Cipran

INSTRUCTIONS for medical use of the medicinal product CIPROFLOXACIN (CIFRAN)

Composition:

Active substance: ciprofloxacin;

One tablet contains ciprofloxacin hydrochloride 596.388 mg, equivalent to ciprofloxacin 500 mg;

Excipients: microcrystalline cellulose, maize starch, magnesium stearate, talc, colloidal anhydrous silicon dioxide, sodium starch glycolate (type A), hydroxypropylmethylcellulose, macrogol 400, titanium dioxide (E 171).

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics: white or almost white, oval, film-coated tablets, with an imprint "500" on one side and smooth on the other side.

Pharmacotherapeutic group. Antibacterials for systemic use.

Fluoroquinolone group. ATC code J01MA02.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

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

Pharmacokinetic/pharmacodynamic relationships

Efficacy is primarily dependent on the ratio between the maximum serum concentration (Cmax) and the minimum inhibitory concentration (MIC) of ciprofloxacin against the bacterial pathogen, as well as on the value of the area under the pharmacokinetic concentration-time curve (AUC) and MIC.

Mechanism of resistance

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

Mechanisms of resistance such as impermeability and/or efflux pumps may differentially affect susceptibility to fluoroquinolones, depending on the physicochemical properties of individual agents within this class and the affinity of transport systems for each active substance. All in vitro resistance mechanisms are generally 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 strains with intermediate susceptibility, and the latter from resistant strains.

EUCAST recommendations

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

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

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

Genera and species of bacteria generally susceptible to ciprofloxacin (for the genus Streptococcus, see section "Special Warnings and Precautions for Use").

Preclinical Safety Data

Based on standard preclinical toxicity studies, including single-dose toxicity, repeated-dose toxicity, carcinogenic potential, and reproductive toxicity, no specific hazard of ciprofloxacin for humans has been identified.

Pharmacokinetics

Absorption

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

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

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

Distribution

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

Biotransformation

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

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

Elimination

Ciprofloxacin is primarily excreted unchanged by the kidneys, with a smaller portion eliminated via the intestine. The elimination half-life from plasma in individuals with normal renal function is approximately 4–7 hours.

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

Non-renal clearance of ciprofloxacin is primarily 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. In studies involving children, no age-dependent differences in Cmax or AUC were observed (in children aged 1 year and older). After multiple dosing (10 mg/kg three times daily), no significant accumulation of Cmax and AUC was observed. In 10 infants under 1 year of age with severe sepsis, Cmax was 6.1 mg/L (range: 4.6–8.3 mg/L) following a 1-hour intravenous infusion at a dose of 10 mg/kg. This value was 7.2 mg/L (range: 4.7–11.8 mg/L) in children aged 1 to 5 years. AUC values were 17.4 mg*h/L (range: 11.8–32 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.

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

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

Adults

• Lower respiratory tract infections caused by gram-negative bacteria:
  • acute exacerbation of chronic obstructive pulmonary disease*;
  • 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 ciprofloxacin-susceptible strains of Neisseria gonorrhoeae;
  • epididymo-orchitis, particularly caused by ciprofloxacin-susceptible strains of Neisseria gonorrhoeae;
  • pelvic inflammatory disease, particularly caused by ciprofloxacin-susceptible strains of Neisseria gonorrhoeae.

For the above-mentioned genital tract infections where Neisseria gonorrhoeae is known or suspected as the causative agent, it is especially important to obtain local data on ciprofloxacin resistance and to confirm susceptibility through laboratory testing.

• Gastrointestinal tract infections (e.g., treatment of traveler's diarrhea).
• Intra-abdominal infections.
• Skin and soft tissue infections caused by gram-negative bacteria.
• Bone and joint infections.
• Pulmonary form of anthrax (post-exposure prophylaxis and definitive treatment).
• Fever in neutropenic patients 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.
• Pulmonary form of anthrax (post-exposure prophylaxis and definitive treatment).

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

Treatment should be initiated only by a physician experienced in managing the above-mentioned infections in children and adolescents (see sections "Pharmacological properties" and "Special precautions for use").

*Only when it has been determined that other antibacterial agents typically used for treating this infection are ineffective or inappropriate.

Contraindications.

Hypersensitivity to the active substance or to other fluoroquinolone group agents, or to any of the excipients of the medicinal product.

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

Interaction with other medicinal products and other forms of interaction.

Effects of other medicinal products on ciprofloxacin

Medicinal products that prolong the QT interval

Ciprofloxacin, like other fluoroquinolones, should be used with caution in 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 complex formation

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

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

Probenecid

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

Metoclopramide

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

Omeprazole

Concomitant administration of ciprofloxacin and medicinal products containing omeprazole leads to 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"). In a clinical study involving healthy volunteers, concomitant administration of ciprofloxacin and tizanidine resulted in increased plasma concentrations of tizanidine (Cmax increased by 7-fold, range 4–21-fold; AUC increased by 10-fold, range 6–24-fold). Elevated tizanidine plasma concentrations are associated with hypotensive and sedative adverse reactions.

Methotrexate

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

Theophylline

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

Other xanthine derivatives

Elevated serum concentrations of caffeine or pentoxifylline (oxpentifylline) have been reported after 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 cyclosporine-containing medicinal products. 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 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 use of ciprofloxacin and vitamin K antagonists (e.g., warfarin, acenocoumarol, phenprocoumon, fluindione).

Duloxetine

Clinical studies have shown 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 for use").

Ropinirole

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

Lidocaine

In healthy volunteers, concomitant administration of ciprofloxacin, a moderate inhibitor of cytochrome P450 1A2 isoenzymes, and lidocaine-containing medicinal products reduced the clearance of intravenous lidocaine by 22%. Despite normal tolerability of lidocaine treatment, interaction with ciprofloxacin may be associated with adverse reactions when these agents are used concomitantly.

Clozapine

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

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, moderately inhibits the metabolism of agomelatine, resulting in a 60-fold increase in agomelatine exposure. Although no clinical data are available on potential interaction with ciprofloxacin, a moderate CYP450 1A2 inhibitor, similar effects may be expected with concomitant use (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 the drug should be avoided in patients who have previously experienced serious adverse reactions to quinolones or fluoroquinolones. Treatment of these patients with ciprofloxacin should be initiated only if no alternative treatment options are available and after careful benefit/risk assessment.

Prolonged, disabling, and potentially irreversible serious adverse reactions

Very rarely, in patients receiving quinolones or fluoroquinolones, regardless of age and existing risk factors, prolonged (lasting for months or years), disabling, and potentially irreversible serious adverse reactions affecting various body systems—sometimes multiple systems simultaneously (musculoskeletal, nervous, psychiatric, and sensory organs)—have been reported. The drug should be discontinued immediately upon the first signs or symptoms of any serious adverse reaction, and medical advice should be sought.

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.

Therefore, ciprofloxacin should be used for the treatment of gonococcal urethritis or cervicitis only if resistance of Neisseria gonorrhoeae to ciprofloxacin is 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 no clinical improvement is observed within 3 days, the therapy should be re-evaluated.

Urinary tract infections

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

Single-dose regimens of ciprofloxacin, which may be used for uncomplicated cystitis in premenopausal women, are considered less effective than longer treatment courses. This 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 therapy, 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 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.

Respiratory tract infections caused by Pseudomonas aeruginosa in patients with 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 acute pyelonephritis

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

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

Other specific severe infections

Use of ciprofloxacin may be justified based on microbiological test results for other severe infections according to official recommendations or after careful benefit/risk assessment when alternative treatments are not possible or standard therapy has failed.

Use of ciprofloxacin for specific severe infections not mentioned above has not been evaluated in clinical trials, and clinical experience is limited. Therefore, caution is recommended when treating patients with such infections.

Hypersensitivity to the drug

Hypersensitivity and allergic reactions, including anaphylactic/anaphylactoid reactions, may occur after a single dose of ciprofloxacin (see section "Adverse reactions") and may be life-threatening. In such cases, ciprofloxacin should be discontinued immediately, and appropriate medical treatment should be initiated if necessary.

Musculoskeletal system

Ciprofloxacin should generally not be used in patients with a history of tendon disorders related to quinolone use. However, in rare cases, after microbiological testing and benefit/risk assessment, ciprofloxacin may be prescribed for the treatment of certain severe infections—particularly when standard therapy has failed or bacterial resistance justifies its use based on microbiological results. Tendinitis and tendon rupture (not limited to the Achilles tendon), sometimes bilateral, may occur within 48 hours of starting fluoroquinolone or fluoroquinolone therapy, and even several months after discontinuation. The risk of tendinitis and tendon rupture is increased in elderly patients, patients with renal impairment, organ transplant recipients, and patients receiving concomitant corticosteroid therapy. Therefore, concomitant use of corticosteroids should be avoided.

If signs of tendinitis (e.g., painful swelling, inflammation) occur, treatment should be discontinued, and alternative therapy should be considered. The affected limb(s) should be appropriately managed (e.g., immobilization). Corticosteroids should not be used if signs of tendinopathy occur.

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

Visual disturbances

Patients should seek immediate medical attention if visual disturbances or any ocular effects occur.

Photosensitivity

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

Central nervous system (CNS)

Ciprofloxacin, like other quinolones, is known to induce 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 "Adverse reactions"). Psychotic reactions may occur even after the first dose. In isolated cases, depression or psychosis may progress to suicidal ideation and behavior, including suicide attempts or completed suicide. In such cases, ciprofloxacin should be discontinued.

Cases of polyneuropathy (based on neurological symptoms such as pain, burning, sensory disturbances, or muscle weakness, alone or in combination) have been reported in patients receiving ciprofloxacin. Ciprofloxacin should be discontinued in patients experiencing symptoms of neuropathy, such as pain, burning, tingling, numbness, and/or weakness, to prevent progression to irreversible conditions (see section "Adverse reactions").

Peripheral neuropathy

Cases of sensory or sensorimotor polyneuropathy, leading to paresthesia, hypoesthesia, dysesthesia, or weakness, have been reported in patients receiving quinolones or fluoroquinolones. Patients receiving the drug 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.

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).

Elderly patients and younger 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 "Interaction with other medicinal products and other forms of interaction," "Method of administration and dosage," "Overdose," and "Adverse reactions").

Aortic aneurysm, aortic dissection, and cardiac valve regurgitation

Epidemiological studies suggest an increased risk of aortic aneurysm and aortic dissection, particularly in elderly patients, following fluoroquinolone use. Cases of aortic aneurysm and aortic dissection, some complicated by aortic rupture (including fatal cases), have been reported in patients receiving fluoroquinolones (see section "Adverse reactions").

Therefore, fluoroquinolones should be used only after careful benefit/risk assessment and consideration of alternative therapies in patients with a personal or family history of aortic aneurysm or dissection, heart failure, or other risk factors:

• aortic aneurysm and aortic dissection with heart failure (including connective tissue disorders such as Marfan syndrome, vascular Ehlers-Danlos syndrome, Turner syndrome, Behçet’s disease, hypertension, rheumatoid arthritis, or additional to aortic aneurysm or dissection (including vascular diseases such as Takayasu arteritis, giant cell arteritis, atherosclerosis, Sjögren’s syndrome)) or additionally
• aortic aneurysm and dissection (e.g., due to vascular diseases such as Takayasu arteritis or giant cell arteritis, atherosclerosis, or Sjögren’s syndrome) or additionally:
• cardiac valve regurgitation/insufficiency (e.g., due to infective endocarditis).

The risk of developing aortic aneurysm and dissection, and their rupture, may be increased in patients receiving the drug concomitantly with systemic corticosteroids.

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

Patients should be advised to seek immediate medical help if acute dyspnea, new episodes of tachycardia, or development of abdominal or lower limb edema occur.

Dysglycemia

As with other quinolones, disturbances in blood glucose levels, including both hypoglycemia and hyperglycemia, have been reported, usually in diabetic patients receiving concomitant therapy with oral hypoglycemic agents (e.g., glyburide) or insulin. Hypoglycemic coma has been reported. Close monitoring of blood glucose levels is recommended in diabetic patients.

Gastrointestinal tract

The onset of severe and persistent diarrhea during or after treatment (even several weeks after therapy) may indicate antibiotic-associated colitis (a potentially life-threatening condition with possible fatal outcome) and requires urgent treatment (see section "Adverse reactions"). In such cases, ciprofloxacin should be discontinued and appropriate therapy initiated. Medicinal products that inhibit peristalsis are contraindicated in this clinical situation.

Kidneys and urinary system

Crystalluria associated with ciprofloxacin use has been reported (see section "Adverse reactions"). Patients receiving ciprofloxacin should maintain adequate fluid intake. Excessive alkalinity of urine should be avoided.

Renal function impairment

Since ciprofloxacin is primarily excreted unchanged by the kidneys, dosage adjustment is required in patients with renal impairment according to the information provided in the section "Method of administration and dosage" to avoid increased frequency of adverse reactions due to ciprofloxacin accumulation.

Hepatobiliary system

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

Glucose-6-phosphate dehydrogenase deficiency

Hemolytic reactions have been reported in patients with glucose-6-phosphate dehydrogenase deficiency receiving ciprofloxacin. Ciprofloxacin should be avoided in such patients unless the expected benefit outweighs the potential risk. In such cases, monitoring for possible hemolysis is necessary.

Resistance

Resistant bacteria may be isolated during or after a course of ciprofloxacin treatment, with or without clinically evident superinfection. There may be an increased risk of isolating ciprofloxacin-resistant bacteria during prolonged treatment courses and in the treatment of nosocomial 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 Mycobacterium tuberculosis culture results by inhibiting mycobacterial growth, potentially leading to false-negative culture results in patients taking ciprofloxacin.

Use during pregnancy or breastfeeding.

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

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

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

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

Administration and Dosage.

The dosage of the medicinal product must be 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. If administration of ciprofloxacin in doses not multiples of 500 mg is required, use another medicinal product with appropriate dosage strength.

Duration of treatment depends on the severity of the disease, specific features 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., pelvic inflammatory disease, intra-abdominal infections, infections in neutropenic patients, bone and joint infections) may require concomitant administration of other necessary antibacterial agents depending on the type of identified pathogens.

Adults

Children and adolescents

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 renal function impairment:

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, without chewing, 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, yoghurt) 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), initiation of therapy with intravenous ciprofloxacin is recommended until oral administration becomes feasible.

Children.

Ciprofloxacin use in children and adolescents should be performed 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 been shown to cause 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 exposure (differing from clinical signs and symptoms directly related to joint involvement) of 7.2% and 4.6% in the ciprofloxacin and comparator groups, respectively, at day 42 after initiation of treatment. The incidence of drug-related arthropathy at one year of follow-up was 9% and 5.7%, respectively. The increase in arthropathy cases related to drug exposure 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 developing adverse reactions affecting joints and/or surrounding tissues.

Overdose.

Overdose following ingestion of 12 g of ciprofloxacin has been reported to result in symptoms of moderate toxicity. Acute overdose of 16 g led to the development of acute renal failure.

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

In addition to standard emergency measures for overdose, 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 ciprofloxacin absorption 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 medicinal product were nausea, diarrhoea, vomiting, transient elevations in transaminase levels, rash, and local reactions at the injection site.

Data on adverse reactions to ciprofloxacin obtained during clinical trials and post-marketing surveillance (oral, parenteral, and sequential administration) are listed below. The frequency of occurrence is defined as follows:
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;
rare: antibiotic-associated colitis (very rare – with potentially fatal outcome) (see section "Special Warnings and Precautions for Use").

Blood and lymphatic system disorders:

uncommon: eosinophilia;
rare: leucopenia, anaemia, neutropenia, leucocytosis, thrombocytopenia, thrombocytosis;
very rare: haemolytic anaemia, agranulocytosis, pancytopenia (potentially life-threatening),
bone marrow suppression (potentially life-threatening).

Immune system disorders:

rare: allergic reactions, allergic/angioneurotic oedema;
very rare: anaphylactic reactions, anaphylactic shock (potentially life-threatening) (see section "Special Warnings and Precautions for Use"), serum sickness-like reactions.

Metabolism and nutrition disorders:

uncommon: decreased appetite;
rare: syndrome of inappropriate antidiuretic hormone secretion, hyperglycaemia, hypoglycaemia (see section "Special Warnings and Precautions for Use");
very rare: hypoglycaemic coma.

Psychiatric disorders*:

uncommon: psychomotor agitation/anxiety;
rare: confusion and disorientation, restlessness, abnormal dreams, depression (with possible suicidal ideation/thoughts or suicide attempts/acts) (see section "Special Warnings and Precautions for Use"), hallucinations;
very rare: psychotic reactions (with possible suicidal ideation/thoughts or suicide attempts/acts) (see section "Special Warnings and Precautions for Use").

Nervous system disorders*:

uncommon: headache, dizziness, sleep disturbances, taste disturbances;
rare: paraesthesia and dysaesthesia, hypoaesthesia, tremor, convulsions (including epileptic status, see section "Special Warnings and Precautions for Use"), vertigo;
very rare: migraine, coordination disturbances, gait disturbances, smell disturbances, intracranial hypertension, and pseudotumour cerebri;
frequency not known: peripheral neuropathy and polyneuropathy (see section "Special Warnings and 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 and torsades de pointes (observed predominantly in patients with risk factors for QT interval prolongation), QT interval prolongation.

Vascular disorders**:

rare: vasodilation, arterial 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, dyspepsia, flatulence;
very rare: pancreatitis.

Hepatobiliary disorders:

uncommon: increased transaminase and bilirubin levels;
rare: liver function disturbances, cholestatic jaundice, hepatitis;
very rare: hepatic necrosis (in rare cases progressing to life-threatening liver failure) (see section "Special Warnings and Precautions for Use").

Skin and subcutaneous tissue disorders:

uncommon: rash, pruritus, urticaria;
rare: photosensitivity reactions (see section "Special Warnings and Precautions for Use");
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.

Musculoskeletal and connective tissue disorders*:

uncommon: musculoskeletal pain (e.g., limb, back, chest pain), arthralgia;
rare: myalgia, arthritis, increased muscle tone, muscle cramps;
very rare: muscle weakness, tendinitis, tendon rupture (predominantly Achilles tendons) (see section "Special Warnings and Precautions for Use"), exacerbation of symptoms of myasthenia gravis (see section "Special Warnings and Precautions for Use").

Renal and urinary disorders:

uncommon: renal function disturbances;
rare: renal failure, haematuria, crystalluria (see section "Special Warnings and Precautions for Use"), tubulointerstitial nephritis.

General disorders and administration site conditions:

uncommon: asthenia, fever;
rare: oedema, increased sweating (hyperhidrosis).

Investigations:

uncommon: increased alkaline phosphatase activity in blood;
rare: increased amylase activity;
frequency not known: increased INR (in patients concomitantly taking vitamin K antagonists).

* In very rare cases, patients receiving quinolones and fluoroquinolones, regardless of existing risk factors, have reported long-term (lasting months or years), disabling, and potentially irreversible serious adverse reactions affecting various systems and sometimes multiple systems simultaneously, as well as sensory organs (including reactions such as tendinitis, tendon rupture, arthralgia, limb pain, gait disturbances, neuropathy associated with paraesthesia, depression, fatigue, memory disturbances, sleep disturbances, hearing, vision, taste, and smell disturbances).

** Cases of cardiac valve regurgitation/insufficiency of any valve have been reported in patients receiving fluoroquinolones who experienced aortic aneurysm and aortic dissection (including fatal outcomes) (see section "Special Warnings and Precautions for Use").

Pediatric use

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 Warnings and Precautions for Use").

Reporting suspected adverse reactions

Reporting suspected adverse reactions after medicinal product authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions.

Shelf life.

3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25°C, in a place inaccessible to children.

Packaging.

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

Prescription status.

Prescription only.

Manufacturer.

Sun Pharmaceutical Industries Limited.

Manufacturer's address and place of business.

V. Ganguwala, Paonta Sahib, District Sirmour, Himachal Pradesh 173025, India.