Ciproted

White coloured, oblong, biconvex film-coated tablet having a break line mark on one side and plain on other side of each tablet.
Each film-coated tablet contains: Ciprofloxacin (as Hydrochloride) equivalent to Ciprofloxacin USP 500 mg, Excipients q.s.

Pharmacotherapeutic group: Fluoroquinolones.
Pharmacology: Pharmacodynamics: Mechanism of Action: As a fluoroquinolones antibacterial agent, the bactericidal action of ciprofloxacin results from the inhibition of both type II topoisomerase (DNA-gyrase) and topoisomerase IV, required for bacterial DNA replication, transcription, repair and recombination.
PK/PD relationship: Efficacy mainly depends on the relation between the maximum concentration in serum (C_max) and the minimum inhibitory concentration (MIC) of ciprofloxacin for a bacterial pathogen and the relation between the area under the curve (AUC) and the MIC.
Mechanism of resistance: In-vitro resistance to ciprofloxacin can be acquired through a stepwise process by target site mutations in both DNA gyrase and topoisomerase IV. The degree of cross-resistance between ciprofloxacin and other fluoroquinolones that results is variable. Single mutations may not result in clinical resistance, but multiple mutations generally result in clinical resistance to many or all active substances within the class.
Impermeability and/or active substance efflux pump mechanisms of resistance may have a variable effect on the susceptibility to fluoroquinolones, which depends on physiochemical properties of the various active substances within the class and the affinity of transport systems for each active substance. All in-vitro mechanisms of resistance are commonly observed in clinical isolates. Resistance mechanisms that inactivate other antibiotics such as permeation barriers (common in Pseudomonas aeruginosa) and efflux mechanisms may affect susceptibility to ciprofloxacin.
Plasmid mediated resistance encoded by qnr-genes has been reported.
Pharmacokinetics: Ciprofloxacin is rapidly absorbed from the gastrointestinal tract. Oral bioavailability is approximately 70% and a peak plasma concentration of about 2.5 mcg per mL is achieved 1 to 2 hours after a dose of 500 mg by mouth. Absorption may be delayed by the presence of food, but is not substantially affected overall. The plasma half-life is about 3.5 to 4.5 hours. Plasma protein binding ranges from 20 to 40%. Ciprofloxacin is eliminated by urinary excretion. Excretion is virtually complete within 24 hours; about 40 to 50% of an oral dose is excreted unchanged in the urine and about 15% as metabolites.

Used in the treatment of a wide range of infections including anthrax, biliary-tract infections, infected bites and stings, bone and joint infections, brucellosis, cat scratch disease, chancroid, exacerbations of cystic fibrosis, gastro-enteritis, gonorrhea, neutropenia, legionnaires' disease, otitis externa, otitis media, peritonitis, Q fever, lower respiratory tract infections, septicemia, skin infections, spotted fevers, surgical infection prophylaxis, typhoid and paratyphoid fever, typus and urinary tract infection. It is also used for meningococcal meningitis prophylaxis.

Adult dosage: 250 mg to 750 mg twice daily depending on the severity and nature of infection.
For the treatment of gonorrhoea: A single oral dose of 250 mg or 500 mg is recommended, depending upon patterns of resistance.
For meningococcal meningitis prophylaxis: A single oral dose of 500 mg is suggested.
For surgical infection prophylaxis: A single dose of 750 mg given 60 to 90 minutes before the procedure. Or as prescribed by the physician.

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 of overdose may include dizziness, tremor, headaches, tiredness, seizures, hallucinations, confusion, abdominal discomfort, renal and hepatic impairment as well as crystalluria and hematuria. Reversible renal toxicity has been reported.
Apart from routine emergency measures e.g. ventricular emptying followed by medical carbon, it is recommended to monitor renal function, including urinary pH and acidify, if required, to prevent crystalluria. Patients should be kept well hydrated.
Calcium or magnesium containing antacids may theoretically reduce the absorption of ciprofloxacin in overdoses.
Only a small quantity of ciprofloxacin (<10%) is eliminated by hemodialysis 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.

The use of ciprofloxacin should be avoided in patients who have experienced serious adverse reactions in the past when using quinolone or fluoroquinolone containing products. Treatment of these patients with ciprofloxacin should only be initiated in the absence of alternative treatment options and after careful benefit/risk assessment.
Prolonged, disabling and potentially irreversible serious adverse drug reactions.
Very rare cases of prolonged (continuing months or years), disabling and potentially irreversible serious adverse drug reactions affecting different, sometimes multiple, body systems (musculoskeletal, nervous, psychiatric and senses) have been reported in patients receiving quinolones and fluoroquinolones irrespective of their age and pre-existing risk factors. Ciprofloxacin should be discontinued immediately at the first signs or symptoms of any adverse reaction and patients should be advised to contact their prescriber for advice.
Severe 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 coadministered with other appropriate antibacterial agents.
Streptococcal Infections (including Streptococcus pneumonia).
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 disease may be caused by fluoroquinolones-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 only 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.
Travelers' diarrhea: 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.
Inhalational 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.
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 in 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 guidelines, 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 a ciprofloxacin use.
The use of ciprofloxacin for specific severe infections other than those mentioned previously has not been evaluated in clinical trials and the clinical experience is limited. Consequently, caution is advised when treating patients with these infections.
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 required.
Tendinitis and tendon rupture: 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 microbiological data may justify the use of ciprofloxacin.
Tendinitis and tendon rupture (especially but not limited to Achilles tendon), sometimes bilateral, may occur as early as within 48 hours of starting treatment with quinolones and fluoroquinolones and have been reported to occur even up to several months after discontinuation of treatment. The risk of tendinitis and tendon rupture is increased in older patients, patients with renal impairment, patients with solid organ transplants, and those treated concurrently with corticosteroids. Therefore, concomitant use of corticosteroids should be avoided.
At the first sign of tendinitis (e.g. painful swelling, inflammation), the treatment with ciprofloxacin should be discontinued and alternative treatment should be considered. The affected limb(s) should be appropriately treated (e.g. immobilisation). Corticosteroids should not be used if signs of tendinopathy occur.
Ciprofloxacin should be used with caution in patients with myasthenia gravis because symptoms can be exacerbated.
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/thoughts culminating in attempted suicide or completed suicide. In the occurrence of such cases, ciprofloxacin should be discontinued.
Peripheral neuropathy: Cases of sensory or sensorimotor polyneuropathy resulting in paraesthesia, hypaesthesia, dysesthesia, or weakness have been reported in patients receiving quinolones and fluoroquinolones. Patients under treatment with ciprofloxacin should be advised to inform their doctor prior to continuing treatment if symptoms of neuropathy such as pain, burning, tingling, numbness, or weakness develop in order to prevent the development of potentially 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. hypokalemia, hypomagnesemia); 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.
Aortic aneurysm and dissection, and heart valve regurgitation/incompetence: Epidemiologic studies report an increased risk of aortic aneurysm and dissection, particularly in elderly patients, and of aortic and mitral valve regurgitation after intake of fluoroquinolones. Cases of aortic aneurysm and dissection, sometimes complicated by rupture (including fatal ones), and of regurgitation/incompetence of any of the heart valves have been reported in patients receiving fluoroquinolones.
Therefore, fluoroquinolones should only be used after careful benefit-risk assessment and after consideration of other therapeutic options in patients with positive family history of aneurysm disease or congenital heart valve disease, or in patients diagnosed with pre-existing aortic aneurysm and/or aortic dissection or heart valve disease, or in presence of other risk factors or conditions predisposing.
For both aortic aneurysm and dissection and heart valve regurgitation/incompetence (e.g. connective tissue disorders such as Marfan syndrome or Ehlers-Danlos syndrome, Turner syndrome, Behcet's disease, hypertension, rheumatoid arthritis) or additionally; for heart valve regurgitation/incompetence (e.g. infective endocarditis).
The risk of aortic aneurysm and dissection, and their rupture may also be increased in patients treated concurrently with systemic corticosteroids.
In case of sudden abdominal, chest or back pain, patients should be advised to immediately consult a physician in an emergency department.
Patients should be advised to seek immediate medical attention in case of acute dyspnea, new onset of heart palpitations, or development of edema of the abdomen or lower extremities.
Dysglycemia: As with other quinolones, disturbances in blood glucose, including both hypoglycemia and hyperglycemia have been reported, usually in diabetic patients receiving concomitant treatment with an oral hypoglycemic agent (e.g. glibenclamide) or with insulin. Cases of hypoglycemic coma have been reported. In diabetic patients, careful monitoring of blood glucose is recommended.
Gastrointestinal System: The occurrence of severe and persistent diarrhea 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: Hemolytic 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 metabolized 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.
Vision disorders: If vision becomes impaired or any effects on the eyes are experienced, an eye specialist should be consulted immediately.
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.

Pregnancy: The data that are available on administration of ciprofloxacin to pregnant women indicates no malformative or feto/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/fetus.
As a precautionary measure, it is preferable to avoid the use of ciprofloxacin during pregnancy.
Breastfeeding: Ciprofloxacin is excreted in breast milk. Due to the potential risk of articular damage, ciprofloxacin should not be used during breast-feeding.

The most commonly reported adverse reactions (ADRs) are nausea and diarrhea. (See table.)

Click on icon to see table/diagram/image

Pediatric patients: The incidence of arthropathy, mentioned previously, 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 or III antiarrhythmics, 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 or lanthanum carbonate), 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 the preparation.
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. Coadministration 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 (oxpentiphylline), 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.
Cyclosporin: A transient rise in the concentration of serum creatinine was observed when ciprofloxacin and cyclosporin 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 anticoagulant effects. The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. The INR should be monitored frequently during and shortly after coadministration 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 coadministration 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.
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 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.
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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