Ciprofloxacin euro

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CIPROFLOXACIN EURO (CIPROFLOXACIN EURO)

Composition:

Active substance: ciprofloxacin;

One 500 mg tablet contains 594 mg of ciprofloxacin hydrochloride equivalent to 500 mg of ciprofloxacin;

Excipients: microcrystalline cellulose, colloidal anhydrous silicon dioxide, sodium starch glycolate (type A), maize starch, magnesium stearate, talc, Opadry White 33G28707.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white to yellowish-white, capsule-shaped, film-coated tablets with a score line on one side.

Pharmacotherapeutic group. Antibacterials for systemic use. Fluoroquinolone group. ATC code J01MA02.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action.

Ciprofloxacin demonstrates high in vitro activity against a broad spectrum of Gram-negative and Gram-positive pathogens. The mechanism of antibacterial action is based on ciprofloxacin's ability to inhibit type II topoisomerases (DNA gyrase and topoisomerase IV), which are essential for various DNA life cycle processes such as replication, transcription, repair, and recombination.

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 value of the area under the curve (AUC) and MIC.

In vitro resistance to ciprofloxacin is usually associated with mutations in the target site occurring in bacterial topoisomerases and DNA gyrase through multiple-step mutations. Single mutations are more likely to lead to reduced susceptibility rather than clinical resistance. However, multiple mutations typically result in clinical resistance to ciprofloxacin and cross-resistance to quinolones.

Resistance mechanisms that inactivate other antibiotics, such as reduced permeability of the bacterial outer membrane (characteristic of Pseudomonas aeruginosa) and active drug efflux from the cell (efflux), may affect susceptibility to ciprofloxacin. Plasmid-mediated resistance, encoded by the antibiotic resistance qnr gene, has also 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
Enterobacteria	≤ 0.5 mg/L	> 1 mg/L
Pseudomonas	≤ 0.5 mg/L	> 1 mg/L
Acinetobacter	≤ 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. – breakpoints for ciprofloxacin apply to high-dose therapy regimens. * Non-species related breakpoints were primarily defined based on pharmacokinetic/pharmacodynamic data relationships and are not dependent on MICs for individual species. They are used only for species without their own specific breakpoints, and not for species where susceptibility testing is not recommended.

The prevalence of acquired resistance in isolated species may vary depending on the region and time; therefore, local information on resistance is necessary, especially when treating severe infections. Consultation with specialists should be sought when local resistance prevalence has reached a level at which the benefit of using the drug, at least for certain types of infections, is questionable.

The following bacterial genera and species are generally susceptible to ciprofloxacin in vitro (for the genus Streptococcus, see section "Special Instructions"):

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* 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 resistance may occur

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

Gram-negative aerobic 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

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

* Clinical efficacy has been demonstrated against susceptible isolates for approved clinical indications. + Resistance rate ≥ 50% in one or more EU countries. ($) Natural intermediate susceptibility in the absence of acquired resistance mechanisms. (1) Animal studies infected via inhalation of Bacillus anthracis spores demonstrate that immediate post-exposure administration of antibiotics can prevent disease by reducing spore counts below the infectious dose. Recommendations for ciprofloxacin use are primarily based on in vitro susceptibility data from animal studies and limited human data. A two-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. Methicillin resistance among all staphylococcal isolates is approximately 20–50%, and is usually high among hospital-acquired isolates.

Preclinical Safety Data

According to preclinical data, no special hazard for humans has been identified based on standard studies of single-dose toxicity, repeated-dose toxicity, carcinogenic potential, or reproductive toxicity.

Like many other quinolones, ciprofloxacin is phototoxic in animals at clinically relevant exposure levels. Photomutagenicity/photocarcinogenicity data indicate a weak photomutagenic or photo-oncogenic effect of ciprofloxacin in vitro and in animal studies. This effect is comparable to that of other gyrase inhibitors.

Joint Effects Studies

Similar to other gyrase inhibitors, ciprofloxacin may cause damage to the large weight-bearing joints of young animals.

The degree of cartilage damage varies depending on age, species, and dose; the extent of damage can be reduced by minimizing weight-bearing stress on the joints. Studies in adult animals (rats, dogs) showed no evidence of cartilage damage. In a study in young beagle dogs, administration of ciprofloxacin at therapeutic doses resulted in joint changes after two weeks of treatment, which persisted after five months.

Pharmacokinetics

Absorption

Following oral administration of 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 are reached within 1–2 hours.

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

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

Distribution

The percentage of ciprofloxacin binding to plasma proteins is low (20–30%), and it remains predominantly in the non-ionized form in plasma. Ciprofloxacin freely diffuses into the extravascular space. The large volume of distribution at steady state, approximately 2–3 L/kg body weight, demonstrates that ciprofloxacin penetrates into tissues at concentrations that may exceed serum levels by several-fold. Ciprofloxacin achieves high concentrations in various tissues, such as lungs (epithelial lining fluid, alveolar macrophages, biopsy samples), sinuses, inflamed and damaged tissues, and tissues of the urinary tract, as well as genital organs (urine, prostate, endometrium).

Metabolism

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

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

Elimination

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

Excretion of ciprofloxacin (% of dose) after oral administration
Name	Excretion pathways
	In urine	In feces
Ciprofloxacin	44.7	25.0
Metabolites (M1–M4)	11.3	7.5

Renal clearance is 180–300 mL/kg/hour, and total clearance is 480–600 mL/kg/hour. 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 pediatric patients are limited. Studies on the use of ciprofloxacin in children have not demonstrated age-dependent differences in Cmax or AUC values. After repeated administration (10 mg/kg three times daily), no significant increase in Cmax and AUC was observed. In ten infants under 1 year of age with severe sepsis, Cmax was 6.1 mg/L (range: 4.6–8.3 mg/L) following a 1-hour intravenous infusion at a dose of 10 mg/kg. In children aged 1 to 5 years, Cmax was 7.2 mg/L (range: 4.7–11.8 mg/L). AUC values were 17.4 mg∗hour/L (range: 11.8–32.0 mg∗hour/L) and 16.5 mg∗hour/L (range: 11.0–23.8 mg∗hour/L), respectively, in the corresponding age groups. These values are within the range observed in adults receiving therapeutic doses. Based on patient population and 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.

The medicinal product is indicated for the treatment of the following infections (see sections "Special precautions for use" and "Pharmacological properties"). Before initiating therapy, due regard should be paid to all available information regarding resistance to ciprofloxacin.

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

Adults

• Lower respiratory tract infections caused by Gram-negative bacteria:
  • Exacerbations of chronic obstructive pulmonary disease, including bronchitis*;
  • Bronchopulmonary infections in cystic fibrosis or bronchiectasis;
  • Community-acquired pneumonia.
• Chronic suppurative otitis media.
• Acute exacerbation of chronic sinusitis, particularly if caused by Gram-negative bacteria*.
• Urinary tract infections:
  • Uncomplicated acute cystitis*;
  • 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 infections (e.g., traveler's diarrhea).
• Intra-abdominal infections.
• Skin and soft tissue infections caused by Gram-negative bacteria.
• Bone and joint infections.
• Malignant external otitis.
• Inhalational anthrax (post-exposure prophylaxis and treatment).

Febrile neutropenia caused by bacterial infection.

Children and adolescents

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

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

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 "Special precautions for use" and "Pharmacological properties").

∗Only when the use of other antibacterial agents typically prescribed for the treatment of this infection has been considered ineffective or inappropriate.

Contraindications.

Do not use in case of hypersensitivity to the active substance – ciprofloxacin – or to other fluoroquinolone antibiotics, or to any of the excipients of the medicinal product.

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

Interaction with other medicinal products and other forms of interaction.

Effect of other agents on ciprofloxacin

Agents that prolong the QT interval

Ciprofloxacin, like other fluoroquinolones, should be administered with caution to patients receiving medicinal products that prolong the QT interval (e.g., class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) (see section "Special precautions for use").

Chelate formation

Concomitant administration of ciprofloxacin (oral) with medicinal products containing multivalent cations, mineral supplements (e.g., calcium, magnesium, aluminium, iron), phosphate-binding polymers (e.g., sevelamer or lanthanum carbonate), sucralfate, or antacids, as well as medicinal products with high buffering 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 agents.

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

Food and dairy products

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

Probenecid

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

Metoclopramide

Metoclopramide accelerates the absorption of 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.

Effect of ciprofloxacin on other medicinal products

Tizanidine

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

Methotrexate

Concomitant administration of ciprofloxacin may slow tubular transport (renal metabolism) of methotrexate, potentially leading to increased methotrexate plasma concentrations. This increases the risk of adverse toxic reactions caused by methotrexate. Concomitant administration is not recommended (see section "Special precautions for use").

Theophylline

Concomitant administration of ciprofloxacin and medicinal products containing theophylline may lead to an undesirable increase in theophylline plasma concentration, which in turn may cause adverse reactions. In isolated cases, such adverse reactions may be life-threatening or fatal. If concomitant use of these agents cannot be avoided, theophylline plasma concentration should be monitored and its dose appropriately reduced (see section "Special precautions for use").

Other xanthine derivatives

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

Phenytoin

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

Cyclosporine

Transient increase in plasma creatinine has been observed during concomitant administration of ciprofloxacin and medicinal products containing cyclosporine. Therefore, frequent monitoring (twice weekly) of plasma creatinine concentration is required in these patients.

Vitamin K antagonists

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

Duloxetine

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

Ropinirole

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

Lidocaine

It has been shown that concomitant administration of ciprofloxacin, a moderate inhibitor of cytochrome P450 1A2 isoenzymes, with medicinal products containing lidocaine reduces the clearance of intravenous lidocaine by 22% in healthy subjects. 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 administration with ciprofloxacin (see section "Special precautions for use").

Sildenafil

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

Oral hypoglycemic agents

Hypoglycemia has been reported during concomitant administration of ciprofloxacin and oral antidiabetic medicinal products, particularly sulfonylureas (e.g., glyburide, glimepiride), likely due to potentiation by ciprofloxacin of the effect of oral antidiabetic agents (see section "Adverse reactions").

Duloxetine

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

Non-steroidal anti-inflammatory drugs (NSAIDs)

Animal studies have shown that the combination of very high doses of quinolones (gyrase inhibitors) and certain non-steroidal anti-inflammatory drugs (except acetylsalicylic acid) may provoke seizures.

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 when used concomitantly (see "Cytochrome P450" in section "Special precautions for use").

Zolpidem

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

Special precautions for use.

The use of ciprofloxacin should be avoided in patients who have previously experienced serious adverse reactions to quinolone- or fluoroquinolone-containing medicinal products (see section "Adverse reactions"). Treatment with ciprofloxacin in such patients should only be initiated if no alternative treatment options are available and after careful benefit/risk assessment (see also section "Contraindications").

Aortic aneurysm/dissection and cardiac valve regurgitation

Epidemiological data suggest an increased risk of aortic aneurysm or aortic dissection associated with fluoroquinolone use, particularly in elderly patients.

Cases of aortic aneurysm and aortic dissection, sometimes leading to aortic rupture (including fatal cases), have been reported in patients receiving fluoroquinolones, along with other adverse reactions (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 history of aortic aneurysm or dissection, or with a personal or family history of heart failure, or in the presence of other risk factors, namely:

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

The risk of aortic aneurysm, dissection, and rupture is increased in patients receiving concomitant systemic corticosteroid therapy.

Patients should be advised to seek immediate medical attention at an emergency department if they experience sudden abdominal, chest, or back pain.

Patients should also seek immediate medical help if they develop acute shortness of breath, a new episode of rapid heartbeat, or swelling of the abdomen or lower extremities.

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 the treatment of severe infections or infections caused by staphylococci or anaerobic bacteria, 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, orchiepididymitis, and pelvic inflammatory disease.

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

Empirical therapy with ciprofloxacin for orchiepididymitis 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 no clinical improvement is observed within 3 days, the treatment should be re-evaluated.

Urinary tract infections.

In European Union countries, varying resistance of Escherichia coli, the most common causative pathogen of urinary tract infections, to fluoroquinolones has been observed. Prescribers are advised to consider local resistance patterns of Escherichia coli to fluoroquinolones when selecting therapy.

Single-dose regimens of ciprofloxacin, which may be used in uncomplicated cystitis in premenopausal women, are considered less effective than longer treatment courses. This should be taken into account 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 ciprofloxacin resistance of relevant microorganisms in the visited countries should be considered.

Bone and joint infections

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

Pulmonary form of anthrax

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

Children

Ciprofloxacin use in children should follow current official recommendations. Treatment with ciprofloxacin should be administered only by physicians experienced in treating children with cystic fibrosis and/or severe infections.

Ciprofloxacin has been associated with arthropathy in weight-bearing joints in immature animals. In 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), the incidence of arthropathy likely related to drug use (distinct from clinical signs and symptoms directly related to joint involvement) was 7.2% and 4.6% in the ciprofloxacin and comparator groups, respectively, at day 42. The incidence of drug-related arthropathy at 1 year was 9% and 5.7%, respectively. The increase in arthropathy cases related to ciprofloxacin use was not statistically significant. However, treatment with ciprofloxacin in children and adolescents should only be initiated after careful benefit/risk assessment due to the potential risk of adverse reactions affecting joints and/or surrounding tissues.

Bronchopulmonary infections in cystic fibrosis

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

Complicated urinary tract infections and pyelonephritis

Treatment of urinary tract infections with ciprofloxacin should be considered when alternative therapies are not feasible. Treatment should be based on microbiological test results.

Ciprofloxacin use in children has been studied in patients aged 1–17 years.

Other specific severe infections

Ciprofloxacin use may be justified based on microbiological test results for other infections according to official recommendations or after careful benefit/risk assessment when alternative treatments are not possible or 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 "Adverse reactions"), and patients should be advised to report such reactions immediately to their physician.

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 should be discontinued immediately and appropriate medical treatment initiated (treatment of anaphylactic shock).

Musculoskeletal system

Ciprofloxacin should generally not be used in patients with a history of tendon disorders associated with quinolone use. However, in rare cases, after microbiological testing and benefit/risk assessment, ciprofloxacin may be prescribed for specific severe infections when standard therapy is ineffective or bacterial resistance justifies its use based on microbiological results.

Tendinitis or tendon rupture (especially of the Achilles tendon), sometimes bilateral, may occur within the first 48 hours of treatment. Inflammation or rupture of tendons may even occur several months after discontinuation of ciprofloxacin. The risk of tendinopathy may be increased in elderly patients, patients with renal impairment, organ transplant recipients, or those receiving concomitant corticosteroid therapy (see section "Adverse reactions"). Concomitant use of corticosteroids should be avoided.

If any signs of tendinitis (e.g., painful swelling, inflammation) occur, ciprofloxacin should be discontinued and the affected limb immobilized.

Corticosteroids should not be used if signs of tendinopathy are present.

Ciprofloxacin should be used with caution in patients with myasthenia gravis due to the potential for worsening of symptoms (see section "Adverse reactions").

Photosensitivity

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

Visual disturbances

Patients should seek immediate medical attention if they experience visual impairment or any ocular symptoms.

Central nervous system

Quinolones may cause seizures or lower the seizure threshold. Ciprofloxacin should be used with caution in patients with CNS disorders predisposing to seizures. Cases of status epilepticus have been reported. If seizures occur, ciprofloxacin should be discontinued (see section "Adverse reactions"). Psychotic reactions may occur even after the first dose. In rare cases, depression or psychosis may progress to suicidal thoughts or actions, including suicide or attempted suicide. 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 diseases (e.g., heart failure, myocardial infarction, bradycardia).

Women generally have a longer QTc interval than men and may be more sensitive to drugs that prolong QTc. Elderly patients may also be more sensitive to drug effects on QT interval duration.

Therefore, fluoroquinolones, including ciprofloxacin, should be used cautiously in these patient groups (see sections "Dosage and administration", "Interaction with other medicinal products and other forms of interaction", "Adverse reactions", "Overdose").

Dysglycemia

As with other quinolones, alterations in blood glucose levels, including both hypoglycemia and hyperglycemia, have been reported, particularly in diabetic patients receiving concomitant oral hypoglycemic agents (e.g., glibenclamide) or insulin. Cases of hypoglycemic coma have been reported. Close monitoring of blood glucose levels is recommended in diabetic patients.

Gastrointestinal tract

Severe and persistent diarrhea occurring during or after treatment may indicate 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. Antiperistaltic medicinal products are contraindicated.

Kidneys and urinary system

Crystalluria associated with ciprofloxacin use has been reported (see section "Adverse reactions"). 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 necessary in patients with renal impairment according to the recommendations in section "Dosage and administration" to avoid increased frequency of adverse reactions due to ciprofloxacin accumulation.

Hepatobiliary system

Cases of hepatic necrosis and life-threatening hepatic failure have been reported with ciprofloxacin use (see section "Adverse reactions"). If any signs or symptoms of liver disease occur (e.g., anorexia, jaundice, dark urine, pruritus, or abdominal distension), treatment should be discontinued. Transient increases in transaminases and alkaline phosphatase, as well as cholestatic jaundice, may also occur, particularly in patients with pre-existing liver damage (see section "Adverse reactions").

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 these patients unless the potential benefit outweighs the potential risk. In such cases, monitoring for possible hemolysis is recommended.

Resistance

Resistant bacteria may be isolated during or after ciprofloxacin treatment, with or without clinically evident superinfection. There is a potential risk of emergence of ciprofloxacin-resistant bacteria during prolonged treatment courses and in hospital-acquired infections and/or infections caused by Staphylococcus and Pseudomonas species.

Cytochrome P450

Ciprofloxacin is a moderate inhibitor of CYP450 1A2 and may therefore increase plasma concentrations of concomitantly administered drugs metabolized by this enzyme (e.g., theophylline, methylxanthines, caffeine, duloxetine, clozapine, olanzapine, ropinirole, tizanidine, agomelatine). Concomitant administration of ciprofloxacin and tizanidine is contraindicated. Increased plasma concentrations associated with drug-specific adverse reactions result from inhibition of metabolic clearance by ciprofloxacin. Therefore, patients receiving these drugs concomitantly with ciprofloxacin should be closely monitored for 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 may in vitro affect culture results for Mycobacterium spp. by inhibiting mycobacterial growth, potentially leading to false-negative culture results in patients receiving ciprofloxacin.

Prolonged, disabling, and potentially irreversible serious adverse reactions.

In very rare cases, prolonged (lasting months or years), disabling, and potentially irreversible serious adverse reactions affecting one or multiple organ systems (e.g., musculoskeletal, nervous, psychiatric, sensory organs) have been reported in patients receiving quinolones or fluoroquinolones, regardless of age or risk factors. Ciprofloxacin should be discontinued immediately upon the first signs or symptoms of any serious adverse reaction, and medical advice should be sought.

Peripheral neuropathy

Sensory or sensorimotor polyneuropathy, leading to paresthesia, hyposthesia, dysesthesia, or weakness, has been reported in patients receiving quinolones or fluoroquinolones. Patients should be advised to inform their physician immediately if symptoms of neuropathy such as pain, burning, tingling, numbness, or weakness occur to prevent potentially irreversible damage (see section "Adverse reactions").

Sodium-containing compounds

This medicinal product contains sodium compounds. One 500 mg tablet contains 30 mg of sodium starch glycolate. Caution is advised when prescribing to patients on a sodium-restricted diet.

Use during pregnancy or breastfeeding.

Pregnancy. Data on ciprofloxacin use in pregnant women show no evidence of malformations or fetal/neonatal toxicity. Animal studies do not indicate direct or indirect toxic effects on reproductive function. However, effects on immature cartilage tissue have been observed in young animals exposed to quinolones before birth, so a potential risk to the joint cartilage of newborns/fetuses cannot be excluded. Therefore, as a precaution, ciprofloxacin should be avoided during pregnancy.

Breastfeeding. Ciprofloxacin is excreted in breast milk. Due to the potential risk of cartilage damage in newborns, ciprofloxacin should not be used during breastfeeding.

Ability to influence the ability to drive and use machines.

Fluoroquinolones, including ciprofloxacin, may affect a patient’s ability to drive or operate machinery due to central 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, pathogen (or pathogens) sensitivity to ciprofloxacin, patient's renal function, and in children and adolescents—according to body weight.

The duration of treatment depends on the severity of the disease, characteristics of the clinical picture, and the 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., inflammatory diseases of the pelvic organs, intra-abdominal infections, infections in neutropenic patients, bone and joint infections) may require concomitant use of other necessary antibacterial agents, depending on the type of pathogens identified.

Adults

Indications		Daily dose, mg		Total duration 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
	Malignant external otitis	750 mg* twice daily		From 28 days to 3 months
Urinary tract infections (see section "Special instructions")	Uncomplicated acute cystitis	From 250 mg* twice daily to 500 mg twice daily		3 days
		Pre-menopausal women may be given a single dose of 500 mg
	Complicated urinary tract infections	500 mg twice daily		7 days
	Acute pyelonephritis	From 500 mg twice daily to 750 mg* twice daily		At least 10 days; in certain special clinical cases (e.g., abscesses), treatment may be extended beyond 21 days
	Bacterial prostatitis	From 500 mg twice daily to 750 mg* twice daily		2 to 4 weeks (acute) and 4 to 6 weeks (chronic)
Genital infections	Gonococcal urethritis and cervicitis caused by susceptible strains of Neisseria gonorrhoeae	Single dose 500 mg		1 day (single dose)
	Orchiepididymitis, particularly caused by susceptible strains of Neisseria gonorrhoeae, pelvic inflammatory disease, particularly caused by susceptible strains of Neisseria gonorrhoeae	From 500 mg twice daily to 750 mg* twice daily		At least 14 days
Gastrointestinal tract infections 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	From 500 mg twice daily to 750 mg* twice daily		5 to 14 days
Skin and soft tissue infections		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
Febrile neutropenia caused by bacterial infection. Ciprofloxacin should be used concomitantly with appropriate antibacterial agent(s) according to official recommendations.		From 500 mg twice daily to 750 mg* twice daily		Treatment should continue throughout the period of neutropenia
Prophylaxis of invasive infections caused by Neisseria meningitidis		Single dose 500 mg		1 day (single dose)
Post-exposure prophylaxis and treatment of pulmonary anthrax in individuals who can receive oral therapy, if clinically indicated. 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 and adolescents

Indications	Daily dose, mg	Total duration of treatment (may include initial parenteral administration of ciprofloxacin)
Respiratory tract infections caused by Pseudomonas aeruginosa in patients with cystic fibrosis	20 mg/kg body weight twice daily, up to a maximum dose of 750 mg*	10 to 14 days
Complicated urinary tract infections and pyelonephritis	From 10 mg/kg body weight twice daily up to 20 mg/kg body weight twice daily, with a maximum dose of 750 mg*	10 to 21 days
Post-exposure prophylaxis and treatment of pulmonary anthrax in patients who can be treated orally, if clinically indicated. Drug administration 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, up to a maximum of 750 mg* per day	Depending on the type of infection

*Administer ciprofloxacin preparations at the appropriate dosage.

Geriatric patients

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

Renal and hepatic impairment

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

Creatinine clearance [ml/min/1.73 m2]	Serum creatinine [µmol/l]	Oral dose [mg]
> 60	< 124	See usual dosage
30–60	124–168	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

In patients with hepatic insufficiency, there is no need to adjust the dosage of ciprofloxacin.

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 and taken 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 oral tablets (e.g., during enteral nutrition), it is recommended to initiate therapy with intravenous ciprofloxacin until transition to oral administration becomes possible.

Children.

Administration of ciprofloxacin in children and adolescents should be performed in accordance with current official recommendations. Treatment with ciprofloxacin should be initiated only by a physician experienced in managing children and adolescents with cystic fibrosis and/or severe infections. Ciprofloxacin has been shown to cause arthropathy in weight-bearing joints in immature animals.

Safety data for ciprofloxacin in children indicate a higher incidence of arthropathy, which is likely associated with ciprofloxacin use (distinct from clinical symptoms related to direct joint involvement). The increase in the number of arthropathy cases associated with ciprofloxacin use is statistically insignificant. 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 developing adverse reactions related to 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 include dizziness, tremor, headache, 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 in overdose management, such as gastric lavage followed by activated charcoal administration, 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 in their composition 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 to the drug are nausea and diarrhoea.

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

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

Adverse reactions reported during ciprofloxacin use are listed below by system organ classes and frequency of occurrence: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1,000, < 1/100), rare (≥ 1/10,000, < 1/1,000), very rare (≤ 1/10,000), frequency not known (cannot be estimated from available data).

Infections and infestations: uncommon – fungal superinfections, antibiotic-associated colitis (very rare – with fatal outcome) (see section "Special precautions for use").

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

Immune system disorders: rare – allergic reactions, allergic/angioneurotic oedema; very rare – anaphylactic reactions, anaphylactic shock (life-threatening) (see section "Special precautions for use"), serum sickness-like reactions.

Metabolism and nutrition disorders: uncommon – decreased appetite, anorexia; rare – hyperglycaemia, hypoglycaemia; frequency not known – hypoglycaemic coma (see section "Special precautions for use").

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

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

Nervous system disorders*: uncommon – headache, weakness, dizziness, sleep disturbances, taste disturbances; rare – paraesthesia, dysaesthesia, hypoaesthesia, tremor, convulsions (including epileptic status, see section "Special precautions for use"), vertigo; very rare – migraine, coordination disturbances, gait disturbances, smell disturbances, intracranial hypertension, pseudotumour cerebri; frequency not known – peripheral neuropathy and polyneuropathy (see section "Special precautions for use").

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

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

Cardiac disorders: rare – tachycardia; frequency not known – ventricular arrhythmia, QT interval prolongation (see sections "Special precautions for use", "Overdose"), torsades de pointes (mainly reported in patients with risk factors for QT interval prolongation).

Vascular disorders**: rare – vasodilation, hypotension, syncope; very rare – vasculitis.

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

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

Hepatobiliary disorders: uncommon – increased plasma transaminase and bilirubin levels; rare – liver function disturbances, cholestatic jaundice, hepatitis; very rare – hepatic necrosis (very rare with progression to life-threatening liver failure) (see section "Special precautions for use").

Skin and subcutaneous tissue disorders: uncommon – rash, pruritus, urticaria; rare – photosensitivity reactions (see section "Special precautions for use"); very rare – petechiae, erythema multiforme, nodular erythema, Stevens-Johnson syndrome (with potential life-threatening risk), toxic epidermal necrolysis (with potential life-threatening risk); frequency not known – acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS syndrome).

Musculoskeletal and connective tissue disorders*: uncommon – musculoskeletal pain (e.g., limb pain, back pain, chest pain), arthralgia; rare – myalgia, arthritis, increased muscle tone and muscle spasms; very rare – muscle weakness, tendinitis, tendon rupture (predominantly Achilles tendons) (see section "Special precautions for use"), exacerbation of symptoms of myasthenia gravis (see section "Special precautions for use").

Renal and urinary disorders: uncommon – renal function disturbances; rare – renal failure, haematuria, crystalluria (see section "Special precautions for use"), tubulointerstitial nephritis.

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

Investigations: uncommon – increased levels of liver enzymes (alkaline phosphatase activity, increased transaminase levels, increased bilirubin levels); rare – abnormal prothrombin levels, increased amylase and lipase activity, fluctuations in blood glucose levels (hyperglycaemia, hypoglycaemia); frequency not known – increased international normalized ratio (INR) (in patients receiving vitamin K antagonists).

Use in children

In children, arthropathy occurs more frequently than in adults (see section "Special precautions for use").

Other adverse reactions reported include allergic oedema, decreased appetite and food intake, behavioural disturbances, hyperaesthesia, blisters, malaise, increased international normalized ratio (INR) in patients taking vitamin K antagonists, transient liver function disturbances, pain, palpitations, atrial flutter, ventricular ectopy, arterial hypertension, angina pectoris, myocardial infarction, cardiac arrest, cerebral vessel thrombosis, phlebitis, insomnia, manic reaction, ataxia, lethargy, somnolence, weakness, malaise, phobia, depersonalization, oral mucosal pain, oral candidiasis, dysphagia, intestinal perforation, gastrointestinal haemorrhage, lymphadenopathy, increased lipase levels, joint disorders, gout exacerbation, nephritis, polyuria, micturition disturbances, urethral bleeding, vaginitis, acidosis, breast pain, epistaxis, pulmonary or laryngeal oedema, hiccough, haemoptysis, bronchospasm, pulmonary embolism, phototoxic reactions, flushing, chills, facial, neck, lip, conjunctival, hand swelling, cutaneous candidiasis, hyperpigmentation, sweating, decreased visual acuity, diplopia, eye pain, taste disturbances, achromatopsia.

Also reported were agitation, exfoliative dermatitis, erythema, hyperaesthesia, hypertension, methaemoglobinaemia, increased INR in patients taking vitamin K antagonists, candidiasis (oral, gastrointestinal, vaginal), myasthenia, nystagmus, polyneuropathy, hyperkalaemia, changes in prothrombin time, psychosis, increased triglyceride levels, gamma-glutamyltransferase levels, uric acid levels, decreased haemoglobin levels, haemorrhagic diathesis, increased monocyte count, leukocytosis, cylindruria.

*In very rare cases, patients receiving quinolones and fluoroquinolones, regardless of the presence of risk factors, have experienced prolonged (lasting several months or years), disabling and potentially irreversible serious adverse reactions affecting various body systems and sensory organs (including such reactions as tendinitis, tendon rupture, arthralgia, limb pain, gait disturbances, neuropathies associated with paraesthesia, depression, fatigue, memory disturbances, sleep disturbances, hearing, vision, taste and smell disturbances); anxiety, suicidal thoughts, panic attacks, neuralgia, and concentration disturbances have also been reported as potential aspects of long-term and disabling adverse reactions caused by fluoroquinolones.

**In patients receiving fluoroquinolones, cases of aortic aneurysm and aortic dissection, sometimes complicated by rupture (including fatal cases), and cases of regurgitation/insufficiency of any cardiac valve have been observed.

Reporting suspected adverse reactions

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

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 30 °C.

Keep out of reach and sight of children.

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

Prescription status. Prescription only.

Manufacturer.

Unique Pharmaceuticals Laboratories (a division of "J. B. Chemicals and Pharmaceuticals Ltd.").

Manufacturer's address and place of business.

Plot Nos. 215-219, G.I.D.C. Industrial Area, Panoli – 394 116, Bharuch District, India.