Ciprofloxacin 750mg Film-Coated Tablets

Each Ciprofloxacin 750mg Tablet contains 873.3mg ciprofloxacin hydrochloride equivalent to 750mg Ciprofloxacin (INN).

For a full list of excipients, see section 6.1.

Film-coated Tablets.

Ciprofloxacin 750mg Tablets are white to off-white, oblong shape, biconvex with beveled edge, film coated tablet with inscription 'CJ' on one side and plain on the other side.

Ciprofloxacin are indicated for the treatment of the following infections (see sections 4.4 and 5.1). 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:

Treatment of infections caused by ciprofloxacin-sensitive pathogens such as:

• Lower Respiratory Tract Infections:- due to gram-negative pathogens

-pneumonia.

-exacerbations of chronic obstructive pulmonary disease

-broncho-pulmonary infections in cystic fibrosis or in bronchiectasis

• Upper Respiratory tract infections:-.

-Chronic suppurative otitis media

-Acute exacerbation of chronic sinusitis especially if these are caused by Gram-negative bacteria

-Malignant external otitis

• Urinary tract infections, including acute uncomplicated cystitis, complicated infections and pyelonephritis.

• Genital organs infections, including acute uncomplicated gonorrhoea, prostatitis

- Gonococcal uretritis and cervicitis

- Epididymo-orchitis including cases due to Neisseria gonorrhoeae

- Pelvic inflammatory disease including cases due to Neisseria gonorrhoea

In the above 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.

• Gastro-intestinal infections (severe gastroenteritis)

• Intra-abdominal infections

• skin and soft tissue infections

• bones and joints infections

• severe systemic infections: septicaemia, peritonitis (in case of peritonitis, the anaerobic component should be covered by another antibacterial agent, such as metronidazole), infections in immuno-suppressed patients.

• Treatment of infections in neutropenic patients

• Prophylaxis of infections in neutropenic patients

• Prophylaxis of invasive infections due to Neisseria meningitidis

• Inhalation anthrax (post-exposure prophylaxis and curative treatment)

Children and adolescents (5 – 17 years):

• Acute pulmonary exacerbation of 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 (see sections 4.4 and 5.1).

The dose of ciprofloxacin tablets is determined by the severity and type of infection, the sensitivity of the causative organism(s) and the age, weight and renal function of the patient.

Treatment may be initiated with tablets or intravenous injection according to the condition of the patient. The duration of treatment depends on the severity of the disorder and on the clinical and bacteriological course. In principle, treatment should be maintained for at least 3 days after body temperature has returned to normal, or clinical symptoms have resolved.

The following dose recommendations are provided as a guideline and refer to oral dosing only (Note that different dose recommendations apply to intravenous administration of ciprofloxacin).

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:

The dosage range for adults is 100–750mg twice daily. The recommended dosages for specific types of infections are as follows:

Children and adolescents(5-17years)

In particularly severe, life-threatening infections – especially those involving Pseudomonas, staphylococci or streptococci, e.g. osteomyelitis, septicaemia, pneumococcal pneumonia, recurrent bouts of infections in mucoviscidosis patients, bone and joint infections or peritonitis – the recommended dose is 750mg ciprofloxacin twice daily.

Elderly patients:

Elderly patients should receive a dose depending on the severity of the disorder and on creatinine clearance.

Impaired renal or hepatic function:

Adults:

Recommended starting and maintenance doses for patients with impaired renal function:

Impaired hepatic function:

Dose adjustment not necessary.

Impaired renal and hepatic function:

Dose adjustment as under 1, with monitoring of serum ciprofloxacin concentrations.

Children and adolescents (5 – 17 years):

Dosage in children with reduced renal and liver function has not been investigated.

Method of administration:

The tablets are to be swallowed with liquid. They can be taken at any time regardless of meals. Ingestion on an empty stomach accelerates the absorption of active substance. Dairy products with a high calcium content (eg.milk, yoghurt) or mineral-fortified fruit juice (e.g. calcium-fortified orange juice) may reduce ciprofloxacin absorption (please refer to section 4.5).

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.

Ciprofloxacin is contra-indicated in patients who have shown hypersensitivity to ciprofloxacin or any of the excipients contained in the tablets (please refer to section 6.1) or other chemotherapeutic agents of the quinolone type.

Concomitant administration of ciprofloxacin and tizanidine (see section 4.5).

Streptococcal Infections (including Streptococcus pneumoniae)

Ciprofloxacin is not recommended for the treatment of streptococcal infections due to inadequate efficacy.

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 co-administered with other appropriate antibacterial agents.

Genital tract infections

Epididymo-orchitis and pelvic inflammatory diseases may be caused by fluoroquinolone-resistant Neisseria gonorrhoeae. Ciprofloxacin should be co-administered with another appropriate antibacterial agent unless ciprofloxacin-resistant Neisseria gonorrhoeae can be excluded. If clinical improvement is not achieved after 3 days of treatment, the therapy should be reconsidered.

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.

bones and joints Infections

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.

Children and adolescents (5-17years)

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 a ciprofloxacin use.

The use of ciprofloxacin for specific severe infections other than those mentioned above 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 (see section 4.8) 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.

Tendonitis and/or rupture of tendons (which mainly affects the 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 (see section 4.8).At any sign of tendonitis (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.(see section 4.8).

Photosensitivity

Ciprofloxacin use has been associated with photosensitivity. However, patients should be recommended to avoid prolonged exposure to sunlight or UV radiation during treatment with ciprofloxacin(see section 4.8). If this is not possible appropriate precautions should be taken.

Central nervous system (CNS) disorders:

In patients with epilepsy or other lesions of the central nervous system (e.g. reduced convulsion threshold, a history of seizures, diminished cerebral bloodflow, changes in brain structure or stroke), ciprofloxacin is only to be used after carefully weighing the benefits against the risk, because the possibility of central nervous side effects puts these patients at increased risk.

Quinolones are known to trigger seizures or lower the seizure threshold. Ciprofloxacin should be used with caution in patients with CNS disorders which may be predisposed to seizure. If seizures occur ciprofloxacin should be discontinued (see section 4.8). Psychiatric reactions may occur even after the first administration of ciprofloxacin. In rare cases, depression or psychosis can progress to self-endangering behaviour. In these 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 (see section 4.8).

Cardiac disorders

Since ciprofloxacin is associated with cases of QT prolongation (see section 4.8), caution should be exercised when treating patients at risk for torsades de pointes arrhythmia.

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 (see section 4.8). 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(see section 4.8). Patients receiving ciprofloxacin should be well hydrated and excessive alkalinity of the urine should be avoided.

Hepatobiliary system

Cases of hepatic necrosis and life-threatening hepatic failure have been reported with ciprofloxacin (see section 4.8). 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, ropinirole, tizanidine). Co-administration of ciprofloxacin and tizanidine is contra-indicated. 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 (see section 4.5).

Methotrexate

The concomitant use of ciprofloxacin with methotrexate is not recommended (see section 4.5).

Interaction with tests

Because ciprofloxacin has some activity against Mycobacterium tuberculosis, false-negative cultures may occur when specimens are obtained during ciprofloxacin treatment.

Effects of other products on ciprofloxacin:

Chelation complex formation

Antacids, iron, zinc, sucralfate, calcium, didanosine, oral nutritional solutions, dairy products:

Absorption of ciprofloxacin is reduced when iron, zinc, polymeric phosphate binders (eg. sevelamer),sucralfate or antacids and highly buffered pharmaceuticals, containing magnesium, aluminium or calcium, are administered simultaneously. This also applies to sucralfate, antiviral drugs containing buffered didanosine formulations, oral nutritional solutions and large quantities of dairy products (milk or liquid milk products such as yoghurt). Therefore ciprofloxacin should be administered either 1 or 2 hours before or at least 4 hours after these preparations.This restriction does not apply to the group of H2 receptor-blocking antacids.

Food and Dairy products:

Dietary calcium as part of a meal does not significantly affect absorption. However, the concurrent administration of dairy products (milk or liquid milk products such as yoghurt) or mineral-fortified drinks alone (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.

Effects of ciprofloxacin on other medicinal products:

Tizanidine

Tizanidine must not be administered together with ciprofloxacin (see section 4.3). 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 (see section 4.4).

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 (See Section 4.4).

Other xanthine derivatives

On concurrent administration of ciprofloxacin and caffeine or pentoxifylline (oxpentifylline), raised serum concentrations of these xanthine derivatives were reported.

NSAIDs:

Animal trials have shown that concurrent administration of very high doses of a quinolone and certain non-steroidal anti-inflammatory drugs (NSAID)(but not acetylsalicylic acid) may provoke convulsions.

Cyclosporin:

A transient increase in the concentration of plasma creatinine is seen when ciprofloxacin and cyclosporin are administered simultaneously. Plasma creatinine concentrations should be checked regularly in these patients.

Oral Anticoagulants:

Simultaneous administration of ciprofloxacin and warfarin may increase the effect of warfarin. 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 an oral anticoagulant agent.

Glibenclamide:

Simultaneous administration of ciprofloxacin and glibenclamide may increase the effect of glibenclamide.

Metoclopramide:

Metoclopramide accelerates the absorption of ciprofloxacin. The maximum plasma concentration of ciprofloxacin is therefore achieved more rapidly. The bioavailability of ciprofloxacin is not affected.

Mexiletine:

Simultaneous administration of ciprofloxacin and mexiletine can lead to increased plasma concentrations of mexiletine.

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.

Premedicants:

It is recommended that opiate premedicants (e.g. papaveretum) or opiate premedicants used with anticholinergic premedicants (e.g. atropine or hyoscine) are not used concomitantly with ciprofloxacin, as the serum levels of ciprofloxacin are reduced.

Co-administration of ciprofloxacin and benzodiazepine premedicants has been shown not to affect ciprofloxacin plasma levels. However, since decreased clearance of diazepam with a prolonged half-life has been reported during co-administration of ciprofloxacin and diazepam, and in an isolated case with midazolam, careful monitoring of benzodiazepine therapy is recommended.

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. A potential for increased plasma levels of ropinirole with possible increase in adverse effects exists. In case of combined use, increased clinical monitoring and dosage adjustment of ropinirole may be required (see section 4.4).

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 (see section 4.4).

Buffered Didanosine formulations:

Clinically important interactions have been reported with buffered didanosine formulations (please refer to the first paragraph above).

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 / foetus (see section 5.3).

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.

Even when used as prescribed, ciprofloxacin can alter the capacity for reactions to an extent that impairs the ability to drive a vehicle, to operate machinery or to work safely. This applies to a greater degree at the start of treatment, when the dose is increased, and when switching medication, as well as in conjunction with alcohol.

Due to its neurological effects, ciprofloxacin may affect reaction time. Thus, the ability to drive or to operate machinery may be impaired.

Adverse effects have been reported in 5 – 14% of patients receiving ciprofloxacin. Most frequently reported adverse effects of the drug involve the gastrointestinal tract and the central nervous system.

The following undesirable effects have been observed:

ADRs derived from clinical studies and post-marketing surveillance with ciprofloxacin (oral, intravenous, and sequential therapy) sorted by categories of frequency are listed below. The frequency analysis takes into account data from both oral and intravenous administration of ciprofloxacin.

* These events were reported during the postmarketing period and were observed predominantly among patients with further risk factors for QT prolongation (see section 4.4).

Paediatric patients

The incidence of arthropathy, mentioned above, is referring to data collected in studies with adults. In children, arthropathy is reported to occur commonly (see section 4.4).

Long-term and repeated use of ciprofloxacin can lead to superinfections with resistant bacteria or fungi.

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.

Pharmacotherapeutic group: Quinolone Antibacterials, fluoroquinolones,ATC code: J 01MA02

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, 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 susceptibility to fluoroquinolones, which depends on the 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.

Spectrum of antibacterial activity:

Breakpoints separate susceptible strains from strains with intermediate susceptibility and the latter from resistant strains:

EUCAST Recommendations

The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.

Groupings of relevant species according to ciprofloxacin susceptibility (for Streptococcus species see section 4.4)

Absorption

Following oral administration of single doses of 250 mg, 500 mg, and 750 mg of ciprofloxacin tablets, ciprofloxacin is predominantly absorbed from the duodenum and upper jejunum and reaches maximum serum concentrations 1-2 hours later.

After single doses of 250 mg and 500 mg, Cmax values are about 0.8–2 mg/L and 1.5–2.9 mg/L, respectively.

Single doses of 100-750 mg produced dose-dependent maximum serum concentrations (C_max) were between 0.56 and 3.7 mg/L. Serum concentrations increase proportionately with doses up to 1000 mg.

The absolute bioavailability is approximately 70–80%; Cmax and AUC values are proportionally increased with the dose.

Ciprofloxacin 500 mg oral dose given every 12 hours has been shown to produce an area under the serum concentration-time curve (AUC) equivalent to that produced by an intravenous infusion of 400 mg ciprofloxacin given over 60 minutes every 12 hours.

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 body weight. Since the protein binding of ciprofloxacin is low (20–30%) and the substance is predominantly present in the blood plasma in non-ionised form, almost the entire quantity of the administered dose can diffuse freely into the extravascular space. Ciprofloxacin reaches high concentrations in a variety of tissues such as lung (epithelial fluid, alveolar macrophages, biopsy tissue), sinuses, inflamed lesions (cantharides blister fluid), and the urogenital tract (urine, prostate, endometrium)As a result, the concentrations in certain body fluids and tissues may be markedly higher than the corresponding serum concentrations.

Metabolism

Low concentrations of four metabolites were found: desethylene ciprofloxacin (M1), sulphociprofloxacin (M2), oxociprofloxacin (M3) and formylciprofloxacin (M4). M1 to M3 show antibacterial activity comparable with or smaller than nalidixic acid. M4 with the lowest quantity, has an antimicrobial activity very much corresponding to norfloxacin.

Ciprofloxacin is known to be a moderate inhibitor of the CYP 450 1A2 iso-enzymes.

Elimination

Ciprofloxacin is essentially excreted in unchanged form, mostly in the urine and to a smaller extent, faecally. The serum elimination half-life in subjects with normal renal function is approximately 4-7 hours.

Excretion of ciprofloxacin after oral administration

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.

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.

Non-renal clearance of ciprofloxacin is mainly due to active trans-intestinal secretion and metabolism. 1% of the dose is excreted via the biliary route. Ciprofloxacin is present in the bile in high concentrations.

Paediatric patients

The pharmacokinetic data in paediatric patients are limited.

In a study in children C_max and AUC were not age-dependent (above one year of age). No notable increase in C_max and AUC upon multiple dosing (10 mg/kg three times daily) was observed.

In 10 children with severe sepsis C_max was 6.1 mg/L (range 4.6-8.3 mg/L) after a 1-hour intravenous infusion of 10 mg/kg in children aged less than 1 year compared to 7.2 mg/L (range 4.7-11.8 mg/L) for children between 1 and 5 years of age. The AUC values were 17.4 mg*h/L (range 11.8 -32.0 mg*h/L) and 16.5 mg*h/L (range 11.0-23.8 mg*h/L) in the respective age groups.

These values are within the range reported for adults at therapeutic doses. Based on population pharmacokinetic analysis of paediatric patients with various infections, the predicted mean half-life in children is approx. 4-5 hours and the bioavailability of the oral suspension ranges from 50 to 80%.

Non-clinical data reveal no special hazards for humans based on conventional studies of single dose toxicity, repeated dose toxicity, carcinogenic potential, or toxicity to reproduction.

Like a number of other quinolones, ciprofloxacin is phototoxic in animals at clinically relevant exposure levels. Data on photomutagenicity/photocarcinogenicity show a weak photomutagenic or phototumorigenic effect of ciprofloxacin in-vitro and in animal experiments. This effect was comparable to that of other gyrase inhibitors.

Articular tolerability:

Like other gyrase inhibitors, ciprofloxacin may induce joint damage during the growth phase of juvenile animals. The extent of the cartilage damage varies according to age, species and dose; the damage can be reduced by taking the weight off the joints. Studies with mature animals (rat, dog) revealed no evidence of cartilage lesions. In a study in young beagle dogs, ciprofloxacin caused severe articular changes at therapeutic doses after two weeks of treatment, which were still observed after 5 months.

Other preclinical effects were observed only at exposures sufficiently in excess of the maximum human exposure that concern for human safety is negligible with regard to the animal data.

Croscarmellose sodium,

Microcrystalline cellulose,

Povidone,

Magnesium stearate.

Hypromellose,

Lactose monohydrate,

Titanium dioxide (E 171),

Macrogol 4000,

Sodium citrate

Not applicable.

24 months

Do not store above 25 °C. Store in the original package.

PVC 250 μm/Al 20 μm blisters.

The Ciprofloxacin 750mg Tablets are available in pack sizes of 10, 20, 50 and 100 tablets.

Not all pack sizes may be marketed.

No special instructions for use/handling.

Accord Healthcare Limited

Sage house, 319, Pinner road,

North harrow, Middlesex HA1 4HF

United Kingdom

PL 20075/0050

30/07/2009

21/02/2011