Cipralet

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CYPROLET® (CIPROLET)

Composition:

Active substance: ciprofloxacin;

One tablet contains ciprofloxacin hydrochloride equivalent to 250 mg or 500 mg of ciprofloxacin;

Excipients: microcrystalline cellulose, talc, corn starch, colloidal anhydrous silicon dioxide, magnesium stearate, sodium croscarmellose, hypromellose, sorbic acid, titanium dioxide (E 171), macrogol 6000, polysorbate 80, dimethicone.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white or almost white, round, biconvex, film-coated tablets.

Pharmacotherapeutic group.

Antibacterial agents of the quinolone group. Fluoroquinolones. ATC code J01M A02.

Pharmacological properties.

Pharmacodynamics.

Ciprolet® is an antimicrobial agent of the fluoroquinolone group. The mechanism of action of ciprofloxacin is related to its effect on bacterial DNA gyrase (topoisomerase), an enzyme essential for bacterial DNA replication. Ciprolet® exerts a rapid bactericidal effect on microorganisms both in the resting phase and during active multiplication.

The spectrum of activity of Ciprolet® includes the following Gram-negative and Gram-positive microorganisms: E. coli, Shigella, Salmonella, Citrobacter, Klebsiella, Enterobacter, Serratia, Hafnia, Edwardsiella, Proteus (indole-positive and indole-negative), Providencia, Morganella, Yersinia, Vibrio, Aeromonas, Plesiomonas, Pasteurella, Haemophilus, Campylobacter, Pseudomonas, Legionella, Neisseria, Moraxella, Branhamella, Acinetobacter, Brucella, Staphylococcus, Streptococcus agalactiae, Listeria, Corynebacterium, Chlamydia, as well as plasmid forms of bacteria. Variable sensitivity is observed in Gardnerella, Flavobacterium, Alcaligenes, Streptococcus pyogenes, Streptococcus pneumoniae, Streptococcus viridans, Mycoplasma hominis, Mycobacterium tuberculosis, Mycobacterium fortuitum. Anaerobes are generally moderately sensitive (Peptococcus, Peptostreptococcus) or resistant (Bacteroides), with some exceptions. Ciprolet® is effective against bacteria producing β-lactamases. Ciprolet® is active against pathogens resistant to almost all antibiotics, sulfonamides, and nitrofuran derivatives. Most commonly resistant organisms include: Streptococcus faecium, Ureaplasma urealyticum, Nocardia asteroides, Treponema pallidum. Resistance to Ciprolet® develops slowly and gradually.

Pharmacokinetics.

Ciprolet® is rapidly and well absorbed after oral administration (bioavailability ranges from 50–85%). Maximum plasma concentrations are achieved within 60–90 minutes. The volume of distribution is 2–3 L/kg. Plasma protein binding is low (20–40%). Ciprolet® penetrates well into organs, tissues, and bones. Approximately 2 hours after oral intake, the drug is detected in tissues and body fluids at concentrations several times higher than those in blood serum.

Ciprolet® is primarily excreted from the body in unchanged form, mainly via the kidneys (50–70%). The elimination half-life from plasma after oral administration ranges from 3 to 5 hours. A significant portion of the drug is also excreted via bile and feces (up to 30%). Therefore, only substantial impairment of renal function leads to delayed elimination.

Clinical characteristics.

Indications.

Ciprole**®** is indicated for the treatment of the following infections (see sections "Special instructions" and "Pharmacological properties"). Before initiating therapy, particular attention should be paid to all available information on resistance to ciprofloxacin.

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

Adults

• Lower respiratory tract infections caused by Gram-negative bacteria:
  • exacerbations of chronic obstructive pulmonary disease*;
  • bronchopulmonary infections in cystic fibrosis or bronchiectasis;
  • community-acquired pneumonia.
• Chronic suppurative otitis media.
• Acute exacerbations of chronic sinusitis, especially if caused by Gram-negative bacteria*.
• Urinary tract infections:
  • uncomplicated acute cystitis*;
  • acute pyelonephritis;
  • complicated urinary tract infections;
  • bacterial prostatitis.
• Gonococcal urethritis and cervicitis.
• 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 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.
• Fever in neutropenic patients due to bacterial infection.
• Inhalational anthrax (post-exposure prophylaxis and definitive treatment).

Children and adolescents

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

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

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

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

Contraindications.

The drug should not be used in patients with hypersensitivity to the active substance – ciprofloxacin – or 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 forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Effects of other medicinal products on ciprofloxacin

Chelate complex formation

Concomitant administration of ciprofloxacin (orally) with medicinal products containing polyvalent cations, mineral supplements (e.g., calcium, magnesium, aluminium, iron), phosphate-binding polymers (e.g., sevelamer), sucralfate, or antacids, as well as 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 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 only 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 absorption of ciprofloxacin may be reduced.

Probenecid

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

Effects of ciprofloxacin on other medicinal products

Tizanidine

Tizanidine must not be administered concurrently 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 (increase in Cmax by 7-fold, range 4–21-fold; increase in AUC by 10-fold, range 6–24-fold). Elevated tizanidine plasma concentrations are associated with 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 may increase the risk of adverse toxic reactions caused by methotrexate. Concomitant administration is not recommended (see section "Special instructions").

Theophylline

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

Other xanthine derivatives

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

Phenytoin

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

Vitamin K antagonists

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

Ropinirole

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

Clozapine

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

QT-prolonging agents

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

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.

Lidocaine

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

Sildenafil

Cmax and AUC of sildenafil approximately doubled 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 Ciprole**®** with sildenafil, and the risk/benefit ratio should be considered.

Oral hypoglycemic agents

When ciprofloxacin is co-administered with oral antidiabetic agents, particularly sulfonylureas (e.g., glyburide, glimepiride), hypoglycemia has been reported, 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 inhibitors of CYP450 1A2, such as fluvoxamine, may lead to increased AUC and Cmax of duloxetine. Although there are no clinical data on possible interaction with ciprofloxacin, similar effects can be expected when these drugs are used concomitantly (see section "Special instructions").

Nonsteroidal anti-inflammatory drugs (NSAIDs)

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

Cyclosporine

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

Agomelatine

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

Zolpidem

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

Sodium-containing compounds

This medicinal product contains sodium compounds. One 250 mg tablet contains 10 mg of sodium croscarmellose; one 500 mg tablet contains 20 mg of sodium croscarmellose. Caution should be exercised when administering this drug to patients on a sodium-restricted diet.

Special precautions for use.

The use of ciprofloxacin should be avoided in patients who have previously experienced serious adverse reactions to fluoroquinolones. Treatment with ciprofloxacin in such patients should only be initiated if no alternative treatment options are available and after careful assessment of benefit–risk (see section "Contraindications").

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

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

For treatment of 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

Gonococcal urethritis, cervicitis, orchitis, epididymitis, and pelvic inflammatory disease
may be caused by fluoroquinolone-resistant isolates of Neisseria gonorrhoeae.

Ciprofloxacin should be administered concomitantly with other appropriate antibacterial agents (e.g., a cephalosporin), except in clinical situations where ciprofloxacin-resistant strains of Neisseria gonorrhoeae have been ruled out. If no clinical improvement occurs within 3 days, the therapy should be re-evaluated.

Urinary tract infections

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 fluoroquinolone resistance in Escherichia coli when prescribing treatment.

A single dose of ciprofloxacin, which may be used in uncomplicated cystitis in postmenopausal women, is expected to be less effective than longer treatment duration. This should be particularly considered in light of increasing resistance of Escherichia coli to quinolones.

Intra-abdominal infections

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

Traveler’s diarrhea

When selecting therapy, information on resistance to ciprofloxacin of relevant microorganisms in countries visited by the patient should be taken into account.

Bone and joint infections

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

Pulmonary 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.

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 contribute to the development of antibiotic-associated diarrhea. Strains producing high levels of toxin are 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 presenting with diarrhea after antibiotic use. A careful medication history is essential, as symptoms may occur up to 2 months after antibiotic administration. If Clostridium difficile-associated diarrhea is suspected or confirmed, antibiotics not active against Clostridium difficile may need to be discontinued. Depending on clinical status, correction of fluid and electrolyte imbalances, consideration of protein supplementation, and administration of antibiotics effective against Clostridium difficile may be required. Surgical intervention may also be necessary.

Children and adolescents

Ciprofloxacin use in children and adolescents should follow current official recommendations. Treatment with ciprofloxacin should only be initiated by a physician experienced in managing pediatric and adolescent patients with cystic fibrosis and/or severe infections. Ciprofloxacin has been associated with arthropathy in weight-bearing joints in immature animals. Safety data from a randomized, double-blind study in children (ciprofloxacin: n=335, mean age = 6.3 years; comparator group: n=349, mean age = 6.2 years; age range: 1–17 years) showed an incidence of arthropathy likely related to treatment (distinct 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. The incidence of drug-related arthropathy at 1 year was 9% and 5.7%, respectively. The increase in arthropathy cases related to treatment was not statistically significant. However, treatment of children and adolescents with ciprofloxacin should only be initiated after careful benefit–risk assessment due to the potential risk of adverse reactions affecting joints and/or surrounding tissues.

Respiratory 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

Ciprofloxacin may be considered for treatment of urinary tract infections when no other treatment options are available. Therapy should be based on microbiological test results.

Clinical studies have evaluated the use of ciprofloxacin in children and adolescents 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 feasible or standard therapy has failed.

Ciprofloxacin use 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 patients should immediately inform 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 (anaphylactic shock management).

Musculoskeletal system

Generally, ciprofloxacin should 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 treatment of specific severe infections—particularly when standard therapy is ineffective or bacterial resistance is present and microbiological results justify ciprofloxacin use. Tendinitis or tendon rupture (especially of the Achilles tendon), sometimes bilateral, may occur during ciprofloxacin therapy, even within the first 48 hours. Cases of tendon rupture have been reported several months after discontinuation of treatment. The risk of tendinopathy may be increased in elderly patients, those with renal impairment, organ transplant recipients, and those receiving concomitant corticosteroids; therefore, concomitant use of corticosteroids with this medicinal product should be avoided (see section "Adverse reactions"). If any signs of tendinitis (e.g., painful swelling, inflammation) occur, ciprofloxacin should be discontinued and alternative therapies considered. The affected limb should be rested, and corticosteroids should not be used in cases of tendinopathy.

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

Photosensitivity

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

Visual disturbances

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

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. If seizures occur, ciprofloxacin should be discontinued (see section "Adverse reactions"). Psychotic reactions, including depression or psychosis, may occur even after the first dose and, in rare cases, may progress to suicidal ideation or attempts. In such cases, ciprofloxacin should be discontinued and appropriate clinical measures taken.

Peripheral neuropathy

Cases of sensory or sensorimotor polyneuropathy, manifesting as paresthesia, hypaesthesia, dysesthesia, or weakness (based on neurological symptoms such as pain, burning, sensory disturbances, or muscle weakness, alone or in combination), have been reported in patients taking ciprofloxacin. Patients experiencing symptoms of neuropathy, including pain, burning, tingling, numbness, and/or weakness, should discontinue ciprofloxacin and seek medical advice before continuing treatment to prevent irreversible conditions (see section "Adverse reactions").

Cardiac disorders

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

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

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

Women and elderly patients may be more sensitive to QT-prolonging drugs. Therefore, fluoroquinolones, including ciprofloxacin, should be used with caution in these patient groups (see sections "Interaction with other medicinal products and other forms of interaction", "Method of administration and dosage", "Overdose", "Adverse reactions").

Gastrointestinal tract

If severe and persistent diarrhea occurs during or after treatment (even weeks later), patients should inform their physician, as this may indicate 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 (e.g., vancomycin, 4 × 250 mg/day orally). Antiperistaltic agents are contraindicated.

Kidneys and urinary system

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

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.

Hepatobiliary system

Cases of hepatic necrosis and life-threatening liver failure have been reported during ciprofloxacin therapy (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 receiving ciprofloxacin (see section "Adverse reactions").

Glucose-6-phosphate dehydrogenase deficiency

Hemolytic reactions have been reported in patients with glucose-6-phosphate dehydrogenase deficiency taking 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 therapy, with or without clinically evident superinfection. There may be an increased risk 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 moderately inhibits CYP450 1A2 and may therefore increase serum concentrations of concurrently 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 occur due to inhibition of metabolic clearance by ciprofloxacin. Therefore, patients receiving these drugs concomitantly with ciprofloxacin should be closely monitored for signs of overdose. Measurement of plasma drug 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 test results

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

Patients at increased risk of aneurysm, aortic dissection, and valvular regurgitation/incompetence

Epidemiological studies report an increased risk of aortic aneurysm and dissection, particularly in elderly patients, as well as aortic and mitral valve regurgitation following fluoroquinolone use.

Cases of aortic aneurysm and dissection, sometimes complicated by rupture (including fatal cases), and valvular regurgitation/incompetence have been reported in patients receiving fluoroquinolones (see section "Adverse reactions").

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

for aortic aneurysm and dissection (e.g., connective tissue disorders such as Marfan syndrome, Ehlers-Danlos syndrome, Turner syndrome, Behçet’s disease, hypertension, rheumatoid arthritis) or additional risk factors for aortic aneurysm and dissection (e.g., vascular disorders such as Takayasu arteritis or giant cell arteritis, known atherosclerosis, or Sjögren’s syndrome), or additional risk factors for valvular regurgitation/incompetence (e.g., infective endocarditis).

The risk of aortic aneurysm, dissection, and rupture may be increased in patients receiving systemic corticosteroids concomitantly.

Patients experiencing sudden abdominal, chest, or back pain should seek immediate medical attention at an emergency department.

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

Fluctuations in blood glucose levels

Fluoroquinolones may cause disturbances in blood glucose levels, including hyperglycemia and hypoglycemia (see section "Adverse reactions"), typically in diabetic patients receiving concomitant therapy with oral hypoglycemic agents (e.g., glibenclamide) or insulin. Severe cases of hypoglycemia leading to coma have been reported. Close monitoring of blood glucose levels is recommended for such patients.

Long-term, disabling, potentially irreversible serious adverse reactions

Very rare reports describe long-term (from several months to years), disabling, potentially irreversible serious adverse reactions affecting various organ systems (musculoskeletal, nervous, psychiatric, and sensory systems), sometimes simultaneously, in patients receiving quinolone and fluoroquinolone therapy, regardless of age or previously identified risk factors. Ciprofloxacin should be discontinued immediately at the first signs or symptoms of any serious adverse reaction, and medical advice should be sought promptly.

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, quinolones have been shown to affect immature cartilage in young animals, and a potential risk to joint cartilage in newborns/fetuses cannot be excluded. Therefore, as a precaution, ciprofloxacin should be avoided during pregnancy.

Lactation.

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 affect reaction speed when driving or operating machinery.

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, driving and operating machinery may be impaired.

Dosage and Administration.

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

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

Treatment of infections caused by certain bacteria (e.g., Pseudomonas aeruginosa, Acinetobacter, or Staphylococci) may require higher doses of ciprofloxacin and concomitant administration 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 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 impaired renal function:

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

The tablets should be swallowed whole with liquid. They may be taken independently of food intake. When administered on an empty stomach, the active substance is absorbed more rapidly. Ciprofloxacin tablets must not be taken together with dairy products (e.g., milk, yogurt) or fruit juices fortified with minerals (e.g., calcium-fortified orange juice) (see section "Interaction with other medicinal products and other forms of interaction").

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

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 of weight-bearing joints in immature animals. Safety data in children indicate a frequency of arthropathy likely associated with ciprofloxacin use (distinct from clinical signs and symptoms related to direct joint involvement). The increased incidence of arthropathy associated with ciprofloxacin use was statistically insignificant. However, treatment with ciprofloxacin in children and adolescents should be initiated only after careful assessment of the benefit-risk ratio due to the potential risk of adverse reactions related to joints and/or surrounding tissues.

Overdose.

Cases of overdose following ingestion of 12 g of the drug have been reported, resulting 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, 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 for overdose, such as gastric evacuation followed by administration of activated charcoal, monitoring of renal function is recommended, including determination of urine pH and, if necessary, acidification of urine to prevent crystalluria. Patients should receive adequate fluid intake.

Antacids containing calcium or magnesium may theoretically reduce ciprofloxacin absorption in cases of overdose.

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

In case of overdose, symptomatic treatment should be applied. ECG monitoring should be performed due to the potential for QT interval prolongation.

Adverse Reactions

The most commonly reported adverse reactions to the drug are nausea and diarrhea.

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

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

Adverse reactions are classified by frequency of occurrence: frequent (≥ 1/100 to <1/10); uncommon (≥ 1/1000 to <1/100); rare (≥ 1/10,000 to <1/1000); very rare (≤ 1/10,000); frequency not known (cannot be estimated based on current data).

Infections and infestations: uncommon – fungal superinfections; rare – antibiotic-associated colitis (very rarely with potentially fatal outcome) (see section "Special Warnings and Precautions for Use").

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

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

Metabolism and nutrition disorders: uncommon – decreased appetite, anorexia; rare – hyperglycemia, hypoglycemia (see section "Special Warnings and Precautions for Use"); frequency not known – hypoglycemic coma.

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

Nervous system disorders*: uncommon – headache, weakness, sleep disturbances, taste disturbances, dizziness; rare – paresthesia, dysesthesia, hypesthesia, 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, pseudotumor 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 – color vision disturbances.

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

Cardiac disorders**: rare – tachycardia; frequency not known – ventricular arrhythmia, torsades de pointes (mainly reported 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 – dyspnea (including asthmatic conditions).

Gastrointestinal disorders: frequent – nausea, diarrhea; uncommon – vomiting, stomach and intestinal pain, abdominal pain, dyspeptic disorders, flatulence, decreased appetite, anorexia; rare – antibiotic-associated colitis (very rarely with potentially fatal outcome) (see section "Special Warnings and Precautions for Use"); very rare – pancreatitis.

Hepatobiliary disorders: uncommon – increased levels of transaminases and bilirubin; rare – liver function disturbances, cholestatic jaundice, hepatitis; very rare – hepatic necrosis (very rarely 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 (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS).

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 tendon) (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, hematuria, crystalluria (see section "Special Warnings and Precautions for Use"), tubulointerstitial nephritis.

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

Investigations: uncommon – increased levels of liver enzymes (alkaline phosphatase activity, increased transaminases, increased bilirubin); rare – deviation from normal prothrombin levels, increased amylase and lipase activity, fluctuations in blood glucose levels (hyperglycemia, hypoglycemia); frequency not known – increased international normalized ratio (INR) (in patients receiving vitamin K antagonists).

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

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

** – In patients receiving fluoroquinolones, cases of aneurysm and dissection of the aorta, sometimes complicated by rupture (including fatal cases), and regurgitation/insufficiency of any heart valve have been reported (see section "Special Warnings and Precautions for Use").

Use in children

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").

The following additional adverse reactions have also been reported in children: allergic edema; decreased appetite and food intake; hypoglycemia; behavioral disturbances; suicidal thoughts; suicide attempt; hyperesthesia; blisters; acute generalized exanthematous pustulosis; malaise; gait disturbances; 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 bleeding; lymphadenopathy; increased lipase levels; joint disorders; gout flare-up; nephritis; polyuria; micturition disorders; urethral bleeding; vaginitis; acidosis; breast pain; epistaxis; pulmonary or laryngeal edema; hiccups; hemoptysis; bronchospasm; pulmonary embolism; phototoxic reactions; hot flushes; chills; facial, neck, lip, conjunctiva, or hand swelling; cutaneous candidiasis; hyperpigmentation; sweating; decreased visual acuity; diplopia; eye pain; taste disturbances; achromatopsia.

Adverse reactions to ciprofloxacin reported during post-marketing surveillance include: agitation, exfoliative dermatitis, erythema, hyperesthesia, hypertension, methemoglobinemia, increased INR in patients taking vitamin K antagonists, candidiasis (oral, gastrointestinal, vaginal), myasthenia, nystagmus, polyneuropathy, hyperkalemia, changes in prothrombin time, psychosis, increased triglycerides, gamma-glutamyltransferase in blood, uric acid; decreased hemoglobin levels, hemorrhagic diathesis, increased monocyte count, leukocytosis, cylindruria, and cases of hypoglycemic coma.

* Very rare reports describe prolonged (from several months to several years), disabling, potentially irreversible serious adverse reactions that may affect multiple organs and organ systems, sometimes simultaneously, including sensory organs (including such reactions as tendinitis, tendon rupture, arthralgia, limb pain, gait disturbances, neuropathies associated with paresthesia, depression, fatigue, memory impairment, sleep disorders, hearing, vision, taste, and smell disturbances) in patients treated with quinolones and fluoroquinolones, regardless of previously identified risk factors.

Shelf life. 3 years.

Storage conditions.

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

Packaging.

10 tablets in a blister, 1 blister per carton.

Prescription status. Prescription only.

Manufacturer 1.

Dr. Reddy’s Laboratories Ltd, FTO – II

Manufacturer’s location and address of place of business.

Plot No. 42R, 43, 44R, 45R, 46R, 53, 54, 83, Bachupally, Bachupally Mandal, Medchal Malkajgiri District – 500090, Telangana State, India

Manufacturer 2.

Dr. Reddy’s Laboratories Limited.

Manufacturer’s location and address of place of business.

Unit – VI, Khol, Nalagarh Road, Baddi, Solan District, Himachal Pradesh, 173205, India

To report an adverse reaction or lack of efficacy when using the medicinal product, please call:

+38 (044) 207-51-97 (24/7), or +38 (050) 414-39-39; or send an email to: [email protected]