Data Sheet
DP-Cipro
Ciprofloxacin 200 mg/100 ml Solution for Infusion
Qualitative and Quantitative Composition
Infusion solution
Each bottle of 100 ml infusion solution contains 200 mg ciprofloxacin. Sodium chloride content is 900 mg (15 mmol) equivalent to sodium 354 mg (15 mmol).
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:
| Intravenous | |
|---|---|
| Respiratory tract infection (according to severity and organism) |
2 x 200-400 mg |
| Urinary tract infections: | |
| - acute, uncomplicated | 2 x 100 mg |
| - cystitis in women (before menopause) | single dose 100 mg |
| - complicated | 2 x 200 mg |
| Gonorrhoea | |
| - extragenital | 2 x 100 mg |
| - acute, uncomplicated | single dose 100 mg |
| Diarrhoea | 2 x 200 mg |
| Other infections (see Indications) | 2 x 200-400 mg |
| Particularly severe, life threatening infections, i.e. - Streptococcal pneumonia - Recurrent infections in cystic fibrosis - Bone and joint infections - Septicaemia - Peritonitis In particular when Pseudomonas, Staphylococcus or Streptococcus is present |
3 x 400 mg |
| Inhalational anthrax (post-exposure) Drug administration should begin as soon as possible after suspected or confirmed exposure. |
2 x 400 mg |
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 10 mg/kg iv three times daily (maximum dose 1200 mg).
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 intravenous infusion 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.
Method of Administration
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.
Renal & Hepatic impairment
Adults
| 1. | Impaired renal function |
| 1.1 | Where creatinine clearance is between 31 and 60 ml/min/1.73m² or where the serum creatinine concentration is between 1.4 and 1.9 mg/100 ml the maximum daily dose should be 800 mg per day for an intravenous regimen. |
| 1.2 | Where creatinine clearance is equal or is less than 30 ml/min/1.73m² or where the serum creatinine concentration is equal or higher than 2.0 mg/100 ml the maximum daily dose should be 400 mg per day for an intravenous regimen. |
| 2. | Impaired renal function + haemodialysis Dose as in 1.2; on dialysis days after dialysis. |
| 3. | Impaired renal function + CAPD Addition of ciprofloxacin infusion solution to the dialysate (intraperitoneal): 50 mg ciprofloxacin / litre dialysate administered 4 times a day every 6 hours |
| 4. | Impaired liver function No dose adjustment is required. |
| 5. | Impaired renal and liver function Dose adjustment as in 1.1 and 1.2 |
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). 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
- DP-Cipro may cause tendonitis or tendon rupture.
- The risk of tendonitis or tendon rupture is increased in patients: over the age of 60 years; on concomitant systemic steroid therapy; or who have received a kidney, heart or lung transplant.
- DP-Cipro should not be used in patients with a history of fluoroquinolone associated tendonopathy.
- Tendonitis and tendon rupture risk is present during use and for 6 months following use of fluoroquinolones such as DP-Cipro.
- Prescribers should advise patients that at the first sign of tendon pain, inflammation or tendon rupture, to stop DP-Cipro, avoid exercise or use of the affected area and immediately contact their doctor.
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
The additional sodium load should be taken into account when using DP-Cipro 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.
Interaction With Other Medicaments And Other Forms Of Interaction
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.
Concomitant administration of ciprofloxacin and omeprazole results in a slight reduction of Cmax and AUC of ciprofloxacin.
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.
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.
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).
The simultaneous administration of ciprofloxacin and warfarin may intensify the action of warfarin.
In particular cases, concurrent administration of ciprofloxacin and glibenclamide can intensify the action of glibenclamide (hypoglycaemia).
Probenecid interferes with renal secretion of ciprofloxacin. Co-administration of probenecid and ciprofloxacin increases the ciprofloxacin serum concentrations.
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.
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 Contraindications).
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.
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.
| Reactions occurring in ≥1% and <10% of patients (i.e. Common) | Adverse Drug Reactions |
|---|---|
| Gastrointestinal disorders: | nausea, diarrhoea |
| General disorders and administration site conditions: | injection and infusion site reactions (only intravenous administration) |
| Reactions occurring in ≥ 0.1% and < 1% of patients (i.e. Uncommon) | |
| Infections and infestations: | candida infections |
| Gastrointestinal disorders: | vomiting, gastrointestinal and abdominal pains, dyspepsia, flatulence |
| Blood and lymphatic system disorders: | eosinophilia |
| Metabolism and nutritional disorder: | anorexia |
| Musculoskeletal, connective tissue and bone disorders: | arthralgia (joint pain) |
| Nervous system disorders: | headache, dizziness, sleep disorders, taste disorders |
| Skin and subcutaneous tissue disorders: | pruritus, rash, urticaria |
| Hepato-biliary disorders: | transient increase in transaminases, increased bilirubin |
| Psychiatric disorders: Renal and urinary disorders: General disorders and administration site conditions: Investigations: |
psychomotor hyperactivity/ agitation renal impairment unspecific pain, feeling unwell, fever transient increase in blood alkaline phosphatase |
| Reactions occurring in ≥ 0.01% and < 0.1% of patients (i.e. Rare) | |
| Infections and infestations: | antibiotic associated colitis (very rarely with possible fatal outcome) |
| Blood and lymphatic system disorders: | leukopenia, anemia, neutropenia, leukocytosis, thrombocytopenia, thrombocytaemia |
| Immune system disorders: | allergic reaction, allergic oedema/angiooedema |
| Metabolism and nutrition disorders: | hyperglycemia |
| Psychiatric disorders: | confusion and disorientation, anxiety reaction, abnormal dreams, depression, hallucinations |
| Nervous system disorders; | par- and dysaesthesia, hypoaesthesia, tremor, seizures, vertigo |
| Eye disorders: | visual disturbances |
| Ear and labyrinth disorders: | tinnitus, hearing loss |
| Cardiac disorders: | tachycardia |
| Vascular disorders: | vasodilatation, hypotension, syncope |
| Respiratory, thoracic and mediastinal disorders: | dyspnea (including asthmatic condition) |
| Hepato-biliary disorders: | transient hepatic impairment, jaundice, hepatitis (non infective) |
| Skin and subcutaneous tissue disorders: | photosensitivity reactions, unspecific blistering |
| Musculoskeletal, connective tissue and bone disorders: | myalgia, arthritis, increased muscle tone and cramping |
| Renal and urinary disorders: | renal failure, haematuria,crystalluria, tubulointerstitial nephritis |
| General disorders and administration site conditions: | oedema, sweating (hyperhidrosis) |
| Investigations: | prothrombin level abnormal, increased amylase |
| Reactions occurring in < 0.01% of patients (i.e. Very rare) |
|
| Blood and lymphatic system disorders: | haemolytic anaemia, agranulocytosis, pancytopenia (life threatening), bone marrow depression (life threatening) |
| Immune system disorders: | anaphylactic reaction, anaphylactic shock (life threatening), serum sickness-like reaction |
| Psychiatric disorders: | psychotic reactions |
| Nervous system disorders; | migraine, disturbed coordination, smell disorders, hyperesthesia, intracranial hypertension |
| Eye disorders: | visual colour distortions |
| Ear and labyrinth disorders: | hearing impaired |
| Vascular disorders: | vasculitis |
| Gastrointestinal disorders: | pancreatitis |
| Hepato-biliary disorders: | liver necrosis (very rarely progressing to life threatening hepatic failure) |
| Skin and subcutaneous tissue disorders: | petechiae, erythema multiforme minor, erythema nodosum, Stevens-Johnson syndrome, toxic epidermal necrolysis |
| Musculoskeletal, connective tissue and bone disorders: | muscular weakness, tendonitis, tendon rupture (predominantly Achilles tendon), exacerbation of symptoms of myasthenia gravis |
| General disorders and administration site conditions: | gait disturbance |
The following undesirable effects have a higher frequency category in the subgroups of patients receiving intravenous or sequential (intravenous to oral) treatment:
Common: vomiting, transient increase in transaminase, rash.
Uncommon: thrombocytopenia, thrombocytaemia, confusion and disorientation, hallucinations, par- and dysaesthesia, seizures, vertigo, visual disturbances, hearing loss, tachycardia, vasodilatation, hypotension, transient hepatic impariement, jaundice, renal failure, oedema.
Rare: pancytopenia, bone marrow depression, anaphylactic shock, psychotic reactions, migraine, smell disorders, hearing impaired, vasculitis, pancreatitis, liver necrosis, petechiae, tendon rupture.
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.
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.
Resistance to ciprofloxacin develops slowly and in stages (multiple-step type).
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.
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.
| Possible combination drugs include: | |
|---|---|
| for Pseudomonas: | azlocillin, ceftazidime |
| for Streptococci: | mezlocillin, azlocillin, other effective β-lactam antibiotics |
| for Staphylococci: | β-lactam antibiotics, particularly isoxazolylpenicillins, vancomycin |
| for anaerobes: | metronidazole, clindamycin |
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 intravenous regimen. (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 400 mg intravenously every 12 hours is 4.56 µg/mL. The mean trough serum concentration at steady-state for intravenous regimen 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 Tmax (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 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 400 mg administered intravenously.
| Mean Ciprofloxacin Serum Concentrations (mg/L) after Intravenous Administration [Time from start of infusion (in hours)] |
|
|---|---|
| Time (h) | 200 mg i.v. (30 min inf.) |
| 0.50 | 3.4 |
| 0.75 | 1.40 |
| 1.00 | 1.00 |
| 1.50 | 0.70 |
| 2.50 | 0.50 |
| 4.50 | 0.30 |
| 8.50 | 0.10 |
| 12.50 | 0.10 |
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 200 mg ciprofloxacin 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 20 mg/kg bd orally or 10 mg/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.
| Excretion of Ciprofloxacin (% of dose) Intravenous Administration |
||
|---|---|---|
| Urine | Faeces | |
| Ciprofloxacin | 61.5 | 15.2 |
| Metabolites (M1-M4) | 9.5 | 2.6 |
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, Cmax and AUC were not age-dependent. No notable increase in Cmax and AUC upon multiple dosing (10 mg/kg/TID) was observed. In 10 children with severe sepsis, less than 1 year of age Cmax 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.
Preclinical Safety Data
Acute toxicity
Depending on the individual species, the LD50 after intravenous infusion is 125-290 mg/kg.
| Species | Mode of administration | LD50 (mg/kg) |
|---|---|---|
| Mouse | i.v. | Approx. 290 |
| Rat | i.v. | Approx. 145 |
| Rabbit | i.v. | Approx. 125 |
| Dog | i.v. | Approx. 250 |
Subacute toxicity
Subacute tolerability studies over 4 weeks.
Parenteral 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.
Parenteral 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.
Parenteral 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
Other ingredients
DL-lactic acid, sodium chloride, hydrochloride acid and water for injection.
Incompatibilities
The ciprofloxacin infusion solution is compatible with 0.9 % sodium chloride solution, Ringer's solution, Ringer's lactate solution, 5 % glucose solution, 10 % glucose solution, 10 % fructose solution, water for injection, 5 % glucose + 0.225 % sodium chloride solution and 5 % glucose + 0.45 % sodium chloride solution. 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).
Shelf-life
3 years, store below 25°C
Special Precautions for use
Since the infusion solution is photosensitive, the infusion bottles should be removed from the box only immediately before use.
Any unused portion should be discarded.
Special precautions for storage
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.
Medicine Classification
Prescription Medicine
Name and Address
Douglas Pharmaceuticals Ltd
P O Box 45-027
AUCKLAND 0651
Ph: (09) 835-0660
Fax: (09) 835-0665
Date of Preparation
July 2008