has been ruled out.

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

If there is no clinical improvement within 3 days, the therapy should be re-evaluated.

Urinary tract infections.

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

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

Intra-abdominal infections.

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

Traveler's diarrhea.

When selecting a treatment, information on resistance to ciprofloxacin of relevant microorganisms in the countries visited should be considered.

Bone and joint infections.

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

Pulmonary anthrax.

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

Children

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 of weight-bearing joints in immature animals. Safety data from a randomized, double-blind study of ciprofloxacin use in children (ciprofloxacin: n=335, mean age = 6.3 years; comparator group: n=349, mean age = 6.2 years; age range 1 to 17 years) showed an incidence of arthropathy, likely related to drug use (distinct from clinical signs and symptoms directly related to joint involvement), at day 42 of

7.2% and 4.6% in the treatment and comparator groups, respectively. The incidence of drug-related arthropathy at one year of follow-up was 9% and 5.7%, respectively. The increase in arthropathy cases associated with drug use was not statistically significant. However, treatment of children and adolescents with ciprofloxacin should only be initiated after careful assessment of the benefit-risk ratio due to the potential risk of adverse reactions affecting joints and/or surrounding tissues.

Respiratory infections in cystic fibrosis.

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

Complicated urinary tract infections and pyelonephritis.

Treatment of urinary tract infections with ciprofloxacin should be considered 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 aged 1 to 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 no other treatment is possible or when standard therapy has failed.

Ciprofloxacin use 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.

In some cases, hypersensitivity and allergic reactions may occur after the first dose of ciprofloxacin (see section "Side effects"), and the physician should be informed immediately.

In rare cases, anaphylactic/anaphylactoid reactions may progress to life-threatening shock. Such reactions may occur even after the first dose of ciprofloxacin. In such cases, ciprofloxacin administration must be discontinued immediately, and emergency medical treatment initiated (treatment of anaphylactic shock).

Musculoskeletal system.

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

Tendinitis and tendon rupture

Tendinitis or tendon rupture (especially of the Achilles tendon), sometimes bilateral, may occur during ciprofloxacin therapy, even within the first 48 hours of treatment. Inflammation or rupture of tendons may occur even several months after completion of ciprofloxacin therapy. The risk of tendinopathy may be increased in elderly patients or in patients concurrently using corticosteroids (see section "Side effects"). If any signs of tendinitis (such as painful swelling, inflammation) occur, ciprofloxacin use should be discontinued. The affected limb should be rested.

Ciprofloxacin should be used with caution in patients with myasthenia gravis due to the potential for exacerbation of symptoms (see section "Side effects").

Visual disturbances

If vision deteriorates or any ocular symptoms occur, the patient should seek immediate medical attention.

Photosensitivity.

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

Central nervous system.

Ciprofloxacin, like other quinolones, is known to cause seizures or lower the seizure threshold. Cases of status epilepticus have been reported. Ciprofloxacin should be used with caution in patients with CNS disorders predisposing to seizures. If seizures occur, ciprofloxacin should be discontinued (see section "Side effects"). 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 attempted suicide. In such cases, ciprofloxacin use should be discontinued.

Prolonged, disabling, and potentially irreversible adverse reactions

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

Ciprofloxacin use should be discontinued immediately upon the first signs or symptoms of any serious adverse reaction, and patients should consult their physician.

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 such as pain, burning, tingling, numbness, or weakness develop, to prevent progression to potentially irreversible conditions (see section "Side effects").

Cardiac disorders.

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

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

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

Hypoglycemia.

As with other fluoroquinolones, ciprofloxacin may alter blood glucose levels, including hypoglycemia and hyperglycemia. Dysglycemia during ciprofloxacin therapy is more likely in elderly patients and in diabetic patients receiving concomitant therapy with oral hypoglycemic agents (e.g., sulfonylureas) or insulin. The risk of hypoglycemia, up to hypoglycemic coma, is increased in such patients when receiving ciprofloxacin. Patients should be informed about symptoms of hypoglycemia (confusion, dizziness, increased appetite, headache, nervousness, palpitations or tachycardia, pallor, sweating, tremor, weakness). If hypoglycemia occurs, ciprofloxacin therapy should be discontinued immediately and appropriate treatment initiated. In such cases, switching to an antibiotic other than a fluoroquinolone is recommended, if possible. Close monitoring of blood glucose levels is recommended when treating elderly patients or diabetic patients with ciprofloxacin (see section "Side effects").

Dysglycemia

As with other quinolones, disturbances in blood glucose levels, including both hypoglycemia and hyperglycemia (see section "Side effects"), have been reported, usually in diabetic patients receiving concomitant therapy with oral antidiabetic agents (e.g., glyburide) or insulin. Diabetic patients should have close monitoring of blood glucose levels.

Gastrointestinal tract.

The occurrence of severe and persistent diarrhea during or after treatment may indicate antibiotic-associated colitis (which may be life-threatening, with possible fatal outcome) and requires immediate treatment (see section "Side effects"). In such cases, ciprofloxacin use should be discontinued and appropriate therapy initiated. Antiperistaltic agents are contraindicated in this clinical situation.

Kidneys and urinary system.

Crystalluria associated with ciprofloxacin use has been reported (see section "Side effects"). Patients taking ciprofloxacin should receive adequate fluid intake. Excessive alkalinity of urine should be avoided.

Renal function impairment.

Since ciprofloxacin is primarily excreted unchanged by the kidneys, dose adjustment is required in patients with impaired renal function according to the recommendations specified in the section "Dosage and administration" to avoid increased frequency of adverse reactions due to ciprofloxacin accumulation.

Hepatobiliary system.

Cases of hepatic necrosis and life-threatening liver failure have been reported with ciprofloxacin use (see section "Side effects"). If any symptoms of liver disease occur (e.g., anorexia, jaundice, dark urine, pruritus, or abdominal distension), treatment should be discontinued.

Glucose-6-phosphate dehydrogenase deficiency.

Hemolytic reactions have been reported in patients with glucose-6-phosphate dehydrogenase deficiency receiving ciprofloxacin. Ciprofloxacin 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 a course of ciprofloxacin treatment, with or without clinically evident superinfection. There may be 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 CYP1A2 and may therefore increase serum concentrations of concurrently administered drugs metabolized by this enzyme (e.g., theophylline, clozapine, olanzapine, ropinirole, tizanidine, duloxetine). Concomitant use of ciprofloxacin and tizanidine is contraindicated. Therefore, patients receiving these drugs concomitantly with ciprofloxacin should be closely monitored for possible signs of overdose. Serum concentration monitoring (e.g., theophylline) may also be necessary (see section "Interaction with other medicinal products and other forms of interaction").

Methotrexate.

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

Effect on laboratory test results.

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

Aortic aneurysm and dissection, and cardiac valve regurgitation/insufficiency

Epidemiological studies report an increased risk of aortic aneurysm and dissection, particularly in elderly patients, and regurgitation of aortic and mitral valves following fluoroquinolone use. Cases of aortic aneurysm and dissection, sometimes complicated by rupture (including fatal cases), and regurgitation/insufficiency of any cardiac valve have been reported in patients receiving fluoroquinolones (see section "Side effects").

Therefore, fluoroquinolones should be used only after careful benefit-risk assessment and consideration of alternative therapeutic options in patients with a positive family history of aneurysm or congenital heart valve defects, or in patients with existing diagnosis of aneurysm and/or aortic dissection, or heart valve disease, or in the presence of other risk factors or predisposing conditions

• for both aortic aneurysm and dissection and cardiac valve regurgitation/insufficiency (e.g., connective tissue disorders such as Marfan syndrome or Ehlers-Danlos syndrome, Turner syndrome, Behçet's disease, rheumatoid arthritis), or additionally
• for aortic aneurysm and dissection (e.g., vascular disorders such as Takayasu arteritis or giant cell arteritis, known atherosclerosis, or Sjögren's syndrome), or additionally
• for cardiac valve regurgitation/insufficiency (e.g., infective endocarditis). The risk of aortic aneurysm, dissection, and rupture may be increased in patients concurrently receiving systemic corticosteroids.

If sudden abdominal, chest, or back pain occurs, patients should seek immediate medical attention at an emergency department.

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

Effect on laboratory test results

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

Use during pregnancy or breastfeeding.

Pregnancy. Data on ciprofloxacin use in pregnant women show no evidence of malformations or fetoneonatal toxicity. However, to prevent potential adverse effects on the fetus, ciprofloxacin should be avoided during pregnancy.

In young animals and animals exposed to quinolones before birth, effects on immature cartilage have been observed; therefore, a potential risk to fetal/neonatal joint cartilage cannot be excluded.

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

Ability to affect reaction speed when driving or operating machinery.

Ciprofloxacin may affect a patient's ability to drive or operate machinery due to nervous system reactions (see section "Side effects"). Therefore, the ability to drive or operate machinery may be impaired.

Method of administration and dosage.

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

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

Treatment of infections caused by certain bacteria (e.g. Pseudomonas aeruginosa, Acinetobacter, or Staphylococci) may require higher doses of ciprofloxacin and concomitant use 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 use of other necessary antibacterial agents depending on the type of identified pathogens.

Adult patients.

Table 3

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 instructions")	Uncomplicated cystitis	From 250 mg twice daily to 500 mg twice daily	3 days
		Postmenopausal women may be given a single dose of 500 mg
	Complicated cystitis, uncomplicated 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., abscess), treatment may be extended beyond 21 days
	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	Single dose of 500 mg	1 day (single dose)
	Orchiepididymitis and pelvic inflammatory disease	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, including Shigella spp., except Shigella dysenteriae type I, and empirical treatment of severe traveler's diarrhea	500 mg twice daily	1 day
	Diarrhea caused by Shigella dysenteriae, type I	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
Infections of skin and soft tissues		From 500 mg twice daily to 750 mg* twice daily	7 to 14 days
Infections of bones and joints		From 500 mg twice daily to 750 mg* twice daily	Up to 3 months
Neutropenic patients with fever suspected of bacterial origin. Ciprofloxacin should be used in combination with appropriate antibacterial agents in accordance with official recommendations		From 500 mg twice daily to 750 mg* twice daily	Treatment should continue throughout the entire period of neutropenia
Prophylaxis of invasive infections caused by Neisseria meningitidis		Single dose of 500 mg	1 day (single dose)
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		500 mg twice daily	60 days from the date of confirmed exposure to Bacillus anthracis

Children.

Table 4

Indications	Daily dose (mg)	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 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. Therapy 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 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

*Use ciprofloxacin preparations at the appropriate dosage.

Geriatric patients.

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

Renal and hepatic impairment.

Recommended initial and maintenance doses for patients with impaired renal function

Table 5

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

There is no need to adjust the dosage of ciprofloxacin in patients with hepatic insufficiency.

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

Method of administration.

The tablets should be swallowed whole, without chewing, with liquid. They may be taken independently of food intake. When administered on an empty stomach, the active substance is absorbed more rapidly. Ciprofloxacin tablets must not be taken together with dairy products (e.g., milk, yogurt) or fruit juices fortified with minerals (e.g., calcium-fortified orange juice) (see section "Interaction with other medicinal products and other forms of interaction").

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

Children.

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

Ciprofloxacin has caused arthropathy of weight-bearing joints in immature animals.

Treatment of children with ciprofloxacin should only be initiated after careful assessment of the benefit-risk ratio due to the potential risk of developing adverse reactions affecting joints and/or surrounding tissues.

Overdose.

Cases of overdose involving ingestion of 12 g of the drug have resulted in symptoms of moderate toxicity. Acute overdose at a dose of 16 g led to the development of acute renal failure.

Symptoms of overdose included dizziness, tremor, headache, increased fatigue, seizures, hallucinations, confusion, abdominal discomfort, renal and hepatic failure, as well as crystalluria and hematuria. Reversible nephrotoxicity has also been reported.

In addition to standard emergency measures taken in overdose situations, monitoring of renal function is recommended, including determination of urine pH and, if necessary, acidification of urine to prevent crystalluria. Patients should receive adequate fluid intake. Antacids containing calcium or magnesium may theoretically reduce absorption of ciprofloxacin in overdose.

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

In case of overdose, symptomatic treatment should be administered. Due to the potential for QT interval prolongation, ECG monitoring is also advisable.

Adverse reactions.

The most commonly reported adverse reactions were nausea and diarrhoea.

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

When analysing the frequency of occurrence, data from both oral and intravenous administration routes of ciprofloxacin are considered.

Infections and infestations: uncommon – fungal superinfections.

Blood and lymphatic system disorders: uncommon – eosinophilia; rare – leukopenia, anaemia, neutropenia, leukocytosis, thrombocytopenia, thrombocytosis; very rare – haemolytic anaemia, agranulocytosis, pancytopenia (life-threatening), bone marrow suppression (life-threatening).

Immune system disorders: rare – allergic reactions, allergic/angioneurotic oedema; very rare – anaphylactic reactions, anaphylactic shock (life-threatening)1, serum sickness-like reactions.

Endocrine disorders: frequency not known – syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Metabolism and nutrition disorders: uncommon – anorexia; rare – hyperglycaemia, hypoglycaemia1; frequency not known – hypoglycaemic coma1.

Psychiatric disorders 1, 2: uncommon – psychomotor agitation/anxiety; rare – confusion and disorientation, anxiety, pathological dreams, depression (with possible suicidal thoughts/ideation or suicide attempts/acts) (see section "Special precautions for use"), hallucinations; very rare – psychotic reactions (with possible suicidal thoughts/ideation or suicide attempts/acts)1; frequency not known – mania, hypomania.

Nervous system disorders 1, 2: uncommon – headache, dizziness, sleep disturbances, taste disturbances; rare – paraesthesia, dysaesthesia, hypoaesthesia, tremor, convulsions (including epileptic status)1, vertigo; very rare – migraine, coordination disturbances, gait disturbances, olfactory nerve disturbances, intracranial hypertension, pseudotumour cerebri; frequency not known – peripheral neuropathy and polyneuropathy1.

Gastrointestinal disorders: common – nausea, diarrhoea; uncommon – vomiting, stomach and intestinal discomfort, abdominal pain, dyspeptic disorders, flatulence; rare – antibiotic-associated diarrhoea, including pseudomembranous colitis (very rare – potentially fatal)1; very rare – pancreatitis.

Hepatobiliary disorders: uncommon – increased plasma transaminase and bilirubin levels; rare – liver function disturbances, cholestatic jaundice, hepatitis; very rare – liver necrosis (very rare cases may progress to life-threatening liver failure)1.

Eye disorders 1, 2: rare – visual disturbances (e.g., diplopia); very rare – colour vision disturbances.

Ear and labyrinth disorders 1, 2: rare – tinnitus, hearing loss/hearing disturbances.

Cardiac disorders 1, 3: rare – tachycardia, vasodilation, hypotension, syncope; very rare – vasculitis; frequency not known – ventricular arrhythmia, torsades de pointes1, 4.

Respiratory, thoracic and mediastinal disorders: rare – dyspnoea (including asthmatic conditions).

Skin and subcutaneous tissue disorders: uncommon – rash, pruritus, urticaria; rare – photosensitivity reactions1; very rare – petechiae, erythema multiforme, nodular erythema, Stevens-Johnson syndrome (potentially life-threatening), toxic epidermal necrolysis (potentially life-threatening); frequency not known – acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS syndrome).

Musculoskeletal and connective tissue disorders 1, 2: uncommon – musculoskeletal pain (e.g., limb, back, chest pain), arthralgia; rare – myalgia, arthritis, increased muscle tone, muscle spasms; very rare – muscle weakness, tendinitis, tendon rupture (predominantly Achilles tendon)1, exacerbation of symptoms of myasthenia gravis1.

Renal and urinary disorders: uncommon – renal function disturbances; rare – renal failure, haematuria, crystalluria1, tubulointerstitial nephritis.

General disorders and administration site conditions 1, 2: uncommon – asthenia, fever; rare – oedema, increased sweating (hyperhidrosis).

Investigations: uncommon – increased alkaline phosphatase activity in blood; rare – increased amylase activity; frequency not known – increased international normalized ratio (INR) (in patients receiving vitamin K antagonists).

1 See section "Special precautions for use".

2 Some cases of very rare, prolonged (several months or years), disabling and potentially irreversible serious adverse reactions affecting multiple organ systems have been reported with quinolones and fluoroquinolones, regardless of the presence of risk factors (including such reactions as tendinitis, tendon rupture, arthralgia, limb pain, gait disturbances, neuropathies associated with paraesthesia and neuralgia, fatigue, psychiatric symptoms (including sleep disturbances, anxiety, panic attacks, depression, and suicidal thoughts), memory and concentration disturbances, as well as hearing, vision, taste, and smell disturbances).

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

4 These reactions were reported during the post-marketing period and were predominantly observed in patients with additional risk factors for QT interval prolongation.

Paediatric population

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

Reporting suspected adverse reactions

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

Shelf life.

3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of the reach and sight of children.

Packaging.

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

Prescription status.

Prescription only.

Manufacturer.

LLC "AstraPharm".

Manufacturer's address and location of business activity.

6 Kyivska Street, Vyshneve, Kyiv-Sviatoshyn District, Kyiv Oblast, 08132, Ukraine.