Data Sheet

Ciproxin

Ciprofloxacin tablets, suspension and infusion solution.

GENERAL INFORMATION

Name of the Medicinal Product

Ciproxin 250, Ciproxin 500, Ciproxin 750 Tablets

Ciproxin Suspension 5%, Ciproxin Suspension 10%

Ciproxin 200 Infusion Solution

Qualitative and Quantitative Composition

Film-coated tablets

Ciproxin 250:

1 tablet contains 291mg ciprofloxacin hydrochloride monohydrate, corresp. to 250mg ciprofloxacin.

Ciproxin 500:

1 tablet contains 582mg ciprofloxacin hydrochloride monohydrate, corresp. to 500mg ciprofloxacin.

Ciproxin 750:

1 tablet contains 873mg ciprofloxacin hydrochloride monohydrate, corresp. to 750mg ciprofloxacin.

Suspension

Ciproxin Suspension 5%

1 bottle consists of 7.95g of microcapsules which contain 5.0g ciprofloxacin.

1 bottle with 99.2g suspension diluent to prepare 100 mL of Ciproxin Suspension 5 %.

1 measuringspoonful (approx. 5.0 mL) contains approx. 250mg ciprofloxacin

Ciproxin Suspension 10%

1 bottle consists of 15.9g of microcapsules which contain 10.0g ciprofloxacin.

1 bottle with 107.6g suspension diluent to prepare 100 mL of Ciproxin Suspension 10 %.

1 measuringspoonful (approx. 5.0 mL) contains approx. 500mg ciprofloxacin

Infusion solution

Ciproxin 200: 1 vial of 100 mL infusion solution contains 254.4mg ciprofloxacin lactate, corresp. to 200mg ciprofloxacin. Sodium content is 900 mg (15 mmol).

Pharmaceutical Form

Clinical Particulars

Indications

Adults

Uncomplicated and complicated infections caused by ciprofloxacin sensitive pathogens:

Infections of the lower respiratory tract.

In the treatment of outpatients with pneumonia due to Pneumococcus, ciprofloxacin should not be used as a drug of first choice. Ciprofloxacin can be regarded as a suitable treatment for pneumonias caused by Klebsiella, Enterobacter, Proteus, E. coli, Pseudomonas, Haemophilus, Branhamella, Legionella, and Staphylococcus.

Infections of the kidneys and/or the efferent urinary tract.

Infections of the genital organs, including adnexitis, gonorrhoea, prostatitis.

Infections of the abdominal cavity (e.g. infections of the gastrointestinal tract or of the biliary tract, peritonitis).

Infections of the skin and soft tissue.

Infections of the bones and joints.

Sepsis.

Inhalational anthrax (post-exposure): To reduce the incidence or progression of disease following exposure to aerosolized Bacillus anthracis. Ciprofloxacin serum concentrations achieved in humans serve as a surrogate endpoint reasonably likely to predict clinical benefit and provide the basis for this indication.

According to in-vitro investigations, the following pathogens can be regarded as sensitive:

E. coli, Shigella, Salmonella, Citrobacter, Klebsiella, Enterobacter, Serratia, Hafnia, Edwardsiella, Proteus (indole-positive and indole-negative), Providencia, Morganella, Yersinia; Vibrio, Aeromonas, Plesiomonas, Pasteurella, Haemophilus, Campylobacter, Pseudomonas, Legionella, , Moraxella, Acinetobacter, Brucella; Staphylococcus, Listeria, Corynebacterium, Chlamydia.

The following show varying degrees of sensitivity:

Neisseria, Gardnerella, Flavobacterium, Alcaligenes, Streptococcus agalactiae, Enterococcus faecalis, Streptococcus pyogenes, Streptococcus pneumoniae, Viridans group Streptococci, Mycoplasma hominis, Mycobacterium tuberculosis, and Mycobacterium fortuitum.

The following are usually resistant:

Enterococcus faecium, Ureaplasma urealyticum, Nocardia asteroides.

With a few exceptions anaerobes are moderately sensitive e.g. Peptococcus, Peptostreptococcus to resistant e.g. Bacteroides.

Ciprofloxacin has been shown to be active against Bacillus anthracis both in vitro and by use of serum levels as a surrogate marker.

Ciprofloxacin is ineffective against Treponema pallidum.

The prevalence of resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. This information gives only an approximate guidance whether microorganisms will be susceptible for ciprofloxacin or not.

Children

Cystic fibrosis

For the treatment of acute pulmonary exacerbation of cystic fibrosis associated with P. aeruginosa infection in paediatric patients aged 5-17 years.

Inhalational anthrax (post-exposure)

For the indication of inhalational anthrax (post-exposure)

Complicated urinary tract infections and pyelonephritis

For complicated urinary tract infections or pyelonephritis due to E.coli in paediatric patients aged 1-17 years.

The risk-benefit assessment indicates that administration of ciprofloxacin to paediatric patients is appropriate. Treatment should only be initiated after careful benefit/risk evaluation, due to possible adverse events related to joints/surrounding tissues. The use of ciprofloxacin for other indications is not recommended in children.

Posology And Method Of Administration

Recommended usual dose:

Adults

Unless otherwise prescribed, the following guideline doses are recommended:

Elderly

Elderly patients should receive a dose as low as possible depending on the severity of their illness and the creatinine clearance.

Children

Cystic Fibrosis

Clinical and pharmacokinetic data support the use of ciprofloxacin in paediatric cystic fibrosis patients (aged 5-17 years) with acute pulmonary exacerbation associated with P. aeruginosa infection, at a dose of 20mg/kg orally twice daily (maximum daily dose 1500mg) or 10mg/kg iv three times daily (maximum dose 1200mg).

Inhalational anthrax (post-exposure)

For the indication of inhalational anthrax (post-exposure), the risk-benefit assessment indicates that treatment of paediatric patients with ciprofloxacin is appropriate. For paediatric patients, the recommended oral dose is 15 mg/kg twice daily (not to exceed a maximum dose of 500 mg per dose, 1000 mg per day). For intravenous infusion, the recommended dose is 10 mg/kg twice daily (not to exceed a maximum dose of 400 mg per dose, 800 mg per day). Drug administration should begin as soon as possible after suspected or confirmed exposure.

Complicated urinary tract infections and pyelonephritis

For the indication of complicated urinary tract infections and pyelonephritis, the recommended dose is 6 to 10 mg/kg i.v. every 8 hours with a maximum of 400 mg per dose or 10 to 20 mg/kg orally every 12 hours with a maximum of 750 mg per dose.

Method of Administration:

Oral

The tablets are swallowed whole with a small amount of fluid.

Tablets and oral suspension can be taken independent of mealtimes. (If the tablets are taken on an empty stomach, the active substance is absorbed more rapidly). In this case, tablets or suspension should not be taken concurrently with dairy products or with mineral fortified drinks alone (e.g. milk, yoghurt, calcium fortified orange juice). However, dietary calcium as part of a meal does not significantly affect ciprofloxacin absorption.

Ciprofloxacin Suspension 5 %:

½ measuringspoonful (approx. 2.5 mL) contains approx. 125mg ciprofloxacin, 1 measuringspoonful (approx. 5.0 mL) contains approx. 250mg ciprofloxacin

Ciprofloxacin Suspension 10 %:

½ measuringspoonful (approx. 2.5 mL) contains approx. 250mg ciprofloxacin, 1 measuringspoonful (approx. 5.0 mL) contains approx. 500mg ciprofloxacin

Always use the graduated measuring spoon to obtain the exact dose for administering the suspension.

No additions should be made to the mixed final ciprofloxacin suspension.

If the patient is unable to take tablets / suspension, because of the severity of the illness or for other reasons, it is recommended to commence the therapy with an intravenous form of ciprofloxacin. After intravenous administration the treatment can be continued orally.

Intravenous

Ciprofloxacin should be administered by intravenous infusion over a period of 60 minutes. Slow infusion into a large vein will minimise patient discomfort and reduce the risk of venous irritation. The infusion solution can be infused either directly or after mixing with other compatible infusion solutions.

Unless compatibility with other infusion solutions/drugs has been confirmed, the infusion solution must always be administered separately. The visual signs of incompatibility are e.g. precipitation, clouding, and discolouration.

Incompatibility appears with all infusion solutions/drugs that are physically or chemically unstable at the pH of the solution (e.g. penicillin's, heparin solutions), especially in combination with solutions adjusted to an alkaline pH (pH of the ciprofloxacin infusion solutions: 3.9-4.5).

Duration of Treatment:

The duration of treatment depends on the severity of the illness and on the clinical and bacteriological course. It is essential to continue therapy for at least 3 days after disappearance of the fever or of the clinical symptoms. Mean duration of treatment:

• 1 day for acute uncomplicated gonorrhoea and cystitis,
• up to 7 days for infections of the kidneys, urinary tract, and abdominal cavity,
• a maximum of 2 months in osteomyelitis,
• 60 days in inhalational anthrax (post-exposure),
• and 7-14 days in all other infections.

In streptococcal infections the treatment must last at least 10 days because of the risk of late complications.

Infections caused by Chlamydia should also be treated for a minimum of 10 days.

Children:

Cystic Fibrosis

For acute pulmonary exacerbation of cystic fibrosis associated with P. aeruginosa infection in paediatric patients (aged 5-17 years), the duration of treatment is 10-14 days.

Inhalation anthrax (post-exposure)

For inhalational anthrax (post-exposure), the duration of treatment is 60 days.

Complicated urinary tract infections and pyelonephritis

For complicated urinary tract infections or pyelonephritis due to E. coli, the duration of treatment is 10-21 days.

Children

Dosing in children with impaired renal and or hepatic function has not been studied.

Contraindications

Ciprofloxacin must not be used in cases of hypersensitivity to ciprofloxacin or other quinolone chemotherapeutics or any of the excipients.

Concurrent administration of ciprofloxacin and tizanidine is contraindicated since an undesirable increase in serum tizanidine concentrations associated with clinically relevant tizanidine-induced side effects (hypotension, somnolence, drowsiness) can occur.

Special Warnings And Precautions For Use

May cause tendonitis, hypoglycaemia.

Paediatric use

As with drugs in its class, ciprofloxacin has been shown to cause arthropathy in weight-bearing joints of immature animals. The analysis of available safety data from ciprofloxacin use in patients less than 18 years of age, the majority of whom had cystic fibrosis, did not disclose any evidence of drug related cartilage or articular damage. The use of ciprofloxacin for indications other than the treatment of acute pulmonary exacerbation of cystic fibrosis caused by P. aeruginosa infection (children aged 5-17 years), complicated urinary tract infections and pyelonephritis due to E.coli (children aged 1-17 years) and for the use in inhalational anthrax (post-exposure) was not studied. For other indications clinical experience is limited.

For the indication of inhalational anthrax (post-exposure), the risk-benefit assessment indicates that administration of ciprofloxacin to paediatric patients is appropriate. For information regarding paediatric dosing in inhalational anthrax (post-exposure), see Posology and Method of Administration.

Cytochrome P450:

Ciprofloxacin is known to be a moderate inhibitor of the CYP 450 1A2 enzymes. Care should be taken when other drugs are administered concomitantly which are metabolized via the same enzymatic pathway (e.g. theophylline, methylxantines, caffeine, duloxetine, clozapine). Increased plasma concentrations associated with drug specific side effects may be observed due to inhibition of their metabolic clearance by ciprofloxacin. (See also Interaction With Other Medicaments And Other Forms Of Interaction)

Gastrointestinal System:

In the event of severe and persistent diarrhoea during or after treatment a doctor must be consulted, since this symptom can hide a serious intestinal disease (life threatening pseudomembranous colitis with possible fatal outcome), requiring immediate treatment. In such cases Ciprofloxacin must be discontinued and appropriate therapy initiated (e. g. vancomycin, orally, 4 x 250 mg/day). Drugs that inhibit peristalsis are contraindicated.

There can be a temporary increase in transaminases, alkaline phosphatase or cholestatic jaundice, especially in patients with previous liver damage.

Nervous System:

In epileptics and in patients who have suffered from previous CNS-disorders (e.g. lowered convulsion threshold, previous history of convulsion, reduced cerebral blood flow, altered brain structure or stroke), ciprofloxacin should only be used where the benefits of treatment exceed the risks, since these patients are at risk because of possible central-nervous side effects.

In some instances the CNS reactions occurred after the first administration of Ciprofloxacin. In rare cases depression or psychosis can progress to self endangering behaviour. In these cases Ciprofloxacin has to be discontinued and the doctor should be informed immediately.

Hypersensitivity:

In some instances, the hypersensitivity and allergic reactions occurred after the first administration. The doctor should be informed immediately.

Anaphylactic/anaphylactoid reactions in very rare instances can progress to a life threatening shock, in some instances after the first administration. In these cases Ciprofloxacin has to be discontinued, medical treatment (e.g. treatment for shock) is required.

Injection Site Reaction:

Local i.v. site reactions have been reported with the intravenous administration of Ciprofloxacin. These reactions are more frequent if the infusion time is 30 minutes or less. These may appear as local skin reactions which resolve rapidly upon completion of the infusion. Subsequent intravenous administration is not contraindicated unless the reactions recur or worsen.

Musculo-Skeletal System:

At any sign of tendinitis (e.g. painful swelling, inflammation), a physician should be consulted and the antibiotic treatment be discontinued. Care should be taken to keep the affected extremity at rest and avoid any inappropriate physical exercise due to increased risk of tendon rupture.

Tendon rupture (predominantly Achilles tendon) has been reported predominantly in the elderly on prior systemic treatment with glucocorticoids.

Ciprofloxacin should be used with caution in patients with a history of tendon disorders related to quinolone treatment.

Skin and Appendages:

Ciprofloxacin has been shown to produce photosensitivity reactions. Patients taking Ciprofloxacin should avoid direct exposure to excessive sunlight or UV-light. Therapy should be discontinued if photosensitisation (i. e. sunburn-like skin reactions) occur.

Hypoglycaemia

Hypoglycaemia has been noted with enoxacin and lomefloxacin but it is not known whether it occurs with ciprofloxacin.

NaCl load for i.v. formulation (bottles)

The additional sodium load should be taken into account when using Ciproxin IV in patients for whom sodium intake is of medical concern (e.g. patients with congestive heart failure, renal failure, nephrotic syndrome, etc.) See "Qualitative and Quantitative Composition" for sodium content.

Sucrose load for suspension formulation

As the oral suspension contains sucrose, it is unsuitable for patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency (see section "PHARMACEUTICAL PARTICULARS".

Interaction With Other Medicaments And Other Forms Of Interaction

Chelation Complex Formulation

The simultaneous administration of ciprofloxacin (oral) and iron, polymeric phosphate binders (e.g. sevelamer), sucralfate or antacids and highly buffered drugs (e.g. antiretrovirals), containing magnesium, aluminium, or calcium reduce the absorption of ciprofloxacin. Consequently, ciprofloxacin should be administered either 1-2 hours before, or at least 4 hours after these preparations.

This restriction does not apply to antacids belonging to the class of H₂ receptor blockers.

Food and Dairy Products

The concurrent administration of dairy products or mineral fortified drinks alone (e.g. milk, yoghurt, calcium fortified orange juice) and ciprofloxacin should be avoided because absorption of ciprofloxacin may be reduced. Dietary calcium as part of a meal, however, does not significantly affect absorption.

Omeprazole

Concomitant administration of ciprofloxacin and omeprazole results in a slight reduction of C_max and AUC of ciprofloxacin.

Theophylline

Concurrent administration of ciprofloxacin and theophylline can cause an undesirable increase in the serum theophylline concentration. This can lead to theophylline-induced side effects; in very rare cases these side effects can be life threatening or fatal. If concurrent use of the two products is unavoidable, the serum theophylline concentration should therefore be checked and the theophylline dose appropriately reduced.

NSAID

Animal studies have shown that the combination of very high doses of quinolones (gyrase inhibitors) and certain non-steroidal anti-inflammatory agents (but not acetylsalicylic acid) can provoke convulsions.

Cyclosporin

A transient rise in the concentration of serum creatinine was observed when ciprofloxacin and cyclosporin were administered simultaneously. Therefore, it is necessary to monitor the serum creatinine concentrations in these patients frequently (twice a week).

Warfarin

The simultaneous administration of ciprofloxacin and warfarin may intensify the action of warfarin.

Gilbenclamide

In particular cases, concurrent administration of ciprofloxacin and glibenclamide can intensify the action of glibenclamide (hypoglycaemia).

Probenecid

Probenecid interferes with renal secretion of ciprofloxacin. Co-administration of probenecid and ciprofloxacin increases the ciprofloxacin serum concentrations.

Methotrexate

Renal tubular transport of methotrexate may be inhibited by concomitant administration of ciprofloxacin potentially leading to increased plasma levels of methotrexate. This might increase the risk of methotrexate associated toxic reactions. Therefore, patients under methotrexate therapy should be carefully monitored when concomitant ciprofloxacin therapy is indicated.

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.

Tizanidine

Tizanidine serum concentrations increase with concomitant administration with ciprofloxacin. Associated with the increased serum concentrations was a potentiated hypotensive and sedative effect. Tizanidine must not be administered together with ciprofloxacin. (see also CONTRAINDICATONS)

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 Cmax of duloxetine. Although no clinical data are available on a possible interaction with ciprofloxacin, similar effects can be expected upon concomitant administration.

Ropinirole

In a clinical study it was shown that concomitant use of ropinirole with ciprofloxacin, a medium inhibitor of the CYP450 1A2 isozyme, resulted in increases in the C_max and AUC of ropinirole of 60% and 84%, respectively. Although ropinirole treatment was well tolerated, case reports suggest that a possible interaction with ciprofloxacin associated with side effects may occur upon concomitant administration.

Lidocaine

It was demonstrated in healthy subjects that concomitant use of lidocaine 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 and administration or 250 mg ciprofloxacin for 7 days, serum concentration of clozapine and N-desmethylclozapine were increased by 29% and 31%, respectively.

Effect on Ability to Drive and Use Machines

Even when the drug is taken exactly as prescribed, it can affect the speed of reaction to such an extent that the ability to drive or to operate machinery is impaired. This applies particularly in combination with alcohol.

Pregnancy and Lactation

Ciprofloxacin must not be prescribed for pregnant women, or nursing mothers, since there is no experience on the drug's safety in these patient groups and since, on the basis of animal studies, it is possible that the drug could cause damage to articular cartilage in the foetus or infant. Animal studies have not shown any evidence of teratogenic effects (malformations).

Undesirable Effects

The most common Adverse Reactions based on all clinical studies with ciprofloxacin (oral, parenteral) sorted by CIOMS III categories of frequency are listed below (n = 51721 patients, data lock point: 15 May 2005). ADRs derived from post marketing reports (status: 31 July 2005) are printed in italic.

The following undesirable effects have a higher frequency category in the subgroups of patients receiving intravenous or sequential (intravenous to oral) treatment:

Overdose

In the event of acute, excessive oral overdosage, reversible renal toxicity has been reported in some cases.

Therefore, apart from routine emergency measures, it is recommended to monitor renal function and to administer Mg- or Ca-containing antacids which reduce the absorption of ciprofloxacin.

Only a small amount of ciprofloxacin (< 10 %) is removed from the body after haemodialysis or peritoneal dialysis.

Pharmacodynamic Properties

Ciprofloxacin is a synthetic broad spectrum antibacterial agent (ATCCODE: J 01 MA 02).

Ciprofloxacin is effective in-vitro against virtually all gram-negative pathogens, including Pseudomonas aeruginosa. It is also effective against gram-positives such as Staphylococci and Streptococci. Anaerobes are generally less susceptible.

Ciprofloxacin has a rapid bactericidal action, not only in the proliferation phase but also in the resting phase. The bactericidal action of ciprofloxacin results from inhibition of bacterial type II topoisomerases (DNA gyrase and topoisomerase IV), which are required for bacterial DNA replication, transcription, repair, and recombination.

During the proliferation phase of a bacterium a segmental twisting and untwisting of the chromosomes take place. An enzyme called DNA gyrase plays a decisive part in this process. Ciprofloxacin inhibits this DNA gyrase in a way that arrests the bacterial metabolism, since vital information can no longer be read from the bacterial chromosome.

In vitro resistance to ciprofloxacin is commonly due to mutations in bacterial topoisomerases and develops slowly through multiple-step mutations. Ciprofloxacin resistance due to spontaneous mutations occurs at a frequency of between <10^-9 to 10^-6. Cross-resistance among fluoroquinolones may occur when resistance arises through mutations. Single mutations may result in reduced susceptibility rather than clinical resistance, but multiple mutations generally result in clinical resistance to ciprofloxacin and cross-resistance across the quinolone class. Bacterial impermeability and/or expression of efflux pumps may impact ciprofloxacin susceptibility. Plasmid-mediated resistance encoded by the qnr gene has been reported. Resistance mechanisms that inactive penicillins, cephalosporins, aminoglycosides, macrolides, and tetracyclines do not interfere with the antibacterial activity of ciprofloxacin and there is no known cross-resistance between ciprofloxacin and other classes of antimicrobials. Organisms resistant to these drugs may be susceptible to ciprofloxacin.

The minimum bactericidal concentration (MBC) generally does not exceed the minimal inhibitory concentration (MIC) by more than a factor of 2.

Plasmid-mediated resistance development of the kind that occurs with β-lactam antibiotics, aminoglycosides, and tetracyclines has not been observed with ciprofloxacin. It is of clinical interest that plasmid-carrying bacteria are also completely sensitive to ciprofloxacin.

On account of its different mode of action, parallel resistance to other important, chemically different, active substance groups, such as β-lactam antibiotics, aminoglycosides, tetracyclines, macrolide or peptide antibiotics, sulphonamides, trimethoprim or nitrofuran derivatives generally is not seen with Ciprofloxacin. In its indication area ciprofloxacin remains completely effective on pathogens resistant to the above-mentioned groups of antibiotics.

Parallel resistance is observed within the group of gyrase inhibitors. However, because of the high primary sensitivity to ciprofloxacin shown by most organisms parallel resistance is less pronounced with this drug. Ciprofloxacin is thus often still effective on pathogens that are already resistant to the less effective gyrase inhibitors.

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

Ciprofloxacin has been shown to be active in vitro against susceptible strains of the microorganisms listed below:

Aerobic Gram-Positive Microorganisms:

Bacillus anthracis; Enterococcus faecalis (many strains are only moderately susceptible); Staphylococcus aureus (methicillin-susceptible); Staphylococcus saprophyticus; Streptococcus pneumoniae.

Aerobic Gram-Negative Microorganisms:

Burkholderia cepacia; Campylobacter species; Citrobacter freudii; Enterobacter aerogenes; Enterobacter clocae; Escherichia coli; Haemophilius influenzae; Klebsiella pneumoniae; Klebsiella oxytoca; Moraxella catarrhalis; Morganella morganii; Neisseria gonorrhoeae; Proteus mirabilis; Proteus vulgaris; Providencia species; Pseudomonas aeruginosa; Pseudomonas fluorescens; Serratia marcescens; Shigella species.

The following microorganisms show varying degrees of susceptibility to ciprofloxacin:

Burkholderia cepacia, Campylobacter species, Enterococcus faecalis, Morganella morganii, Neisseria gonorrhoeae, Proteus mirabilis, Pseudomonas aeruginosa, Pseudomonas fluorescens, Serratia marcescens.

The following microorganisms are considered inherently resistant to ciprofloxacin: Staphylococcus aureus (methicillin-resistant) and Stenotrophomonas maltophilia.

Ciprofloxacin has been shown to be active against Bacillus anthracis both in vitro and by use of serum levels as a surrogate marker.

Because of its chemical structure ciprofloxacin is completely effective on β-lactamase-forming bacteria.

Ciprofloxacin can be used in combination with another antibiotic. In-vitro studies with usually sensitive pathogens, carried out using ciprofloxacin in combination with β-lactam antibiotics and aminoglycosides, have shown primarily additive or indifferent effects; synergistic increases in efficacy were relatively rare and antagonistic effects very rare.

Inhalational anthrax - additional information

Ciprofloxacin serum concentrations achieved in humans serve as a surrogate endpoint reasonably likely to predict clinical benefit and provide the basis for this indication. The mean serum concentrations of ciprofloxacin associated with a statistically significant improvement in survival in the rhesus monkey model of inhalational anthrax are reached or exceeded in adult and pediatric patients receiving oral and intravenous regimens. (See POSOLOGY AND METHOD OF ADMINISTRATION.) Ciprofloxacin pharmacokinetics have been evaluated in various human populations. The mean peak serum concentration achieved at steady state in human adults receiving 500 mg orally every 12 hours is 2.97 µg/mL, and 4.56 µg/mL following 400 mg intravenously every 12 hours. The mean trough serum concentration at steady-state for both of these regimens is 0.2 µg/mL. In a study of 10 paediatric patients between 6 and 16 years of age, the mean peak plasma concentration achieved is 8.3 µg/mL and trough concentrations range from 0.09 to 0.26 µg/mL, following two 30-minute intravenous infusions of 10 mg/kg administered 12 hours apart. After the second intravenous infusion patients switched to 15 mg/kg orally every 12 hours achieve a mean peak concentration of 3.6 µg/mL after the initial oral dose. Long-term safety data, including effects on cartilage, following the administration of ciprofloxacin to paediatric patients are limited. (For additional information, see SPECIAL WARNINGS AND PRECAUTIONS.)

A placebo-controlled animal study in rhesus monkeys exposed to an inhaled mean dose of 11 LD₅₀ (~5.5 x 10⁵) spores (range 5-30 LD₅₀) of B. anthracis was conducted. The minimal inhibitory concentration (MIC) of ciprofloxacin for the anthrax strain used in this study was 0.08 µg/mL. In the animals studied, mean serum concentrations of ciprofloxacin achieved at expected T_max (1 hour post-dose) following oral dosing to steady state ranged from 0.98 to 1.69 µg/mL. Mean steady-state trough concentrations at 12 hours post-dose ranged from 0.12 to 0.19 µg/mL. Mortality due to anthrax for animals that received a 30-day regimen of oral ciprofloxacin beginning 24 hours post-exposure was significantly lower (1/9), compared to the placebo group (9/10) [p = 0.001]. The one ciprofloxacin-treated animal that died of anthrax did so following the 30-day drug administration period.

Pharmacokinetic Properties

Absorption:

Following oral administration of single doses of 250mg, 500mg, and 750mg tablets ciprofloxacin is absorbed rapidly and extensively mainly from the small intestine, reaching maximum serum concentrations 1-2 hours later.

The absolute bioavailability is approximately 70-80%. Maximum serum concentrations (C_max) and total areas under serum concentration vs. time curves (AUC) increased in proportion to dose.

The pharmacokinetics of ciprofloxacin oral suspension 5% and 10% are virtually identical to those of tablets.

Following an intravenous infusion of ciprofloxacin the mean maximum serum concentrations were achieved at the end of infusion. Pharmacokinetics of ciprofloxacin were linear over the dose range up to 400mg administered intravenously.

Comparison of the pharmacokinetic parameters for a bid and tid i.v. dose regimen indicated no evidence of drug accumulation for ciprofloxacin and its metabolites.

A 60-minute i.v. infusion of 200mg ciprofloxacin or the oral administration of 250mg ciprofloxacin both given every 12 hours produced an equivalent area under the serum concentration time curve (AUC).

Results of pharmacokinetic studies in paediatric cystic fibrosis patients have shown dosages of 20mg/kg bd orally or 10mg/kg tid iv are recommended to achieve plasma concentration/time profiles comparable to those achieved in the adult population at the currently recommended dosage regimens.

Distribution:

The protein binding of ciprofloxacin is low (20-30%), and the substance is present in plasma largely in a non-ionised form. Ciprofloxacin can diffuse freely into the extravascular space. The large steady-state volume of distribution of 2-3 L/kg body weight shows that ciprofloxacin penetrates into tissues resulting in concentrations which clearly exceed the corresponding serum levels.

Bioavailability:

Small concentrations of 4 metabolites have been reported. They were identified as desethyleneciprofloxacin (M 1), sulphociprofloxacin (M 2), oxociprofloxacin (M 3) and formylciprofloxacin (M 4). M 1 to M 3 display antibacterial activity comparable to or inferior to that of nalidixic acid. M 4, with the smallest quantity, is largely equivalent to norfloxacin in its antimicrobial activity.

Excretion:

Ciprofloxacin is largely excreted unchanged both renally and, to a smaller extent, non-renally.

Renal clearance is between 0.18-0.3 L/h/kg and the total body clearance between 0.48-0.60 L/h/kg. Ciprofloxacin undergoes both glomerular filtration and tubular secretion.

Non-renal clearance of ciprofloxacin is mainly due to active transintestinal secretion as well as metabolisation. 1% of the dose is via the biliary excreted route. Ciprofloxacin is present in the bile in high concentrations.

Children

In a study in children, C_max and AUC were not age-dependent. No notable increase in C_max and AUC upon multiple dosing (10 mg/kg/TID) was observed. In 10 children with severe sepsis, less than 1 year of age C_max was 6.1 mg/L (range 4.6 - 8.3 mg/L) after a 1-hour intravenous infusion at a dose level of 10 mg/kg; and 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 approx. 60%.

Preclinical Safety Data

Acute toxicity:

The acute toxicity of ciprofloxacin after oral administration can be classified as very low. Depending on the individual species, the LD₅₀ after intravenous infusion is 125-290 mg/kg.

Subacute toxicity:

Subacute tolerability studies over 4 weeks

Oral administration: Doses up to and including 100 mg/kg were tolerated without damage by rats. Pseudoallergic reactions due to histamine release were observed in dogs.

Parental administration: In the highest-dose group in each case (rats 80 mg/kg and monkeys 30 mg/kg), crystals containing ciprofloxacin were found in the urine sediment. There were also changes in individual renal tubules, with typical foreign-body reactions due to crystal-like precipitates.

The tubular changes observed should not (as e.g. in the case of aminoglycosides) be interpreted as a primary toxic effect of ciprofloxacin, but as secondary inflammatory foreign-body reactions due to the precipitation of a crystalline complex in the distal renal tubule system (cf. also the subchronic and chronic tolerability studies).

Subchronic Toxicity:

Subchronic tolerability studies over 3 months

Oral administration: All doses up to and including 500 mg/kg were tolerated without damage by rats. In monkeys, crystalluria and changes in the renal tubules were observed in the highest-dose group (135 mg/kg).

Parental administration: Although the changes in the renal tubules observed in rats were in some cases very slight, they were present in every dose group. In monkeys they were found only in the highest-dose group (18 mg/kg) and were associated with slightly reduced erythrocyte counts and haemoglobin values.

Chronic toxicity:

Chronic tolerability studies over 6 months

Oral administration: Doses up to and including 500 mg/kg and 30 mg/kg were tolerated without damage by rats and monkeys, respectively. Changes in the distal renal tubules were again observed in some monkeys in the highest-dose group (90 mg/kg).

Parental administration: In monkeys slightly elevated urea and creatinine concentrations and changes in the distal renal tubules were recorded in the highest-dose group (20 mg/kg).

Carcinogenicity:

In carcinogenicity studies in mice (21 months) and rats (24 months) with doses up to approx. 1000 mg/kg bw/day in mice and 125 mg/kg bw/day in rats (increased to 250 mg/kg bw/day after 22 weeks), there was no evidence of a carcinogenic potential at any dose level.

Reproduction toxicology:

Fertility studies in rats

Fertility, the intrauterine and postnatal development of the young, and the fertility of F1 generation were not affected by ciprofloxacin.

Embryotoxicity studies

These yielded no evidence of any embryotoxic or teratogenic action of ciprofloxacin.

Perinatal and postnatal development in rats

No effects on the perinatal or postnatal development of the animals were detected. At the end of the rearing period histological investigations did not bring to light any sign of articular damage in the young.

Mutagenicity:

Eight in vitro mutagenicity tests have been conducted with ciprofloxacin.

Test results are listed below:

• Salmonella: Microsome Test (Negative)
• E. coli: DNA Repair Assay (Negative),
• Mouse Lymphoma Cell Forward Mutation Assay (Positive)
• Chinese Hamster V₇₉ Cell HGPRT Test (Negative),
• Syrian Hamster Embryo Cell Transformation Assay (Negative)
• Saccharomyces cerev.: Point Mutation Assay (Negative), Mitotic Crossover and Gene Conversion Assay (Negative)
• Rat Hepatocyte Primary Culture DNA Repair Assay (UDS) (Positive)

Thus, two of the eight tests were positive, but results of the following four in vivo test systems gave negative results:

• Rat Hepatocyte DNA Repair Assay
• Micronucleus Test (Mice)
• Dominant Lethal Test (Mice)
• Chinese Hamster Bone Marrow

Although two of the eight in-vitro assays (i.e. the Mouse Lymphoma Cell Forward Mutation Assay and the Rat Hepatocyte Primary Culture DNA Repair Assay (UDS)) were positive, all of the in-vivo test systems covering all relevant endpoints gave negative results.

In summary, ciprofloxacin poses no significant mutagenic potential. This assessment is confirmed by the negative outcome of the long-term carcinogenicity studies in mice and rats.

Special tolerability studies

It is known from comparative studies in animals, both with the older gyrase inhibitors (e.g. nalidixic and pipemidic acid) and the more recent ones (e.g. norfloxacin and ofloxacin), that this substance class produces a characteristic damage pattern. Kidney damage, cartilage damage in weight-bearing joints of immature animals, and eye damage may be encountered.

Renal tolerability

The crystallisation observed in the animal studies occurred preferentially under pH conditions that do not apply in man.

Compared to rapid infusion, a slow infusion of ciprofloxacin reduces the danger of crystal precipitation.

The precipitation of crystals in renal tubules does not immediately and automatically lead to kidney damage. In the animal studies damage occurred only after high doses, with correspondingly high levels of crystalluria. For example, although they always caused crystalluria, even high doses were tolerated over 6 months without damage and without foreign-body reactions occurring in individual distal renal tubules.

Damage to the kidneys without the presence of crystalluria has not been observed. The renal damage observed in animal studies must not, therefore, as is the case e.g. with the aminoglycosides, be regarded as a primary toxic action of ciprofloxacin on the kidney tissue, but as typical secondary inflammatory foreign-body reactions due to the precipitation of a crystalline complex of ciprofloxacin, magnesium, and protein.

Articular tolerability studies

As with other gyrase inhibitors, ciprofloxacin causes damage to the large, weight-bearing joints in immature 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 at high doses (1.3 to 3.5 times the therapeutic dose) caused articular changes after two weeks of treatment, which were still observed after 5 months. At therapeutic doses, no effects were observed.

Studies aimed at excluding cataractogenic effects

On the basis of the investigations it may be stated from a toxicological point of view that ciprofloxacin treatment does not involve any risk of cataract induction, particularly because in parental administration maximal bioavailability can be assumed and the duration of administration was 6 months.

Retina tolerability studies

Ciprofloxacin binds to the melanin containing structures including the retina. Potential effects of ciprofloxacin on the retina were assessed in various pigmented animal species. Ciprofloxacin treatment had no effect on the morphological structures of the retina and on electroretinographic findings.

Pharmaceutical Particulars

List of Excipients:

Tablets:

Ciproxin 250, Ciproxin, 500, Ciproxin 750

microcrystalline cellulose, maize starch, poly(1-vinyl-2-pyrrolidone) crosslinked, highly dispersed silicon dioxide, magnesium stearate, methylhydroxypropylcellulose, macrogol 4000, titanium dioxide (E171).

Suspension:

copolymer of ethyl acrylate and methyl methacrylate, magnesium stearate, methylhydroxypropylcellulose, polysorbate, polyvidone, lecithin, sucrose, strawberry flavour, medium chain triglycerides, water.

Infusion solution:

Ciproxin 200

lactic acid, sodium chloride, hydrochloric acid, water for injection.

Incompatibilities

The ciprofloxacin infusion solution is compatible with physiological saline, Ringer solution and Ringer lactate solution, 5% and 10% glucose solutions, 10% fructose solution, and 5% glucose solution with 0.225% NaCl or 0.45% NaCl. When ciprofloxacin infusion solutions are mixed with compatible infusion solutions, they should be administered shortly after admixture for microbiological and light sensitivity reasons.

Unless compatibility with other infusion solutions/drugs has been confirmed, the infusion solution must always be administered separately. The visual signs of incompatibility are e.g. precipitation, clouding, and discolouration.

Incompatibility appears with all infusion solutions/drugs that are physically or chemically unstable at the pH of the solution (e.g. penicillin's, heparin solutions), especially in combination with solutions adjusted to an alkaline pH (pH of the ciprofloxacin infusion solutions: 3.9-4.5).

No additions should be made to the mixed final ciprofloxacin suspension.

Shelf-life:

Special Precautions for Storage:

Ciprofloxacin IV solution

Since the infusion solution is photosensitive, the infusion bottles should be removed from the box only immediately before use. In daylight conditions complete efficacy is guaranteed for a period of 3 days.

Nature and Contents of Container:

Tablets

Foil, Strips of 14

Infusion Solution

Glass bottle

Suspension

Bottle, PET active ingredient microcapsule

Bottle, PET diluent

Instruction for Use / Handling:

Ciprofloxacin Suspension:

The small bottle contains the active substance, the large bottle contains the suspension fluid. Open both bottles.

Childproof cap: Press down according to instructions on the cap while turning to the left.

Pour the microcapsules completely into the large bottle with the suspension fluid.

Do not pour water into the suspension!

Reclose the large bottle properly according to the instructions on the cap and shake vigorously for about 15 seconds. The suspension is now ready to use.

Taking the ready-to-use suspension.

Take the prescribed amount of suspension by using the measuring spoon. Do not chew the microcapsules present in the suspension, simply swallow them. A drink of water may be taken afterwards. Reseal the bottle properly after use according to the instructions on the cap. The ready-to-use suspension is stable for 14 days when stored in a refrigerator or at ambient temperatures below 30 C. After treatment has been completed, discard any surplus suspension.

Shake vigorously each time before use for approx. 15 seconds

The graduated measuring spoon with the markings ½ is equivalent to 2.6 mL contains 2.5 mL of final suspension and 1/1 is equivalent to 5.2 mL contains 5.0 mL of final suspension. The graduated measuringspoon must be used for measuring the required prescribed amount of Ciprofloxacin Suspension 5 % or 10%.

Special precautions for use

Ciprofloxacin IV solution

At cool storage temperatures precipitation may occur, which will re-dissolve at room temperature. It is therefore recommended not to store the infusion solution in a refrigerator.

For glass bottles: For ease of use the infusion vial stopper should be penetrated in the central ring. Penetration of the outer ring may result in damage to the vial stopper.

Ciprofloxacin Suspension 5 % and 10 %:

Each consists of two individual components, Microcapsules and Suspension diluent. These should not be used after the expiration date has been reached.

Occasionally a slight yellow layer is observed on the surface of the sugar in the suspension. This has no influence on the pharmaceutical quality of the product.

The ready mixed final suspension is stable when stored in a refrigerator or at ambient temperatures below 30°C for 14 days. After this time it should not be taken.

Medicine Classification:

Prescription Medicine

Name and Address:

Bayer New Zealand Limited
3 Argus Place
Hillcrest, North Shore
Auckland 0627
New Zealand

Date of Preparation:

19 March 2008