Cipran od

I N S T R U C T I O N for medical use of the medicinal product CIPRAN OD (CIFRANOD)

Composition:

Active substance: ciprofloxacin;

One prolonged-release film-coated tablet contains 500 mg or 1000 mg of ciprofloxacin;

Excipients: sodium alginate, hypromellose, sodium bicarbonate, crospovidone, magnesium stearate, colloidal anhydrous silicon dioxide, talc;

White Opadry: hypromellose; lactose monohydrate; titanium dioxide (E 171); polyethylene glycol 400;

Printing ink: shellac, iron oxide black (E 172), propylene glycol.

Medicinal form. Prolonged-release film-coated tablets.

Main physicochemical properties:

500 mg tablets – white or almost white, elongated-shaped tablets, film-coated, marked with "Cifran OD 500 mg" in food-grade printing ink on one side;

1000 mg tablets – white or almost white, elongated-shaped tablets, film-coated, marked with "Cifran OD 1000 mg" in food-grade printing ink on one side.

Pharmacotherapeutic group. Antibacterial agents of the quinolone group. Fluoroquinolones.

ATC code J01MA02.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

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

Resistance mechanisms

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

Resistance mechanisms that inactivate other antibiotics, such as decreased permeability of the bacterial outer membrane (commonly observed in Pseudomonas aeruginosa) and active drug efflux from the cell (efflux), may affect susceptibility to ciprofloxacin. Plasmid-mediated resistance, encoded by the qnr resistance gene, has been reported. Resistance mechanisms that inactivate penicillins, cephalosporins, aminoglycosides, macrolides, and tetracyclines may not affect the antibacterial activity of ciprofloxacin. Organisms resistant to these agents may still be susceptible to ciprofloxacin.

Minimal bactericidal concentration (MBC) usually does not exceed minimal inhibitory concentration (MIC) by more than two-fold.

*Susceptibility to ciprofloxacin in vitro

The prevalence of acquired resistance among isolated species may vary depending on geographical location and time; therefore, local resistance data are necessary, especially when treating severe infections. Consultation with specialists should be considered when local resistance prevalence reaches levels at which the benefit of the drug's use, at least for certain types of infections, becomes questionable.

The following genera and species of bacteria are generally in vitro susceptible to ciprofloxacin.

Aerobic Gram-positive microorganisms

Aerobic gram-negative microorganisms

Anaerobic microorganisms

Mobiluncus

Other microorganisms

Chlamydia trachomatis, Chlamydia pneumoniae, Mycoplasma hominis, Mycoplasma pneumoniae.

Variable susceptibility to ciprofloxacin is exhibited by: Acinetobacter baumannii, Burkholderia cepacia, Campylobacter spp., Citrobacter freudii, Enterococcus faecalis, Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Morganella morganii, Neisseria gonorrhoeae, Proteus mirabilis, Proteus vulgaris, Providencia spp., Pseudomonas aeruginosa, Pseudomonas fluorescens, Serratia marcescens, Streptococcus pneumoniae, Peptostreptococcus spp., Propionibacterium acnes.

Microorganisms considered to exhibit innate resistance to ciprofloxacin include:

Staphylococcus aureus (methicillin-resistant) and Stenotrophomonas maltophilia, Actinomyces, Enterococcus faecium, Listeria monocytogenes, Mycoplasma genitalium, Ureaplasma urealyticum, anaerobic microorganisms (except Mobiluncus, Peptostreptococcus, Propionibacterium acnes).

Data on pulmonary anthrax

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Recommendations for human use are primarily based on in vitro microbial susceptibility data, animal experimental studies, and limited human data. Effective prophylaxis against anthrax in humans is considered to be achieved with ciprofloxacin administered for two months at a dose of 500 mg. Physicians should manage treatment according to national and/or international consensus guidelines for anthrax management.

Preclinical safety data

The likelihood of acute toxicity following oral administration of ciprofloxacin is considered very low. Depending on the species, the intravenous LD50 ranged from 125 to 290 mg/kg.

Chronic toxicity

6-month tolerability study

Oral administration

Doses up to 500 mg/kg and 30 mg/kg were well tolerated by rats and monkeys, respectively. Changes in distal renal tubules were observed in some monkeys in the group receiving the highest dose (90 mg/kg).

Carcinogenicity

Carcinogenicity studies in mice (21 months) and rats (24 months) with doses up to 1000 mg/kg body weight/day in mice and 125 mg/kg body weight/day in rats (increased to 250 mg/kg body weight/day after 22 weeks) provided no evidence of a potential carcinogenic effect at any dose.

Reproductive toxicology

Fertility study in rats

Administration of ciprofloxacin showed no toxic effects on fertility, intrauterine and postnatal development of offspring, or fertility of the F1 generation.

Embryotoxicity studies

The studies provided no evidence of any embryotoxic or teratogenic effects of ciprofloxacin.

Perinatal and postnatal development in rats

No effects of the drug on perinatal or postnatal development were observed. At the end of the rearing period, histological examinations showed no signs of joint damage in young animals.

Mutagenicity

Six in vitro mutagenicity tests with ciprofloxacin were conducted.

Although two out of eight in vitro tests (such as the Mouse Lymphoma Cell Forward Mutation Assay and Rat Hepatocyte Primary Culture DNA Repair Assay) were positive, all in vivo test systems, covering all relevant endpoints, yielded negative results.

Studies on joint effects

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

The degree of cartilage damage varies depending on age, species, and dose; the extent of damage may be reduced by decreasing weight-bearing stress on the joints. Studies in adult animals (rats, dogs) showed no signs of cartilage damage. In studies on young beagle dogs, administration of high doses of ciprofloxacin (1.3 to 3.5 times higher than the therapeutic dose) resulted in joint changes after two weeks of treatment, which persisted for up to five months. No joint effects were observed at therapeutic doses.

Pharmacokinetics

Extended-release ciprofloxacin tablets are designed to release the active ingredient more slowly compared to immediate-release tablets.

The pharmacokinetic profile of extended-release ciprofloxacin 500 mg administered once daily is comparable to that of immediate-release ciprofloxacin 250 mg administered twice daily in terms of equivalent AUC over a 24-hour dosing period. The pharmacokinetic profile of extended-release ciprofloxacin 1000 mg administered once daily is comparable to that of immediate-release ciprofloxacin 500 mg administered twice daily in terms of equivalent AUC over a 24-hour dosing period.

The PK-PD ratio indicates that extended-release ciprofloxacin administered at 500 mg once daily provides AUC values relative to the above-mentioned MIC (0.5 µg/mL) comparable to those of immediate-release ciprofloxacin administered at 250 mg twice daily.

The PK-PD ratio indicates that extended-release ciprofloxacin administered at 1000 mg once daily provides AUC values relative to the above-mentioned MIC (1 µg/mL) comparable to those of immediate-release ciprofloxacin administered at 500 mg twice daily.

The volume of distribution calculated for intravenous ciprofloxacin is approximately 2.1–2.7 L/kg. Studies comparing oral and intravenous formulations of ciprofloxacin have demonstrated the drug's ability to penetrate various body tissues. Plasma protein binding of ciprofloxacin ranges from 20% to 40%, which is unlikely to be high enough to cause significant protein-binding interactions with other drugs.

Four metabolites of ciprofloxacin have been identified in human urine. These metabolites exhibit antimicrobial activity but are less active than unchanged ciprofloxacin. The main metabolites are oxociprofloxacin (M3) and sulfociprofloxacin (M2), each accounting for approximately 3% to 8% of the total dose. Other minor metabolites are desethylene-ciprofloxacin (M1) and formylciprofloxacin (M4). The relative proportions of the drug and its metabolites in plasma are consistent with those found in urine. Excretion of these metabolites is largely complete within 24 hours after administration.

Elimination kinetics of ciprofloxacin are similar for immediate-release and extended-release tablets. In studies comparing extended-release and immediate-release ciprofloxacin, approximately 35% of the orally administered dose was excreted unchanged in urine for both formulations. The renal clearance of ciprofloxacin, approximately 300 mL/min, exceeds the normal glomerular filtration rate of 120 mL/min, indicating that active tubular secretion plays a significant role in the elimination of ciprofloxacin. Concomitant administration of probenecid with immediate-release ciprofloxacin reduces renal clearance of ciprofloxacin by approximately 50% and increases its systemic concentration by 50%. Although biliary concentrations of ciprofloxacin are several times higher than plasma concentrations after oral administration of immediate-release tablets, only a small amount of the administered dose is excreted unchanged in bile. Additionally, 1% to 2% of the dose is excreted in bile as metabolites. Approximately 20% to 35% of orally administered immediate-release ciprofloxacin is excreted in feces over 5 days after dosing, possibly due to biliary excretion or transintestinal secretion.

Special patient groups

Pharmacokinetic studies of oral administration of immediate-release ciprofloxacin tablets (single dose) and intravenous administration (single and multiple doses) indicate higher ciprofloxacin concentrations in elderly patients (>65 years) compared to younger adults. Cmax increases by 16–40%, and mean AUC increases by approximately 30%, which may be at least partially related to reduced renal clearance in elderly patients. The elimination half-life of the drug is only slightly (~20%) prolonged in elderly patients. These differences are not considered clinically significant.

In patients with impaired renal function, the elimination half-life of the drug is somewhat prolonged. Dose adjustment is not required for patients with uncomplicated urinary tract infections receiving extended-release ciprofloxacin tablets at 500 mg. For complicated urinary tract infections and acute uncomplicated pyelonephritis, where a 1000 mg dose is appropriate, the dose of extended-release ciprofloxacin should be reduced to 500 mg every 24 hours in patients with creatinine clearance below 30 mL/min.

In studies conducted in patients with stable chronic liver cirrhosis, no significant changes in ciprofloxacin pharmacokinetics were observed. However, the pharmacokinetics of ciprofloxacin in patients with acute hepatic insufficiency have not been fully elucidated.

Clinical characteristics.

Indications.

Uncomplicated and complicated infections caused by microorganisms sensitive to ciprofloxacin.

Adults.

• Respiratory tract infections: ciprofloxacin may be recommended for the treatment of community-acquired pneumonia caused by Klebsiella spp., Enterobacter spp., Proteus spp., Escherichia coli, Pseudomonas aeruginosa, Haemophilus spp., Moraxella catarrhalis, Legionella, and staphylococci.
• Ear infections (otitis media) and paranasal sinus infections (sinusitis), particularly those caused by gram-negative microorganisms, including Pseudomonas aeruginosa, or staphylococci.
• Eye infections.
• Kidney and/or urinary tract infections:
  • uncomplicated acute cystitis*;
  • acute pyelonephritis;
  • complicated urinary tract infections;
  • bacterial prostatitis.
• Genital tract infections, including adnexitis and gonorrhea.
• Intra-abdominal infections (e.g., gastrointestinal tract infections, biliary tract infections, peritonitis).
• Skin and soft tissue infections.
• Bone and joint infections.
• Fever in neutropenic patients caused by bacterial infection.

Children.

Ciprofloxacin should be prescribed to children only after careful assessment of the risk-benefit ratio due to the potential for adverse effects on joints and/or periarticular tissues.

Treatment of children in clinical trials has been conducted only for the following indications. Clinical experience with ciprofloxacin in children for other indications is limited.

Ciprofloxacin may be used in children as a second- or third-line agent for the treatment of complicated urinary tract infections and pyelonephritis caused by Escherichia coli (age range of children treated in clinical trials: 1 to 17 years), and for the treatment of pulmonary complications caused by Pseudomonas aeruginosa in children with cystic fibrosis (age range of children treated in clinical trials: 5 to 17 years).

Inhalational form of anthrax in adults and children.

Reduction of the risk of developing or progression of anthrax after aerosol exposure to Bacillus anthracis.

*Only when other antibacterial agents typically used for treatment of this infection have been deemed ineffective or inappropriate.

Contraindications.

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

Concomitant use of ciprofloxacin and tizanidine is contraindicated due to clinically significant adverse effects (arterial hypotension, somnolence) associated with increased plasma concentrations of tizanidine.

Interaction with other medicinal products and other forms of interaction.

Effects of other medicinal products on ciprofloxacin

Medicinal products that prolong the QT interval

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

Chelate complex formation

Concomitant administration of oral ciprofloxacin with medicinal products containing multivalent cations, mineral supplements (e.g., calcium, magnesium, aluminum, iron), phosphate binders (e.g., sevelamer, lanthanum carbonate), sucralfate, antacids, or buffered formulations (e.g., 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, including dairy products

Concomitant intake of ciprofloxacin with dairy products or mineral-enriched foods (such as milk, yogurt, or calcium-fortified orange juice) should be avoided. Other calcium-containing foods have little effect on ciprofloxacin absorption.

Probenecid

Probenecid slows the biliary excretion of ciprofloxacin. Concomitant use of probenecid-containing medicinal products and ciprofloxacin leads to increased plasma concentrations of ciprofloxacin.

Metoclopramide

Metoclopramide accelerates the absorption of ciprofloxacin (after oral administration), resulting in a shorter time to reach maximum plasma concentration. No effect on the bioavailability of ciprofloxacin has been observed.

Omeprazole

Concomitant administration of ciprofloxacin and omeprazole-containing medicinal products results in a slight reduction in Cmax and the area under the concentration-time curve (AUC) of ciprofloxacin.

Effects of ciprofloxacin on other medicinal products

Tizanidine

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 serum tizanidine concentrations are associated with hypotensive and sedative adverse reactions. Therefore, concomitant use of ciprofloxacin and tizanidine-containing medicinal products is contraindicated (see section "Contraindications").

Theophylline

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

Other xanthine derivatives

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

Methotrexate

Concomitant administration of ciprofloxacin may impair tubular transport (renal metabolism) of methotrexate, potentially leading to increased plasma methotrexate concentrations. This may increase the risk of methotrexate-induced toxic adverse reactions. Therefore, concomitant use of ciprofloxacin and methotrexate is not recommended.

Nonsteroidal anti-inflammatory drugs (NSAIDs)

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

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 concentrations have been observed during concomitant administration of ciprofloxacin and cyclosporine. Therefore, frequent monitoring of serum creatinine levels (twice weekly) is required in such patients.

Vitamin K antagonists

Concomitant administration of ciprofloxacin and vitamin K antagonists may enhance the anticoagulant effect of ciprofloxacin. The degree of risk may vary depending on the type of infection, age, and general condition of the patient, making it difficult to precisely assess the impact of ciprofloxacin on the 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, or fluindione).

Glibenclamide

In individual cases, concomitant administration of ciprofloxacin and glibenclamide-containing medicinal products may enhance the effect of glibenclamide (hypoglycemia).

Duloxetine

Clinical studies have shown that concomitant administration of duloxetine and potent inhibitors of the CYP450 1A2 enzyme (e.g., fluvoxamine) may increase the AUC and Cmax of duloxetine. Despite the lack of clinical data on interaction with ciprofloxacin, potential interaction with concomitant use of ciprofloxacin and duloxetine cannot be excluded (see section "Special warnings and precautions for use").

Ropinirole

Clinical studies have shown that concomitant administration of ropinirole with ciprofloxacin, a moderate inhibitor of the 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 coadministration with ciprofloxacin (see section "Special warnings and precautions for use").

Lidocaine

Studies in healthy volunteers have shown that concomitant administration of lidocaine-containing medicinal products and ciprofloxacin, a moderate inhibitor of the CYP450 1A2 isoenzyme, reduces the clearance of intravenously administered lidocaine by 22%. Although lidocaine is generally well tolerated, some interaction may occur after concomitant use with ciprofloxacin, potentially leading to adverse reactions.

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 warnings and precautions for use").

Sildenafil

Studies in healthy volunteers have shown that Cmax and AUC of sildenafil increase approximately twofold after oral administration of 50 mg sildenafil together with 500 mg ciprofloxacin. Therefore, concomitant administration of ciprofloxacin and sildenafil should be done with caution, and the risk-benefit ratio should be carefully evaluated.

Agomelatine

Clinical studies have demonstrated that fluvoxamine, a potent inhibitor of the CYP450 1A2 isoenzyme, markedly inhibits the metabolism of agomelatine, resulting in a 60-fold increase in agomelatine exposure. Although clinical data on potential interaction with ciprofloxacin, a moderate inhibitor of CYP450 1A2, are lacking, similar effects may be expected with concomitant use.

Zolpidem

Concomitant administration with ciprofloxacin may increase blood levels of zolpidem; therefore, concomitant use 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 with ciprofloxacin in such patients should be initiated only if there are no alternative treatment options and after careful benefit/risk assessment.

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

For treatment of severe infections, infections caused by staphylococci or anaerobic bacteria, ciprofloxacin should be used in combination with appropriate antibacterial agents.

Pneumococci

Ciprofloxacin is not recommended for the treatment of pneumococcal infections due to insufficient efficacy against Streptococcus pneumoniae.

Genital tract infections

Genital tract infections may be caused by fluoroquinolone-resistant isolates of Neisseria gonorrhoeae. If infection with N. gonorrhoeae is suspected or confirmed, it is particularly important to obtain information on resistance levels to ciprofloxacin and to confirm susceptibility based on laboratory test results.

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. Prescribers are advised to consider the local prevalence of E. 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-term treatment. This should be taken into account given the increasing resistance of E. 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 of relevant microorganisms to ciprofloxacin in the visited countries should be considered.

Bone and joint infections

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

Pulmonary form of anthrax

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

Cardiac disorders

Ciprofloxacin has been associated with QT interval prolongation on electrocardiogram (see section "Adverse reactions"). Ciprofloxacin should be used with caution in combination with medicinal products that may induce QT prolongation (e.g., class Ia or III antiarrhythmics), and in patients with risk factors for such conditions (e.g., history of QT prolongation, uncorrected hypokalemia).

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

Therefore, fluoroquinolones, including ciprofloxacin, should be used with caution in these patient groups.

Aortic aneurysm and dissection

Epidemiological studies suggest an increased risk of aortic aneurysm and dissection following fluoroquinolone use, particularly in elderly patients.

Thus, fluoroquinolones should be used only after careful benefit/risk assessment and consideration of alternative therapies in patients with a positive family history of aneurysmal disease, or in patients diagnosed with aortic aneurysm and/or dissection, or in patients with risk factors or conditions predisposing to aneurysm and dissection (e.g., Marfan syndrome, Ehlers-Danlos vascular type, Takayasu arteritis, giant cell arteritis, Behçet’s disease, arterial hypertension, known atherosclerosis).

Patients should be advised to seek immediate medical attention in emergency departments if sudden abdominal, chest, or back pain occurs.

Children

Like other drugs in this class, ciprofloxacin may cause arthropathy in weight-bearing joints in young animals.

Safety data from a randomized, double-blind study of ciprofloxacin use in children aged 1 to 17 years showed an incidence of arthropathy likely related to drug use (distinct from clinical signs and symptoms directly related to joint involvement) of 7.2% and 4.6% in the treatment and comparator groups, respectively, on day 42. The incidence of drug-related arthropathy at one year was 9% and 5.7%, respectively. The increase in arthropathy cases related to drug use 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.

The use of ciprofloxacin for other indications, apart from treatment of pulmonary complications caused by Pseudomonas aeruginosa in children with cystic fibrosis (patients aged 5–17 years), complicated urinary tract infections and pyelonephritis caused by E. coli (patients aged 1–17 years), and post-exposure anthrax, has not been studied. Clinical experience with ciprofloxacin use in children for other indications is limited.

Other specific severe infections

The use of ciprofloxacin 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 proven ineffective.

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

Hypersensitivity to the drug

In some cases, hypersensitivity and allergic reactions may occur after the first dose of ciprofloxacin, and this should be reported to a physician immediately.

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

Gastrointestinal tract

Patients should inform their physician if severe and persistent diarrhea develops during or after treatment, as this symptom may indicate a serious gastrointestinal disorder (e.g., pseudomembranous colitis, potentially fatal), requiring immediate treatment. In such cases, ciprofloxacin should be discontinued and appropriate therapy initiated (e.g., oral vancomycin 4 x 250 mg/day). Medicinal products that inhibit peristalsis are contraindicated.

Transient increases in transaminase and alkaline phosphatase activity or cholestatic jaundice may occur, particularly in patients with pre-existing liver damage.

Musculoskeletal system

Generally, ciprofloxacin should not be used in patients with tendon disorders or history of tendon disorders associated with quinolone use. Nevertheless, 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 its use. Tendinitis and tendon rupture (not limited to the Achilles tendon), sometimes bilateral, may occur within 48 hours of starting quinolone 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 corticosteroids. 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 considered. The affected limb(s) should be appropriately managed (e.g., immobilization). Corticosteroids should not be used if signs of tendinopathy occur.

Visual disorders

If visual impairment or any ocular effects occur, medical advice should be sought.

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").

Nervous system

Patients with epilepsy or a history of central nervous system disorders (e.g., lowered seizure threshold, history of seizures, reduced cerebral blood flow, structural brain changes, or stroke) should only take ciprofloxacin if the expected benefit outweighs the potential risk, as these patients are at higher risk for central nervous system-related adverse reactions.

Sometimes, central nervous system adverse reactions may occur after the first dose of ciprofloxacin. In rare cases, depression or psychosis may progress to life-threatening conditions. In such cases, ciprofloxacin should be discontinued immediately and a physician notified.

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 taking ciprofloxacin. Ciprofloxacin should be discontinued in patients experiencing symptoms of neuropathy, including pain, burning, tingling, numbness, and/or weakness, to prevent irreversible conditions (see section "Adverse reactions").

Dysglycemia

As with other quinolones, disturbances in blood glucose levels, including both hypoglycemia and hyperglycemia, have been reported, usually in diabetic patients receiving concomitant treatment with oral hypoglycemic agents (e.g., glibenclamide) or insulin. Cases of hypoglycemic coma have been reported. Close monitoring of blood glucose levels is recommended in diabetic patients (see section "Adverse reactions").

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 impaired renal function according to the instructions in the "Dosage and administration" section to avoid increased frequency of adverse reactions due to ciprofloxacin accumulation.

Hepatobiliary system.

Cases of hepatic necrosis and life-threatening liver failure have been reported with ciprofloxacin use (see section "Adverse reactions"). If any signs or symptoms of liver disease occur (e.g., anorexia, jaundice, dark urine, pruritus, or abdominal wall tension), 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 potential benefit outweighs the potential risk. In such cases, monitoring for possible hemolysis is advised.

Resistance.

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

Metotrexate.

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

Skin and subcutaneous tissue

Ciprofloxacin has been shown to cause photosensitivity reactions; therefore, patients taking ciprofloxacin should avoid intense sunlight or ultraviolet radiation. If photosensitivity reactions occur (e.g., sunburn-like reactions), ciprofloxacin therapy should be discontinued.

Cytochrome P450

Ciprofloxacin is known to be a moderate inhibitor of cytochrome P450 1A2 enzymes. Caution should be exercised when ciprofloxacin is used concomitantly with drugs metabolized via the same enzymatic pathway (e.g., theophylline, methylxanthines, caffeine, duloxetine, clozapine). Increased serum concentrations of these drugs due to inhibition of their metabolic clearance by ciprofloxacin may lead to specific adverse effects.

Effect on laboratory test results

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

Use during pregnancy or breastfeeding.

Pregnancy.

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

Lactation period. Ciprofloxacin passes into 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 or operating machinery.

Fluoroquinolones, including ciprofloxacin, may affect a patient's ability to drive or operate machinery due to central nervous system adverse reactions (see section "Adverse reactions").

Method of administration and dosage.

It is necessary to follow official recommendations regarding the proper use of antibacterial agents.

Dosing regimen

If not otherwise prescribed, the recommended daily doses indicated in the table below should be followed.

For adults

Additional information regarding specific patient groups

Children

In children, if administration of this medicinal form is not feasible, other medicinal forms with appropriate dosing should be used.

• Exacerbations of cystic fibrosis and bronchopulmonary infections caused by Pseudomonas aeruginosa in patients with cystic fibrosis.

Available clinical and pharmacokinetic data support the use of ciprofloxacin for the treatment of pulmonary exacerbations caused by Pseudomonas aeruginosa in children and adolescents with cystic fibrosis (patients aged 5 to 17 years), for the treatment of pulmonary complications of cystic fibrosis caused by Pseudomonas aeruginosa (experience limited to children aged 5 to 17 years), at a dose of 20 mg ciprofloxacin/kg body weight orally once daily (maximum daily dose – 1500 mg ciprofloxacin).

• Complicated urinary tract infections and pyelonephritis.

For complicated urinary tract infections and pyelonephritis, the dose is 20 mg ciprofloxacin/kg body weight orally once daily, but not exceeding the maximum dose of 750 mg.

Dosing regimen for elderly patients (> 65 years of age)

When treating elderly patients, the lowest possible doses of ciprofloxacin should be used, depending on the severity of the disease and creatinine clearance.

Dosing regimen in renal or hepatic impairment

Adults

• Renal function impairment.
  • With creatinine clearance of 30 to 60 mL/min/1.73 m² (moderate renal impairment) or plasma creatinine concentration of 1.4 to 1.9 mg/100 mL, the maximum oral daily dose of ciprofloxacin should be 1000 mg per day.
  • With creatinine clearance below 30 mL/min/1.73 m² (severe renal impairment) or plasma creatinine concentration equivalent to or above 2 mg/100 mL, the maximum oral daily dose of ciprofloxacin should be 500 mg per day.
• Renal impairment and hemodialysis.
  • With creatinine clearance of 30 to 60 mL/min/1.73 m² (moderate renal impairment) or plasma creatinine concentration of 1.4 to 1.9 mg/100 mL, the maximum oral daily dose of ciprofloxacin should be 1000 mg per day.
  • With creatinine clearance below 30 mL/min/1.73 m² (severe renal impairment) or plasma creatinine concentration equivalent to or above 2 mg/100 mL, the maximum oral daily dose of ciprofloxacin should be 500 mg per day.
• Renal impairment and chronic ambulatory peritoneal dialysis:
  • Oral administration of ciprofloxacin in prolonged-release film-coated tablets at a dose of 1 tablet of 500 mg ciprofloxacin.
• Hepatic impairment.
  • Dose adjustment is not required.

There is no experience with the use of the drug in children with renal or hepatic impairment.

Method of administration

Prolonged-release film-coated tablets of ciprofloxacin should be swallowed whole without chewing and taken with a small amount of liquid.

Prolonged-release film-coated tablets of ciprofloxacin may be taken independently of food intake.

Administration on an empty stomach accelerates absorption of the active substance. In this case, prolonged-release film-coated tablets of ciprofloxacin should not be taken simultaneously with dairy products or mineral-fortified beverages (such as milk, yogurt, or calcium-fortified orange juice). However, dietary calcium does not significantly affect ciprofloxacin absorption.

In severe disease or for other reasons (e.g., if the patient is receiving enteral nutrition), when oral administration of ciprofloxacin tablets is not possible, it is recommended to switch to the injectable form of ciprofloxacin. After administration of the injectable form, treatment may be continued with ciprofloxacin tablets.

Duration of treatment

The duration of treatment is determined by the physician depending on the severity of the disease, clinical course, and bacteriological profile. It is important to continue treatment for at least 2 days after normalization of body temperature or disappearance of clinical symptoms. The average duration of treatment is:

• 1 day for acute uncomplicated gonorrhea and cystitis;
• up to 7 days for kidney, urinary tract, and intra-abdominal infections;
• in immunocompromised patients, treatment should continue throughout the period of neutropenia;
• in osteomyelitis, the treatment course may last up to 2 months;
• 7–14 days for all other infections;
• the total duration of treatment for pulmonary anthrax (post-exposure) with ciprofloxacin (intravenous or oral) is 60 days.

For infections caused by streptococci, treatment should continue for at least 10 days to prevent the risk of late complications.

For infections caused by Chlamydia, the treatment course should also last at least 10 days.

Children

• Complications of cystic fibrosis

For pulmonary complications of cystic fibrosis caused by Pseudomonas aeruginosa in children (aged 5 to 17 years), the duration of treatment is 10–14 days.

• Complicated urinary tract infections or pyelonephritis

For complicated urinary tract infections or pyelonephritis caused by Escherichia coli, the treatment course lasts 10–21 days.

For the treatment of pulmonary anthrax (post-exposure), the risk-benefit ratio supports the use of ciprofloxacin in pediatric patients.

Children.

Ciprofloxacin may be used in children as a second- or third-line agent for the treatment of complicated urinary tract infections and pyelonephritis caused by Escherichia coli (age of children treated in clinical trials ranged from 1 to 17 years), as well as for the treatment of pulmonary complications caused by Pseudomonas aeruginosa in children with cystic fibrosis (age of children treated in clinical trials ranged from 5 to 17 years).

Ciprofloxacin should be prescribed only after careful risk-benefit assessment due to the potential for adverse effects on joints and/or periarticular tissues.

Treatment of children in clinical trials was conducted only for the above-mentioned indications. Clinical experience with ciprofloxacin in children for other indications is limited.

This medicinal form (prolonged-release tablets) may be used in children only if dosing according to body weight is feasible.

Overdose.

Cases of overdose with ingestion of 12 g of the drug have been reported to cause symptoms of moderate toxicity. Acute overdose with a dose of 16 g led to 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, 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.

Infections and infestations:

candidiasis – uncommon;

antibiotic-associated colitis – rare, very rare – with fatal outcome.

Blood and lymphatic system disorders:

eosinophilia – uncommon;

leukopenia, anemia, neutropenia, leukocytosis, thrombocytopenia, thrombocytosis – rare;

hemolytic anemia, agranulocytosis, pancytopenia (life-threatening), bone marrow suppression (life-threatening) – very rare.

Immune system disorders:

allergic reactions, allergic/angioneurotic edema – rare;

anaphylactoid reactions, anaphylactic shock (life-threatening), and serum sickness-like reactions – very rare.

Psychiatric disorders*:

psychomotor agitation/anxiety – uncommon;

confusion and disorientation, restlessness, increased drowsiness, depression (which may lead to suicidal thoughts and behavior), hallucinations – rare;

psychoses – very rare.

Mania, including hypomania – frequency not known.

Nervous system disorders*:

headache, dizziness, sleep disorders, taste disturbances – uncommon;

paraesthesia, dysaesthesia, hypoesthesia, tremor, seizures, vertigo – rare;

migraine, coordination disturbances, olfactory disturbances, hyperesthesia, and intracranial hypertension – very rare;

peripheral neuropathy and polyneuropathy – frequency unknown.

Eye disorders*:

visual disturbances (e.g. diplopia, visual anomalies, chromatopsia) – rare;

color vision disturbances – very rare.

Ear and labyrinth disorders*:

tinnitus, deafness – rare;

hearing disturbances – very rare.

Cardiac disorders:

tachycardia – rare;

vasodilation, decreased blood pressure, syncope – rare;

vasculitis – very rare;

QT interval prolongation, ventricular arrhythmia, bidirectional ventricular tachycardia – frequency unknown.

Respiratory system disorders:

dyspnea (including asthmatic conditions) – rare.

Gastrointestinal disorders:

anorexia – uncommon;

nausea, diarrhea – common;

vomiting, bitter taste in mouth, epigastric pain, dyspeptic disorders, flatulence, antibiotic-associated colitis (very rare – with fatal outcome) – uncommon;

pancreatitis – very rare.

Endocrine disorders: hyperglycemia, hypoglycemia (cases of hypoglycemic coma);

syndrome of inappropriate secretion of antidiuretic hormone.

Hepatobiliary disorders:

transient increase in transaminase levels, hyperbilirubinemia – uncommon;

liver function abnormalities, jaundice, hepatitis (non-infectious) – rare;

liver necrosis (very rarely progressing to life-threatening liver failure) – very rare.

Skin and subcutaneous tissue disorders:

rash (petechial, maculopapular, urticarial, etc.), pruritus, urticaria – uncommon;

photosensitivity reactions, appearance of non-specific blisters – rare;

petechiae, erythema multiforme, nodular erythema, Stevens-Johnson syndrome, and toxic epidermal necrolysis – very rare.

Acute generalized exanthematous pustulosis (AGEP), DRESS syndrome with eosinophilia and systemic manifestations – frequency not known.

Musculoskeletal and connective tissue disorders*:

arthralgia – uncommon;

myalgia, arthritis, increased muscle tone, and seizures – rare;

muscle weakness, tendinitis, tendon rupture (predominantly Achilles tendons), exacerbation of myasthenia symptoms – very rare.

Renal and urinary disorders:

renal function impairment – uncommon;

tubulointerstitial nephritis, renal failure, hematuria, crystalluria – rare.

General disorders and administration site conditions:

non-specific pain syndrome, malaise, weakness, fever – uncommon;

edema, increased sweating (hyperhidrosis) – rare;

gait disturbances – very rare.

Laboratory abnormalities:

elevated liver enzymes (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase), liver function abnormalities, increased serum creatinine and urea levels – uncommon;

prothrombin time abnormalities – rare;

elevated amylase and lipase levels – very rare.

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

Other: pseudotumor cerebri.

Laboratory parameters: uncommon – elevated blood alkaline phosphatase; rare – abnormal prothrombin levels; frequency unknown – elevated international normalized ratio (INR) in patients receiving vitamin K antagonists.

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

Shelf life.

24 months.

Storage conditions.

Store at temperatures not exceeding 25 °C, in a dry place protected from light and inaccessible to children.

Packaging.

5 tablets in a blister pack, 1 blister pack in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Sun Pharmaceutical Industries Limited.

Manufacturer's address and place of business.

1. Industrial Area 3, Dewas - 455001, India.

Industrial Area 3, Dewas, 455001, India.

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

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

Date of last review.