Cirok

White to off-white coloured, capsule-shaped, film-coated tablet. Break-line on one side and plain on the other side.
Each film-coated tablet contains: Ciprofloxacin (as hydrochloride) equivalent to Ciprofloxacin, USP 500 mg.

Pharmacology: Pharmacodynamics: Activity: Ciprofloxacin is a synthetic 4-quinolone derivative antibacterial agent of the fluoroquinolone class.
Mechanism of action: As a fluoroquinolone antibacterial agent, ciprofloxacin acts on the DNA-DNA-gyrase complex and topoisomerase IV.
Pharmacokinetics: Absorption: After oral administration, ciprofloxacin is predominantly absorbed from the duodenum and upper jejunum, and reaches peak serum concentrations within 60-90 min. After single doses of 250 mg and 500 mg C_max values are about 0.8-2.0 mg/1 L and 1.5-2.9 mg/1 L respectively.
The absolute bioavailability is approximately 70 to 80%. C_max- and AUC-values are proportionally increased with the dose.
Food intake has no effect on the plasma concentration profile of ciprofloxacin.
Distribution: The steady-state volume of distribution of ciprofloxacin is 2-3 L/kg. Since the protein binding of ciprofloxacin is low (20-30%) and the substance is predominantly present in the blood plasma in non-ionized form, almost the entire quantity of the administered dose can diffuse freely into the extravasal space. As a result, the concentrations in certain body fluids and tissues may be markedly higher than the corresponding serum concentrations.
Metabolism/Elimination: Ciprofloxacin is essentially excreted in unchanged form, mostly in the urine. Renal clearance lies between 3 and 5 mL/min/kg, and total clearance amounts to 8-10 mL/min/kg. Both glomerular filtration and tubular secretion play a part in the elimination of ciprofloxacin.
Small concentrations of 4 metabolites were found: desethylene ciprofloxacin (M 1), sulphociprofloxacin (M 2), oxociprofloxacin (M 3) and formylciprofloxacin (M 4). M 1 to M 3 show antibacterial activity comparable with or smaller than nalidixic acid. M 4 with the lowest quantity, has an antimicrobial activity very much corresponding to norfloxacin. (See Table 1.)

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The half-life of ciprofloxacin lies between 3 and 5 hours, both after oral and after intravenous administration. Since ciprofloxacin is excreted not only via the kidneys, but also to a major extent via the gut, renal function must be substantially impaired before increases in serum elimination half-life of up to 12 hours are observed.

Indicated for the treatment of the following infections. Special attention should be paid to available information on resistance to ciprofloxacin before commencing therapy.
Consideration should be given to official guidance on the appropriate use of antibacterial agents.
Adults: Lower respiratory tract infections due to gram-negative bacteria: exacerbations of chronic obstructive pulmonary disease; broncho-pulmonary infections in cystic fibrosis or in bronchiectasis; pneumonia.
Chronic suppurative otitis media; Acute exacerbation of chronic sinusitis especially if these are caused by gram-negative bacteria; Urinary tract infections; Genital tract infections.
Gonococcal urethritis and cervicitis due to susceptible Neisseria gonorrhoeae.
Epididymo-orchitis including cases due to susceptible Neisseria gonorrhoeae.
Pelvic inflammatory disease including cases due to susceptible Neisseria gonorrhoeae.
In the previously mentioned genital tract infections when thought or known to be due to Neisseria gonorrhoeae, it is particularly important to obtain local information on the prevalence of resistance to ciprofloxacin and to confirm susceptibility based on laboratory testing.
Infections of the gastro-intestinal tract (e.g. travelers' diarrhoea).
Intra-abdominal infections.
Infections of the skin and soft tissue caused by gram-negative bacteria; Malignant external otitis; Infections of the bones and joints.
Treatment of infections in neutropenic patients.
Prophylaxis of infections in neutropenic patients.
Prophylaxis of invasive infections due to Neisseria meningitides.
Inhalation anthrax (post-exposure prophylaxis and curative treatment).
Ciprofloxacin may be used in the management of neutropenic patients with fever that is suspected to be due to a bacterial infection.
Paediatric population: Broncho-pulmonary infections in cystic fibrosis caused by Pseudomonas aeruginosa.
Complicated urinary tract infections and pyelonephritis.
Inhalation anthrax (post-exposure prophylaxis and curative treatment).
Ciprofloxacin may also be used to treat severe infections in children and adolescents when this is considered to be necessary.
Treatment should be initiated only by physicians who are experienced in the treatment of cystic fibrosis and/or severe infections in children and adolescents.

Posology: The dosage is determined by the indication, the severity and the site of the infection, the susceptibility to ciprofloxacin of the causative organism(s), the renal function of the patient and, in children and adolescents the bodyweight.
The duration of treatment depends on the severity of the illness and on the clinical and bacteriological course. Treatment of infections due to certain bacteria (e.g. Pseudomonas aeruginosa, Acinetobacter or Staphylococci) may require higher ciprofloxacin doses and co-administration with other appropriate antibacterial agents.
Treatment of some infections (e.g. pelvic inflammatory disease, intra-abdominal infections, infections in neutropenic patients and infections of bones and joints) may require co-administration with other appropriate antibacterial agents depending on the pathogens involved.
Adults: See Table 2.

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Paediatric population: See Table 3.

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Elderly Patients: Elderly patients should receive a dose selected according to the severity of the infection and the patient's creatinine clearance.
Renal and hepatic impairment: Recommended starting and maintenance doses for patients with impaired renal function: See Table 4.

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In patients with impaired liver function no dose adjustment is required.
Dosing in children with impaired renal and/or hepatic function has not been studied.
Method of administration: The tablets are to be swallowed unchewed with fluid. They can be taken independent of meal times. If taken on an empty stomach, the active substance is absorbed more rapidly. Ciprofloxacin tablets should not be taken with dairy products (e.g. milk, yoghurt) or mineral-fortified fruit-juice (e.g. calcium-fortified orange juice).
In severe cases or if the patient is unable to take tablets (e.g. patients on enteral nutrition), it is recommended to commence therapy with intravenous ciprofloxacin until a switch to oral administration is possible.

An overdose of 12 g has been reported to lead to mild symptoms of toxicity. An acute overdose of 16 g has been reported to cause acute renal failure.
Symptoms in overdose consist of dizziness, tremor, headache, tiredness, seizures, hallucinations, confusion, abdominal discomfort, renal and hepatic impairment as well as crystalluria and haematuria
Reversible renal toxicity has been reported.
Apart from routine emergency measures, it is recommended to monitor renal function, including urinary pH and acidify, if required, to prevent crystalluria. Patients should be kept well hydrated. Only a small quantity of ciprofloxacin (<10%) is eliminated by haemodialysis or peritoneal dialysis.
In the event of overdose, symptomatic treatment should be implemented. ECG monitoring should be undertaken, because of the possibility of QT interval prolongation.

Hypersensitivity to the active substance, to other quinolones or to any of the excipients.
Concomitant administration of ciprofloxacin and tizanidine.

evere infections and mixed infections with gram-positive and anaerobic pathogens: Ciprofloxacin monotherapy is not suited for treatment of severe infections and infections that might be due to gram-positive or anaerobic pathogens. In such infections ciprofloxacin must be co-administered with other appropriate antibacterial agents.
Streptococcal Infections (including Streptococcus pneumoniae): Ciprofloxacin is not recommended for the treatment of streptococcal infections due to inadequate efficacy.
Genital tract infections: Gonococcal urethritis, cervicitis, epididymo-orchitis and pelvic inflammatory diseases may be caused by fluoroquinolone-resistant Neisseria gonorrhoeae isolates.
Therefore, ciprofloxacin should be administered for the treatment of gonococcal urethritis or cervicitis only if ciprofloxacin-resistant Neisseria gonorrhoeae can be excluded.
For epididymo-orchitis and pelvic inflammatory diseases, empirical ciprofloxacin should be considered in combination with another appropriate antibacterial agent (e.g. a cephalosporin) unless ciprofloxacin-resistant Neisseria gonorrhoeae can be excluded. If clinical improvement is not achieved after 3 days of treatment, the therapy should be reconsidered.
Urinary tract infections: Resistance to fluoroquinolones of Escherichia coli - the most common pathogen involved in urinary tract infections - varies across the European Union. Prescribers are advised to take into account the local prevalence of resistance in Escherichia coli to fluoroquinolones.
The single dose of ciprofloxacin that may be used in uncomplicated cystitis in pre-menopausal women is expected to be associated with lower efficacy than the longer treatment duration. This is all the more to be taken into account as regards the increasing resistance level of Escherichia coli to quinolones.
Intra-abdominal infections: There are limited data on the efficacy of ciprofloxacin in the treatment of post-surgical intra-abdominal infections.
Travellers' diarrhoea: The choice of ciprofloxacin should take into account information on resistance to ciprofloxacin in relevant pathogens in the countries visited.
Infections of the bones and joints: Ciprofloxacin should be used in combination with other antimicrobial agents depending on the results of the microbiological documentation.
lnhalational anthrax: Use in humans is based on in-vitro susceptibility data and on animal experimental data together with limited human data. Treating physicians should refer to national and/or international consensus documents regarding the treatment of anthrax.
Hypersensitivity: Hypersensitivity and allergic reactions, including anaphylaxis and anaphylactoid reactions, may occur following a single dose and may be life-threatening. If such reaction occurs, ciprofloxacin should be discontinued and an adequate medical treatment is required.
Musculoskeletal System: Ciprofloxacin should generally not be used in patients with a history of tendon disease/disorder related to quinolone treatment. Nevertheless, in very rare instances, after microbiological documentation of the causative organism and evaluation of the risk/benefit balance, ciprofloxacin may be prescribed to these patients for the treatment of certain severe infections, particularly in the event of failure of the standard therapy or bacterial resistance, where the microbiological data may justify the use of ciprofloxacin.
Tendinitis and tendon rupture (especially Achilles tendon), sometimes bilateral, may occur with ciprofloxacin, as soon as the first 48 hours of treatment. The risk of tendinopathy may be increased in elderly patients or in patients concomitantly treated with corticosteroids.
At any sign of tendinitis (e.g. painful swelling, inflammation), ciprofloxacin treatment should be discontinued.
Care should be taken to keep the affected limb at rest.
Ciprofloxacin should be used with caution in patients with myasthenia gravis, because symptoms can be aggravated.
Vision disorders: If vision becomes impaired or any effects on the eyes are experienced, an eye specialist should be consulted immediately.
Photosensitivity: Ciprofloxacin has been shown to cause photosensitivity reactions. Patients taking ciprofloxacin should be advised to avoid direct exposure to either extensive sunlight or UV irradiation during treatment.
Central Nervous System: Ciprofloxacin like other quinolones are known to trigger seizures or lower the seizure threshold. Cases of status epilepticus have been reported. Ciprofloxacin should be used with caution in patients with CNS disorders which may be predisposed to seizure. If seizures occur ciprofloxacin should be discontinued. Psychiatric reactions may occur even after the first administration of ciprofloxacin. In rare cases, depression or psychosis can progress to suicidal ideations/thought culminating in attempted suicide or completed suicide. In the occurrence of such cases, ciprofloxacin should be discontinued.
Cases of polyneuropathy (based on neurological symptoms such as pain, burning, sensory disturbances or muscle weakness, alone or in combination) have been reported in patients receiving ciprofloxacin.
Ciprofloxacin should be discontinued in patients experiencing symptoms of neuropathy, including pain, burning, tingling, numbness, and/or weakness in order to prevent the development of an irreversible condition.
Cardiac disorders: Caution should be taken when using fluoroquinolones, including ciprofloxacin, in patients with known risk factors for prolongation of the QT interval such as, for example: Congenital long QT syndrome; concomitant use of drugs that are known to prolong the QT interval (e.g. Class IA and III anti-arrhythmics, tricyclic antidepressants, macrolides, antipsychotics); uncorrected electrolyte imbalance (e.g. hypokalaemia, hypomagnesaemia); cardiac disease (e.g. heart failure, myocardial infarction, bradycardia).
Elderly patients and women may be more sensitive to QTc-prolonging medications. Therefore, caution should be taken when using fluoroquinolones, including ciprofloxacin, in these populations.
Hypoglycaemia: As with other quinolones, hypoglycaemia has been reported most often in diabetic patients, predominantly in the elderly population. In all diabetic patients, careful monitoring of blood glucose is recommended.
Gastrointestinal System: The occurrence of severe and persistent diarrhoea during or after treatment (including several weeks after treatment) may indicate an antibiotic-associated colitis (life-threatening with possible fatal outcome), requiring immediate treatment. In such cases, ciprofloxacin should immediately be discontinued, and an appropriate therapy initiated. Anti-peristaltic drugs are contraindicated in this situation.
Renal and urinary system: Crystalluria related to the use of ciprofloxacin has been reported. Patients receiving ciprofloxacin should be well hydrated and excessive alkalinity of the urine should be avoided.
Impaired renal function: Since ciprofloxacin is largely excreted unchanged via renal pathway dose adjustment is needed in patients with impaired renal function to avoid an increase in adverse drug reactions due to accumulation of ciprofloxacin.
Hepatobiliary system: Cases of hepatic necrosis and life-threatening hepatic failure have been reported with ciprofloxacin. In the event of any signs and symptoms of hepatic disease (such as anorexia, jaundice, dark urine, pruritus, or tender abdomen), treatment should be discontinued.
Glucose-6-phosphate dehydrogenase deficiency: Haemolytic reactions have been reported with ciprofloxacin in patients with glucose-6-phosphate dehydrogenase deficiency. Ciprofloxacin should be avoided in these patients unless the potential benefit is considered to outweigh the possible risk. In this case, potential occurrence of haemolysis should be monitored.
Resistance: During or following a course of treatment with ciprofloxacin bacteria that demonstrate resistance to ciprofloxacin may be isolated, with or without a clinically apparent superinfection. There may be a particular risk of selecting for ciprofloxacin-resistant bacteria during extended durations of treatment and when treating nosocomial infections and/or infections caused by Staphylococcus and Pseudomonas species.
Cytochrome P450: Ciprofloxacin inhibits CYP1A2 and thus may cause increased serum concentration of concomitantly administered substances metabolised by this enzyme (e.g. theophylline, clozapine, olanzapine, ropinirole, tizanidine, duloxetine, agomelatine). Co-administration of ciprofloxacin and tizanidine is contraindicated. Therefore, patients taking these substances concomitantly with ciprofloxacin should be monitored closely for clinical signs of overdose, and determination of serum concentrations (e.g. of theophylline) may be necessary.
Methotrexate: The concomitant use of ciprofloxacin with methotrexate is not recommended.
Interaction with tests: The in-vitro activity of ciprofloxacin against Mycobacterium tuberculosis might give false negative bacteriological test results in specimens from patients currently taking ciprofloxacin.
Effects on ability to drive and use machines: Due to its neurological effects, ciprofloxacin may affect reaction time. Thus, the ability to drive or to operate machinery may be impaired.
Use in Children: The use of ciprofloxacin in children and adolescents should follow available official guidance.
Ciprofloxacin treatment should be initiated only by physicians who are experienced in the treatment of cystic fibrosis and/or severe infections in children and adolescents.
Ciprofloxacin has been shown to cause arthropathy in weight-bearing joints of immature animals. Safety data from a randomised double-blind study on ciprofloxacin use in children (ciprofloxacin: n=335, mean age=6.3 years; comparators: n=349, mean age=6.2 years; age range=1 to 17 years) revealed an incidence of suspected drug-related arthropathy (discerned from joint-related clinical signs and symptoms) by Day +42 of 7.2% and 4.6%. Respectively, an incidence of drug-related arthropathy by 1-year follow-up was 9.0% and 5.7%. The increase of suspected drug-related arthropathy cases over time was not statistically significant between groups. Treatment should be initiated only after a careful benefit/risk evaluation, due to possible adverse events related to joints and/or surrounding tissue.
Broncho-pulmonary infections in cystic fibrosis: Clinical trials have included children and adolescents aged 5-17 years. More limited experience is available in treating children between 1 and 5 years of age.
Complicated urinary tract infections and pyelonephritis: Ciprofloxacin treatment of urinary tract infections should be considered when other treatments cannot be used, and should be based on the results of the microbiological documentation. Clinical trials have included children and adolescents aged 1-17 years.
Other specific severe infections: Other severe infections in accordance with official guidance, or after careful benefit-risk evaluation when other treatments cannot be used, or after failure to conventional therapy and when the microbiological documentation can justify ciprofloxacin use.
The use of ciprofloxacin for specific severe infections other than those previously mentioned has not been evaluated in clinical trials and the clinical experience is limited. Consequently, caution is advised when treating patients with these infections.

Pregnancy: The data that are available on administration of ciprofloxacin to pregnant women indicates no malformative or foeto/neonatal toxicity of ciprofloxacin. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. In juvenile and prenatal animals exposed to quinolones, effects on immature cartilage have been observed, thus, it cannot be excluded that the drug could cause damage to articular cartilage in the human immature organism/foetus.
As a precautionary measure, it is preferable to avoid the use of ciprofloxacin during pregnancy.
Lactation: Ciprofloxacin is excreted in breast milk. Due to the potential risk of articular damage, ciprofloxacin should not be used during breast-feeding.

Summary of the safety profile: The most commonly reported adverse drug reactions (ADRs) are nausea and diarrhoea.
Tabulated list of adverse reactions: ADRs derived from clinical studies and post-marketing surveillance with Ciprofloxacin (oral, intravenous, and sequential therapy) sorted by categories of frequency are listed as follows. The frequency analysis takes into account data from both oral and intravenous administration of ciprofloxacin. (See Table 5.)

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Paediatric population: The incidence of arthropathy, as previously mentioned, is referring to data collected in studies with adults. In children, arthropathy is reported to occur commonly.

Effects of other products on ciprofloxacin: Drugs known to prolong QT interval: Ciprofloxacin, like other fluoroquinolones, should be used with caution in patients receiving drugs known to prolong QT interval (e.g. Class IA and Ill anti-arrhythmics, tricyclic antidepressants, macrolides, antipsychotics).
Chelation Complex Formation: The simultaneous administration of ciprofloxacin (oral) and multivalent cation-containing drugs and mineral supplements (e.g. calcium, magnesium, aluminium, iron), polymeric phosphate binders (e.g. sevelamer), sucralfate or antacids, and highly buffered drugs (e.g. didanosine tablets) containing magnesium, aluminium, or calcium reduces the absorption of ciprofloxacin. Consequently, ciprofloxacin should be administered either 1-2 hours before or at least 4 hours after these preparations. The restriction does not apply to antacids belonging to the class of H2 receptor blockers.
Food and Dairy Products: Dietary calcium as part of a meal does not significantly affect absorption. However, the concurrent administration of dairy products or mineral-fortified drinks alone (e.g. milk, yoghurt, calcium-fortified orange juice) with ciprofloxacin should be avoided because absorption of ciprofloxacin may be reduced.
Probenecid: Probenecid interferes with renal secretion of ciprofloxacin. Co-administration of probenecid and ciprofloxacin increases ciprofloxacin serum concentrations.
Metoclopramide: Metoclopramide accelerates the absorption of ciprofloxacin (oral) resulting in a shorter time to reach maximum plasma concentrations. No effect was seen on the bioavailability of ciprofloxacin.
Omeprazole: Concomitant administration of ciprofloxacin and omeprazole containing medicinal products results in a slight reduction of C_max and AUC of ciprofloxacin.
Effects of ciprofloxacin on other medicinal products: Tizanidine: Tizanidine must not be administered together with ciprofloxacin. In a clinical study with healthy subjects, there was an increase in serum tizanidine concentration (C_max increase: 7-fold, range: 4 to 21-fold; AUC increase: 10-fold, range: 6 to 24-fold) when given concomitantly with ciprofloxacin. Increased serum tizanidine concentration is associated with a potentiated hypotensive and sedative effect.
Methotrexate: Renal tubular transport of methotrexate may be inhibited by concomitant administration of ciprofloxacin, potentially leading to increased plasma levels of methotrexate and increased risk of methotrexate-associated toxic reactions. The concomitant use is not recommended.
Theophylline: Concurrent administration of ciprofloxacin and theophylline can cause an undesirable increase in serum theophylline concentration. This can lead to theophylline-induced side effects that may rarely be life threatening or fatal. During the combination, serum theophylline concentrations should be checked and the theophylline dose reduced as necessary.
Other xanthine derivatives: On concurrent administration of ciprofloxacin and caffeine or pentoxifylline (oxpentifylline), raised serum concentrations of these xanthine derivatives were reported.
Phenytoin: Simultaneous administration of ciprofloxacin and phenytoin may result in increased or reduced serum levels of phenytoin such that monitoring of drug levels is recommended.
Ciclosporin: A transient rise in the concentration of serum creatinine was observed when ciprofloxacin and ciclosporin containing medicinal products were administered simultaneously. Therefore, it is frequently (twice a week) necessary to control the serum creatinine concentrations in these patients.
Vitamin K antagonists: Simultaneous administration of ciprofloxacin with a vitamin K antagonist may augment its anti-coagulant effects. There have been many reports of increases in oral anticoagulant activity in patients receiving antibacterial agents, including fluoroquinolones. The risk may vary with the underlying infection, age and general status of the patient so that the contribution of the fluoroquinolone to the increase in INR (international normalised ratio) is difficult to assess. It is recommended that the INR should be monitored frequently during and shortly after co-administration of ciprofloxacin with a vitamin k antagonist (e.g. warfarin, acenocoumarol, phenprocoumon or fluindione).
Duloxetine: In clinical studies, it was demonstrated that concomitant use of duloxetine with strong inhibitors of the CYP450 1A2 isozyme such as fluvoxamine, may result in an increase of AUC and C_max of duloxetine. Although no clinical data are available on a possible interaction with ciprofloxacin, similar effects can be expected upon concomitant administration.
Ropinirole: It was shown in a clinical study that concomitant use of ropinirole with ciprofloxacin, a moderate inhibitor of the CYP450 1A2 isozyme, results in an increase of C_max and AUC of ropinirole by 60% and 84%, respectively. Monitoring of ropinirole-related side effects and dose adjustment as appropriate is recommended during and shortly after co-administration with ciprofloxacin.
Lidocaine: It was demonstrated in healthy subjects that concomitant use of lidocaine containing medicinal products with ciprofloxacin, a moderate inhibitor of CYP450 1A2 isozyme, reduces clearance of intravenous lidocaine by 22%. Although lidocaine treatment was well tolerated, a possible interaction with ciprofloxacin associated with side effects may occur upon concomitant administration.
Clozapine: Following 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 surveillance and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
Sevelamer: The bioavailability of ciprofloxacin is reduced by the concomitant administration with sevelamer (up to 50%), therefore, it is recommended that the two should not be taken concomitantly.
Sildenafil: C_max and AUC of sildenafil were increased approximately twofold in healthy subjects after an oral dose of 50 mg given concomitantly with 500 mg ciprofloxacin. Therefore, caution should be used prescribing ciprofloxacin concomitantly with sildenafil taking into consideration the risks and the benefits.
Agomelatine: In clinical studies, it was demonstrated that fluvoxamine, as a strong inhibitor of the CYP450 1A2 isoenzyme, markedly inhibits the metabolism of agomelatine resulting in a 60-fold increase of agomelatine exposure. Although no clinical data are available for a possible interaction with ciprofloxacin, a moderate inhibitor of CYP450 1A2, similar effects can be expected upon concomitant administration (see Cytochrome P450 under Precautions).
Zolpidem: Co-administration of ciprofloxacin may increase blood levels of zolpidem; concurrent use is not recommended.

Store at temperatures not exceeding 30°C.

Quinolones

J01MA02 - ciprofloxacin ; Belongs to the class of fluoroquinolones. Used in the systemic treatment of infections.

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