Ciprofloxacin

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT CIPROFLOXACIN (CIPROFLOXACIN)

Composition:

Active substance: ciprofloxacin;

100 ml of solution contain 200 mg of ciprofloxacin;

Excipients: lactic acid, sodium chloride, disodium edetate, concentrated hydrochloric acid, sodium hydroxide, water for injections.

Pharmaceutical form. Infusion solution.

Main physico-chemical properties: clear, colorless solution.

Pharmacotherapeutic group. Antibacterial agents for systemic use. Fluoroquinolone group. ATC code J01MA02.

Pharmacological Properties

Pharmacodynamics

Ciprofloxacin inhibits the enzyme DNA gyrase, which plays a crucial role in the process of segmental despiralization and spiralization of the bacterial chromosome during the replication phase, thereby preventing chromosomal transcription of information required for normal bacterial cell metabolism. This leads to inhibition of the microorganism's ability to multiply. The drug exerts a rapid and pronounced bactericidal effect on microorganisms both in the replicating and resting phases. It demonstrates high efficacy against almost all Gram-negative and Gram-positive pathogens. Microorganisms sensitive to ciprofloxacin include Escherichia coli, Shigella spp., Salmonella spp., Citrobacter spp., Klebsiella spp., Enterobacter spp., Serratia spp., Hafnia spp., Edwardsiella spp., Proteus (both indole-positive and indole-negative strains), Morganella spp., Providencia spp., Yersinia, Vibrio spp., Aeromonas spp., Plesiomonas, Pasteurella, Haemophilus, Campylobacter spp., Pseudomonas spp. (including Pseudomonas aeruginosa), Legionella, Neisseria spp., Moraxella spp., Branhamella spp., Acinetobacter spp., Brucella spp., Staphylococcus spp., Listeria spp., Corynebacterium, Chlamydia, as well as plasmid forms of bacteria. Variable sensitivity is observed in Gardnerella spp., Flavobacterium spp., Alcaligenes spp., Streptococcus agalactiae, Streptococcus faecalis, Streptococcus pyogenes, Streptococcus pneumoniae, Streptococcus viridans, Mycoplasma hominis, Mycobacterium tuberculosis, Mycobacterium fortuitum. Anaerobic cocci (Peptococcus, Peptostreptococcus) are moderately sensitive to ciprofloxacin, whereas Bacteroides is resistant. Ciprofloxacin is effective against bacteria producing beta-lactamases. It also shows activity against microorganisms resistant to nearly all antibiotics, sulfonamides, and nitrofuran derivatives. In some cases, ciprofloxacin remains active against strains resistant to other fluoroquinolone agents. However, it should be noted that cross-resistance exists among different fluoroquinolones. Generally resistant organisms include Streptococcus faecium, Ureaplasma urealyticum, Nocardia asteroides, Treponema pallidum. Resistance to ciprofloxacin develops slowly and gradually (the "multistep" type).

Pharmacokinetics

Ciprofloxacin rapidly and effectively penetrates into all body tissues. Maximum plasma concentration (Cmax) is achieved within 60–90 minutes after intravenous administration. The volume of distribution at steady state reaches 2–3 L/kg. Since protein binding of ciprofloxacin is low (20–30%) and the substance exists in plasma predominantly in non-ionized form, nearly the entire amount of administered drug can freely diffuse into the extravascular space. Consequently, ciprofloxacin concentrations in certain body fluids and tissues may significantly exceed serum levels (particularly, high concentrations of ciprofloxacin are observed in bile). Ciprofloxacin is primarily excreted by the kidneys (approximately 45% unchanged, about 11% as metabolites). Another portion of the dose is excreted via the gastrointestinal tract (approximately 20% unchanged, nearly 5–6% as metabolites). Renal clearance is 3–5 mL/min/kg, total clearance is 8–10 mL/min/kg. The elimination half-life is 3–5 hours. Since the drug is eliminated via multiple pathways, prolongation of the elimination half-life occurs only in cases of significant renal impairment (this parameter may increase up to 12 hours).

Clinical characteristics.

Indications.

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:
  • exacerbations of chronic obstructive pulmonary disease*;
  • community-acquired pneumonia.
• Chronic suppurative otitis media.
• Acute exacerbations of chronic sinusitis, particularly when caused by Gram-negative bacteria*.
• Urinary tract infections:
  • uncomplicated acute cystitis*;
  • acute pyelonephritis;
  • complicated urinary tract infections;
  • bacterial prostatitis.
• Genital tract infections:
  • epididymo-orchitis, particularly caused by Neisseria gonorrhoeae;
  • pelvic inflammatory disease, particularly caused by 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 resistance data to ciprofloxacin and to confirm susceptibility based on 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 only be initiated 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.

The drug must not be used in patients with hypersensitivity to the active substance – ciprofloxacin, to other drugs of the fluoroquinolone group, or to any of the excipients of the drug.

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

Interaction with other medicinal products and other types of interactions.

Effect of other medicinal products on ciprofloxacin.

Probenecid.

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

Medicinal products that prolong the QT interval.

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

Effect of ciprofloxacin on other medicinal products.

Tizanidine.

Tizanidine must not be co-administered with ciprofloxacin (see section "Contraindications"). Increased serum concentrations of tizanidine are associated with hypotensive and sedative adverse reactions.

Methotrexate.

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

Theophylline.

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

Other xanthine derivatives.

Elevated serum concentrations of xanthines such as caffeine or pentoxifylline (oxpentifylline) have been reported following concomitant administration with ciprofloxacin.

Phenytoin.

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

Cyclosporine.

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

Vitamin K antagonists.

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

Duloxetine.

Clinical studies have shown that concomitant use of duloxetine with strong CYP450 1A2 inhibitors, such as fluvoxamine, may increase the area under the concentration-time curve (AUC) and Cmax of duloxetine. Although there are no clinical data on potential interaction with ciprofloxacin, similar effects can 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 the 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 co-administration with ciprofloxacin (see section "Special precautions for use").

Lidocaine.

In healthy subjects, concomitant use of ciprofloxacin, a moderate inhibitor of cytochrome P450 1A2 isoenzymes, with intravenous lidocaine-containing medicinal products, has been shown to reduce lidocaine clearance by 22%. Despite normal tolerability of lidocaine treatment, interaction with ciprofloxacin may occur, associated with adverse reactions.

Clozapine.

After concomitant administration of 250 mg ciprofloxacin with clozapine for 7 days, serum concentrations of clozapine and N-desmethylclozapine 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.

AUC and Cmax of sildenafil approximately doubled in healthy volunteers after oral administration of 50 mg sildenafil and concomitant use of 500 mg ciprofloxacin. Therefore, caution should be exercised when co-administering ciprofloxacin with sildenafil, and the risk-benefit ratio should be carefully considered.

Agomelatine.

Clinical studies have demonstrated that fluvoxamine, as a strong inhibitor of CYP450 1A2 isoenzyme, significantly inhibits agomelatine metabolism, resulting in a 60-fold increase in agomelatine concentration. Despite the lack of clinical data on potential interaction with ciprofloxacin, a moderate inhibitor of CYP450 1A2, similar effects may be expected upon concomitant administration (see "Cytochrome P450" in section "Special precautions for use").

Zolpidem.

Concomitant use of ciprofloxacin may increase blood levels of zolpidem. Concomitant administration is not recommended.

Special precautions for use.

Administration of the drug should be avoided in patients who have previously experienced serious adverse reactions to quinolones or fluoroquinolones. Treatment with ciprofloxacin in such patients should be initiated only if no alternative treatment options are available and after careful assessment of the benefit-risk ratio.

Ciprofloxacin should be prescribed to patients with epilepsy, history of seizures, vascular diseases, or organic brain disorders only under life-threatening conditions due to the risk of adverse reactions affecting the central nervous system (CNS).

In case of severe and persistent diarrhea occurring during or after ciprofloxacin treatment, pseudomembranous colitis should be ruled out, which requires immediate discontinuation of the drug and initiation of appropriate therapy.

Prolonged, disabling, and potentially irreversible serious adverse reactions

Very rarely, in patients receiving quinolones and fluoroquinolones, regardless of age and existing risk factors, prolonged (lasting for months or years), disabling, and potentially irreversible serious adverse reactions affecting various, and sometimes multiple simultaneously, body systems (particularly 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 mixed infections caused by Gram-positive bacteria and anaerobic pathogenic microorganisms

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, as well as 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.

Urinary tract infections

Orchiepididymitis and pelvic inflammatory diseases may be caused by fluoroquinolone-resistant Neisseria gonorrhoeae. Ciprofloxacin should be prescribed simultaneously with other appropriate antibacterial agents, except in clinical situations where resistance of Neisseria gonorrhoeae strains to ciprofloxacin is excluded. If there is no clinical improvement within 3 days of treatment, the therapy should be re-evaluated.

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

Single-dose regimens of ciprofloxacin used for uncomplicated cystitis in premenopausal women are considered less effective than longer-term therapy. This fact should be taken into account given the increasing resistance levels 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 the drug, information on resistance to ciprofloxacin 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

The possibility of human use is based on in vitro susceptibility data, animal studies, and limited human data. The physician should act according to national and/or international anthrax treatment protocols.

Antibiotic-associated diarrhea caused by Clostridium difficile

Cases of antibiotic-associated diarrhea caused by Clostridium difficile, ranging in severity from mild diarrhea to fatal colitis, have been reported with nearly all antibacterial agents, including ciprofloxacin. Antibacterial therapy alters the normal flora of the colon, leading to overgrowth of Clostridium difficile.

Clostridium difficile produces toxins A and B, which cause antibiotic-associated diarrhea. Clostridium difficile producing large amounts of toxin is associated with increased morbidity and mortality due to possible resistance to antimicrobial therapy and the need for colectomy. The possibility of Clostridium difficile-associated diarrhea should be considered in all patients with diarrhea following antibiotic use. A careful medication history is required, as Clostridium difficile-associated diarrhea may develop up to two months after administration of antibacterial agents. If Clostridium difficile-associated diarrhea is suspected or confirmed, antibiotics not active against Clostridium difficile may need to be discontinued. Depending on clinical findings, correction of fluid and electrolyte balance, consideration of additional protein supplementation, and administration of antibiotics to which Clostridium difficile is sensitive should be performed. Surgical intervention may also be necessary.

Children and adolescents

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

Ciprofloxacin has caused arthropathy in weight-bearing joints in immature animals. The increase in arthropathy cases associated with drug use was statistically insignificant. However, ciprofloxacin treatment in children and adolescents should be initiated only after careful assessment of the benefit-risk ratio due to the risk of adverse reactions affecting joints and/or adjacent tissues.

Respiratory tract infections caused by Pseudomonas aeruginosa in patients with cystic fibrosis

Children and adolescents aged 5–17 years were included in clinical trials. Experience with treatment of 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 when other treatments are not possible. Therapy should be based on microbiological test results.

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

Other specific severe infections

The use of ciprofloxacin may be justified in cases of other infections identified by microbiological testing, according to official recommendations or after careful benefit-risk assessment, when other treatments cannot be used or standard therapy has proven ineffective.

The 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

In some cases, hypersensitivity and allergic reactions may occur after the first dose of ciprofloxacin (see section "Adverse reactions"), and immediate medical attention should be sought.

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

Tendinitis and tendon rupture

Ciprofloxacin should generally not be administered to patients with tendon disorders or a history of tendon disorders associated with quinolone use. Nevertheless, in rare cases, after microbiological testing and benefit-risk assessment, ciprofloxacin may be prescribed to such patients for the treatment of specific severe infections, particularly when standard therapy is ineffective or bacterial resistance is present, and microbiological test results justify the use of ciprofloxacin. Tendinitis and tendon rupture (not limited to the Achilles tendon), sometimes bilateral, may occur within 48 hours of starting treatment with quinolones and fluoroquinolones and, as reported, even several months after discontinuation of treatment. The risk of tendinitis and tendon rupture is increased in elderly patients, patients with renal impairment, patients with organ transplants, and patients receiving corticosteroids concurrently. Therefore, concomitant use of corticosteroids should be avoided.

Upon first signs of tendinitis (e.g., painful swelling, inflammation), treatment with the drug should be discontinued, and alternative therapy should be considered. The affected limb(s) should be properly 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 (see section "Adverse reactions").

Photosensitivity

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

CNS

Quinolones may cause seizures or lower the seizure threshold. Cases of epileptic status have been reported. Ciprofloxacin should be used with caution in patients with CNS disorders predisposed to seizures. If seizures occur, ciprofloxacin should be discontinued (see section "Adverse reactions"). Psychotic reactions may occur even after the first dose of ciprofloxacin. In rare cases, depression or psychosis may progress to suicidal thoughts and actions, including suicide or suicide attempts. In such cases, ciprofloxacin should be discontinued, and appropriate measures should be taken.

Peripheral neuropathy

Cases of sensory or sensorimotor polyneuropathy leading to paresthesia, hypoesthesia, dysesthesia, or weakness have been reported in patients receiving quinolones and fluoroquinolones. If symptoms of neuropathy such as pain, burning, tingling, numbness, or weakness occur, patients should inform their physician to prevent the development of potentially irreversible conditions.

Cardiac disorders

Ciprofloxacin use has been associated with QT interval prolongation (see section "Adverse reactions").

Since women generally have a longer QT interval than men, they may be more sensitive to drugs causing QT prolongation. Elderly patients may also be more sensitive to the effects of drugs on QT interval duration. Caution should be exercised when co-administering ciprofloxacin with drugs that may cause QT prolongation (such as class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) (see section "Interaction with other medicinal products and other forms of interaction"), as well as in patients with risk factors for QT prolongation or development of bidirectional ventricular tachycardia (e.g., congenital long QT syndrome, uncorrected electrolyte imbalances such as hypokalemia or hypomagnesemia, and cardiac diseases, including heart failure, myocardial infarction, or bradycardia).

Aortic aneurysm and dissection, and valvular regurgitation/incompetence

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

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

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

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

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

Hypoglycemia

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

Gastrointestinal tract

If severe and persistent diarrhea occurs during or after treatment (even weeks after treatment), the physician should be informed, as this symptom may mask a serious gastrointestinal condition (e.g., pseudomembranous colitis, which may be fatal) requiring immediate treatment (see section "Adverse reactions"). In such cases, ciprofloxacin should be discontinued and appropriate therapy initiated. Medicinal products that inhibit peristalsis 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 to avoid increased adverse reactions due to accumulation of ciprofloxacin.

Hepatobiliary system

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

Glucose-6-phosphate dehydrogenase deficiency

Hemolytic reactions have been reported with ciprofloxacin use in patients with glucose-6-phosphate dehydrogenase deficiency. 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 a course of ciprofloxacin treatment, with or without clinically evident superinfection. There is a certain risk of isolating ciprofloxacin-resistant bacteria during prolonged treatment courses and in the treatment of hospital-acquired infections and/or infections caused by Staphylococcus and Pseudomonas species.

Cytochrome P450

Ciprofloxacin moderately inhibits CYP450 1A2 and may therefore increase serum concentrations of concurrently administered substances metabolized by this enzyme (e.g., theophylline, clozapine, olanzapine, ropinirole, tizanidine, duloxetine, agomelatine). Concomitant administration of ciprofloxacin and tizanidine is contraindicated. Increased plasma concentrations associated with specific drug-related adverse reactions are determined by inhibition of their metabolic clearance by ciprofloxacin. Therefore, patients receiving these substances concurrently with ciprofloxacin should be closely monitored for clinical signs of overdose. Determination of serum concentrations, e.g., theophylline, may also be necessary (see section "Interaction with other medicinal products and other forms of interaction").

Methotrexate

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

Effect on laboratory parameters

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

Injection site reactions

Reactions at the site of ciprofloxacin administration have been reported. The frequency of such reactions increases if the infusion duration is up to 30 minutes. Reactions may manifest as transient local skin reactions that resolve quickly after infusion completion. Further intravenous administration is not contraindicated if reactions do not recur or intensify.

NaCl load

In patients on a low-sodium diet (patients with congestive heart failure, renal failure, nephrotic syndrome), additional salt load should be considered.

Visual disturbances

In case of visual disturbances or any sensation of eye involvement, immediate consultation with an ophthalmologist is required.

Use during pregnancy or breastfeeding

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

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

Ability to affect reaction speed when driving or operating machinery.

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

Dosage and Administration.

The dosage regimen is determined individually by a physician depending on the site and severity of the infection, the pathogen's sensitivity, and the patient's renal function; for children and adolescents, it is determined according to body weight.

The duration of treatment depends on the severity of the disease and the clinical and bacteriological findings.

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

Treatment of certain infections (e.g., pelvic inflammatory disease, intra-abdominal infections, infections in neutropenic patients, and bone and joint infections) may require combination with other appropriate antibacterial agents depending on the causative organism.

Children.

Dosage for elderly patients.

Elderly patients should be given lower doses of ciprofloxacin, depending on the severity of the disease and creatinine clearance.

Dosage regimen in adults with renal or hepatic impairment.

Renal impairment.

Hepatic impairment.

Dose adjustment is not required.

Dosing regimens in children with renal or hepatic impairment have not been studied.

Ciprofloxacin should be administered by intravenous infusion. In children, the infusion duration is 60 minutes. In adult patients, the infusion duration is 60 minutes for the "Ciprofloxacin, infusion solution" containing 400 mg ciprofloxacin and 30 minutes for the "Ciprofloxacin, infusion solution" containing 200 mg ciprofloxacin. Slow infusion into a large vein will minimize patient discomfort and reduce the risk of venous irritation.

The infusion solution may be administered either separately or after mixing with other compatible infusion solutions.

Compatibility with other solutions.

The ciprofloxacin infusion solution is compatible with Ringer's solution, 0.9% sodium chloride solution, 5% and 10% glucose solutions, 10% fructose solution, 5% glucose with 0.225% NaCl or 0.45% NaCl. If compatibility with other infusion solutions has not been confirmed, the ciprofloxacin infusion solution should be administered separately. Visible signs of incompatibility include precipitation, cloudiness, or discoloration of the solution.

Children.

Ciprofloxacin is not recommended for use in children for the treatment of infections other than those specified in the section "Indications."

Overdose.

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

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

In addition to standard emergency measures in overdose, monitoring of renal function is recommended, including determination of urine pH and, if necessary, increasing urine acidity to prevent crystalluria. Patients should receive adequate fluid intake.

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

In case of overdose, symptomatic treatment should be administered. ECG parameters should be monitored, as QT interval prolongation may occur.

Adverse reactions.

The most commonly reported adverse reactions to the drug are nausea, diarrhea, vomiting, transient elevation of 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 presented below.

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

The frequency of adverse reactions corresponds to the following criteria: common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10,000, < 1/1000), very rare (< 1/10,000), frequency not known (cannot be estimated from available data).

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

Blood and lymphatic system disorders: uncommon – eosinophilia; rare – anemia, neutropenia, leukopenia (granulocytopenia), leukocytosis, altered prothrombin levels, thrombocytopenia, thrombocytosis (thrombocythemia); very rare – hemolytic anemia, petechiae (intermediate skin hemorrhage), agranulocytosis, pancytopenia (life-threatening), bone marrow suppression (life-threatening).

Metabolism and nutrition disorders: uncommon – anorexia (decreased appetite), increased creatinine levels, increased blood urea nitrogen; rare – edema (peripheral, vascular, facial), hyperglycemia, hypoglycemia; very rare – increased amylase activity, increased lipase activity; frequency not known – hypoglycemic coma.

Endocrine system disorders: frequency not known – syndrome of inappropriate antidiuretic hormone secretion.

Psychiatric disorders*: uncommon – agitation, psychomotor restlessness/anxiety; rare – confusion and disorientation, apprehension, sleep disturbances (nightmares), pathological dreams, depression with possible suicidal ideation/thoughts or suicide attempts/acts, hallucinations; very rare – psychosis, psychotic reactions with possible suicidal ideation/thoughts or suicide attempts/acts (see section "Special precautions").

Nervous system disorders*: uncommon – dizziness, headache, sleep disorders; uncommon – taste disturbances; rare – paresthesia (peripheral paraesthesia), dysaesthesia, hyperaesthesia, tremor, convulsions including epileptic status (see section "Special precautions"), vertigo; very rare – migraine, coordination disturbances, gait disturbances, parosmia (disturbance of smell), loss of smell (usually reversible upon discontinuation of the drug), intracranial (intracerebral) hypertension, ataxia, hyperaesthesia, twitching; frequency not known – peripheral neuropathy and polyneuropathy (see section "Special precautions").

Gastrointestinal disorders: common – nausea, diarrhea; uncommon – vomiting, stomach and intestinal pain, abdominal pain, dyspeptic disorders, flatulence; rare – candidiasis (oral); very rare – candidiasis, pseudomembranous colitis (life-threatening), pancreatitis.

Hepatobiliary disorders: uncommon – increased levels of liver transaminases: ALT, AST, bilirubinemia, abnormal liver function tests; rare – liver function disorders, jaundice, cholestatic jaundice, hepatitis; very rare – liver necrosis (very rarely progressing to life-threatening liver failure) (see section "Special precautions").

Skin and subcutaneous tissue disorders: uncommon – rash, pruritus, maculopapular rash, urticaria; rare – photosensitivity reaction (see section "Special precautions"); very rare – petechiae, erythema multiforme, nodular erythema, Stevens-Johnson syndrome (life-threatening), toxic epidermal necrolysis (Lyell's syndrome) (life-threatening), persistent rashes; frequency not known – acute generalized exanthematous pustulosis.

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

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

Reproductive system disorders: rare – vaginal candidiasis.

Immune system disorders: rare – allergic reactions, allergic edema/angioedema; very rare – anaphylactoid (anaphylactic) reaction, anaphylactic shock (life-threatening) (see section "Special precautions"), serum sickness-like reaction.

Eye disorders*: rare – visual disturbances (visual abnormalities), diplopia, chromatopsia; very rare – disturbance of color vision.

Ear and labyrinth disorders*: rare – tinnitus, hearing loss/hearing impairment; very rare – temporary deafness (especially at high frequencies).

Respiratory, thoracic and mediastinal disorders: rare – dyspnea (including asthmatic conditions), laryngeal edema.

Vascular disorders**: uncommon – thrombophlebitis (at infusion site); very rare – vasculitis.

Cardiac disorders**: rare – tachycardia, vasodilation (flushing), arterial hypotension, syncope (fainting); frequency not known – ventricular arrhythmia, QT interval prolongation, torsades de pointes*.

*These reactions were reported during the post-marketing period and were predominantly observed in patients with additional risk factors for QT interval prolongation (see section "Special precautions").

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

Other: pseudotumor cerebri.

Laboratory findings: uncommon – elevated alkaline phosphatase levels in blood; rare – deviation from normal prothrombin levels, elevated amylase activity; frequency not known – elevated INR in patients receiving vitamin K antagonists.

The following adverse events occur more frequently in subgroups of patients who received intravenous or sequential (switch from intravenous to oral) treatment:

Use in children

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

*In very rare cases, patients receiving quinolones and fluoroquinolones, regardless of existing risk factors, have reported prolonged (lasting for months or years), disabling and potentially irreversible serious adverse reactions affecting different systems of the body and sensory organs, sometimes several simultaneously (including such reactions as tendinitis, tendon rupture, arthralgia, limb pain, gait disturbance, neuropathies associated with paresthesia, depression, fatigue, memory impairment, sleep disturbances, hearing, vision, taste and smell disorders).

**In patients receiving fluoroquinolones, cases of aneurysms and aortic dissection, sometimes complicated by rupture (including fatal cases), and regurgitation/insufficiency of any of the heart valves have been reported (see section "Special precautions for use").

Description of individual adverse reactions

Anxiety, suicidal thoughts, panic attacks, neuralgia, and difficulty concentrating have been reported with fluoroquinolone use as potential components of prolonged and disabling adverse reactions that may lead to loss of working ability.

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after drug registration is of great importance. It allows ongoing monitoring of the benefit-risk balance of the use of this medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua

Shelf life. 3 years.

Storage conditions.

Store at temperatures not exceeding 25°C in the original packaging. Keep out of reach of children.

Any unused medicinal product remaining should be destroyed.

Incompatibility.

This medicinal product should not be mixed with other medicinal products except those specified in the section "Method and dosage of administration".

If compatibility with another infusion product has not been confirmed, the Ciprofloxacin infusion solution should be administered separately.

Incompatibility occurs when used with all infusion solutions/products that are physically or chemically unstable (e.g., penicillins, heparin solutions), particularly in combination with solutions whose pH has been adjusted to alkaline.

Packaging.

100 ml of the product in a container, 1 container in a polyvinyl chloride film, together with the instruction for medical use, in a carton.

Prescription status. Prescription only.

Manufacturer.

EuroLife Healthcare Pvt. Ltd.

Manufacturer's location and address of place of business.

Plot No. 520, Bhagwanpur, Roorkee, Haridwar, Uttarakhand, India.

Marketing Authorization Holder.

Ananta Medikare Ltd.

Location of the Marketing Authorization Holder and/or its representative.

Suite 1, 2 Station Court, Imperial Wharf, Townmead Road, Fulham, London, United Kingdom.