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2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Ciprofloxacin
200mg Ciprofloxacin (as lactate) in a 100ml solution (2mg/ml)
For excipients, see 6.1.
Each glass bottle with 100 mL infusion solution contains 200 mg ciprofloxacin. The sodium chloride content is 900 mg (15.4 mmol).
For a full list of excipients, see section 6.1.
3. PHARMACEUTICAL form
Solution for Infusion.
Type II (Ph. Eur.) infusion bottle containing 100ml of a clear, yellowish, solution for infusion.
Solution for infusion.
Clear, nearly colourless to slightly yellowish solution.
The pH-value of the solution for infusion ranges from 3.9 to 4.5.
4.1 Therapeutic indications
Adults:
Ciprofloxacin is indicated for the treatment of the following infections caused by sensitive bacteria:
Respiratory tract infections: e.g. lobar and bronchopneumonia, acute and chronic bronchitis, acute exacerbation of cystic fibrosis, bronchiectasis, empyema. Ciprofloxacin is not recommended as first-line therapy for the treatment of pneumococcal pneumonia. Ciprofloxacin may be used for treating Gram-negative pneumonia.
Urinary tract infections: e.g. uncomplicated and complicated urethritis, cystitis, pyelonephritis, prostatitis, epididymitis.
Gastro-intestinal infections: e.g. enteric fever, infective diarrhoea.
Children and adolescents:
Ciprofloxacin may be used for the 2nd and 3rd line treatment of complicated urinary tract infections and pyelonephritis in children and adolescents 1-17 years of age and for the treatment of acute pulmonary exacerbation of cystic fibrosis associated with P. aeruginosa in children and adolescents 5-17 years of age. The use of Ciproxin in paediatric patients with complicated urinary tract infections and pyelonephritis should be restricted to infections caused by organisms, for which Ciproxin is the drug of choice, based on the results of antimicrobial susceptibility testing. Treatment should be initiated by a physician, who is experienced in the treatment of severe infections in children and adolescents and after careful benefit/risk evaluation, due to possible adverse events related to joints and/or surrounding tissues (see 4.4. and 5.1.).
Inhalation Anthrax in Adults and in Children: To reduce the incidence or progression of disease following confirmed or suspected exposure to aerosolised Bacillus anthracis.
Consideration should be given to official guidance on the appropriate use of antibacterial agents.
Ciproxin Solution for Infusion 2mg/ml is 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.
Adults
· Lower respiratory tract infections due to Gram-negative bacteria
- exacerbations of chronic obstructive pulmonary disease
- broncho-pulmonary infections in cystic fibrosis or in bronchiectasis
- pneumonia
· Chronic suppurative otitis media
· Acute exacerbation of chronic sinusitis especially if these are caused by Gram-negative bacteria
· Urinary tract infections
· Epididymo-orchitis including cases due to Neisseria gonorrhoeae
· Pelvic inflammatory disease including cases due to Neisseria gonorrhoeae
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.
· Infections of the gastro-intestinal tract (e.g. travellers` diarrhoea)
· Intra-abdominal infections
· Infections of the skin and soft tissue caused by Gram-negative bacteria
· Malignant external otitis
· Infections of the bones and joints
· Treatment of infections in neutropenic patients
· Prophylaxis of infections in neutropenic patients
· Inhalation anthrax (post-exposure prophylaxis and curative treatment)
Children and adolescents
· Broncho-pulmonary infections in cystic fibrosis caused by Pseudomonas aeruginosa
· Complicated urinary tract infections and pyelonephritis
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).
4.2 Posology and method of administration
General dosage recommendations: the dosage of intravenous ciprofloxacin 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.
The dosage range for adults is 100-400mg twice daily, or 400mg three times daily for severe life-threatening infections. The product should be infused directly and administered by short-term infusion over a period of 30-60 minutes. Initial intravenous administration may be followed by oral treatment.
The following dosages for specific types of infection are recommended:
Table 1: Recommended Adult (including the Elderly) Dosage (refer to Section 5.1)
Indication
Dosage
(mg ciprofloxacin)
Treatment
Upper and lower urinary tract infections
100 mg b.d.
Upper and lower respiratory tract infections (depending on severity and sensitivity of causative organism).
200-400mg b.d.
For severe life-threatening respiratory tract infections and those where the causative organism is less sensitive.
400mg t.d.s.
Pneumococcal pneumonia (second-line where physician considers it appropriate)
Cystic fibrosis patients with pseudomonal lower RTI *
Gastro-intestinal infections
Empiric treatment of severe life-threatening infection and where the causative organism is less sensitive or difficult-to-treat, i.e. Pseudomonas or staphylococci.
400mg t.d.s. **
Inhalation Anthrax
400mg b.d.
* As the pharmacokinetics of ciprofloxacin remain unchanged in patients with cystic fibrosis, the low bodyweight of these patients should be taken into consideration when determining dosage.
** Can be reduced to 400mg b.d. if causative organism is found to be fully sensitive.
_____________________________________________________________________
Initial intravenous administration may be followed by oral treatment at an equivalent dosage. Pharmacokinetic studies have shown an intravenous dosage of 400mg twice daily to be equivalent to 500mg twice daily orally, and an intravenous dosage of 400mg three times daily equivalent to 750mg twice daily orally (in terms of AUC).
Impaired Renal Function
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.
Where creatinine clearance is equal or 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.
For patients with impaired renal function undergoing haemodialysis the maximum daily dose should be 400 mg per day for an intravenous regimen. Ciprofloxacin should be administered on dialysis days after dialysis.
For patients with impaired renal function and on continuous ambulatory peritoneal dialysis (CAPD), ciprofloxacin infusion solution should be added to the dialysate (intraperitoneal): 50 mg ciprofloxacin / litre dialysate administered 4 times a day every 6 hours.
Impaired Hepatic Function
No adjustment of dosage is necessary. In cases of impaired renal and liver function follow instructions as for impaired renal function
Elderly
Elderly patients should receive a dose as low as possible depending on the severity of their illness and the creatinine clearance.
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 10mg/kg i.v. three times daily (maximum daily dose 1200mg) for a period of 10-14 days. The infusion should be administered over 60 minutes.
Sequential therapy can also be used. Dosage as follows: 10mg/kg i.v. three times daily (maximum daily dose 1200mg) followed by 20mg/kg orally twice daily (maximum daily dose 1500mg).
Complicated urinary tract infections and pyelonephritis
For complicated urinary tract infections or pyelonephritis the dose is 6 to 10 mg/kg IV every 8 hours with a maximum of 400 mg per dose.
Inhalation anthrax
For the indication of inhalation anthrax, the risk-benefit assessment indicates that administration of ciprofloxacin to paediatric patients at a dose of 10 mg/kg i.v. twice daily (maximum daily dose of 800 mg) is appropriate.
Dosing in children with impaired renal and/or hepatic function has not been studied.
Duration of Treatment
The duration of treatment depends upon the severity of infection, clinical response and bacteriological findings.
For acute infections, the usual treatment period is five to seven days. Generally, treatment should be continued for at least 3 days after the signs and symptoms of the infection have disappeared.
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.
For complicated urinary tract infections or pyelonephritis the duration of treatment in paediatric patients is 10-21 days.
For inhalation anthrax, drug administration should begin as soon as possible after confirmed or suspected exposure and should be continued for 60 days.
Prolonged treatment or use in chronic conditions should only be initiated under Consultant direction with regular surveillance.
The dosage is determined by the indication, the severity and the site of the infection, the susceptibility to ciprofloxacin of the causative organism(s), the renal function of the patient and, in children and adolescents the body weight.
The duration of treatment depends on the severity of the illness and on the clinical and bacteriological course.
After intravenous initiation of treatment, the treatment can be switched to oral treatment with tablet or suspension if clinically indicated at the discretion of the physician. IV treatment should be followed by oral route as soon as possible.
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.
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.
Indications
Daily dose in mg
Total duration of treatment (including switch to oral therapy as soon as possible)
Infections of the lower respiratory tract
400 mg twice daily to 400 mg three times a day
7 to 14 days
Infections of the upper respiratory tract
Acute exacerbation of chronic sinusitis
Chronic suppurative otitis media
Malignant external otitis
400 mg three times a day
28 days up to 3 months
Urinary tract infections
Complicated and uncomplicated pyelonephritis
7 to 21 days, it can be continued for longer than 21 days in some specific circumstances (such as abscesses)
Prostatitis
2 to 4 weeks (acute)
Genital tract infections
Epididymo-orchitis and pelvic inflammatory diseases
at least 14 days
Infections of the gastro-intestinal tract and intra-abdominal infections
Diarrhoea caused by bacterial pathogens including Shigella spp. other than Shigella dysenteriae type 1 and empirical treatment of severe travellers’ diarrhoea
400 mg twice daily
1 day
Diarrhoea caused by Shigella dysenteriae type 1
5 days
Diarrhoea caused by Vibrio cholerae
3 days
Typhoid fever
7 days
Intra-abdominal infections due to Gram-negative bacteria
5 to 14 days
Infections of the skin and soft tissue
Bone and joint infections
max. of 3 months
Treatment of infections or prophylaxis of infections in neutropenic patients
Ciprofloxacin should be co-administered with appropriate antibacterial agent(s) in accordance to official guidance.
Therapy should be continued over the entire period of neutropenia
Inhalation anthrax post-exposure prophylaxis and curative treatment for persons requiring parenteral treatment
Drug administration should begin as soon as possible after suspected or confirmed exposure.
60 days from the confirmation of Bacillus anthracis exposure
10 mg/kg body weight three times a day with a maximum of 400 mg per dose.
10 to 14 days
6 mg/kg body weight three times a day to 10 mg/kg body weight three times a day with a maximum of 400 mg per dose.
10 to 21 days
Inhalation anthrax post-exposure curative treatment for persons requiring parenteral treatment
10 mg/kg body weight twice daily to 15 mg/kg body weight twice daily with a maximum of 400 mg per dose.
Other severe infections
According to the type of infections
Geriatric patients
Geriatric patients should receive a dose selected according to the severity of the infection and the patient`s creatinine clearance.
Renal and hepatic impairment
Recommended starting and maintenance doses for patients with impaired renal function:
Creatinine Clearance [mL/min/1.73 m²]
Serum
Creatinine [µmol/L]
Intravenous Dose [mg]
> 60
< 124
See Usual Dosage.
30‑60
124 to 168
200‑400 mg every 12 h
< 30
> 169
200‑400 mg every 24 h
Patients on haemodialysis
200‑400 mg every 24 h (after dialysis)
Patients on peritoneal dialysis
In patients with impaired liver function no dose adjustment is required.
Method of administration
Ciproxin should be checked visually prior to use. It must not be used if cloudy.
Ciprofloxacin should be administered by intravenous infusion. For children, the infusion duration is 60 minutes.
In adult patients, infusion time is 60 minutes for 400 mg Ciproxin and 30 minutes for 200 mg Ciproxin. 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 (see section 6.6).
4.3 Contraindications
Ciprofloxacin is contra-indicated in patients who have shown hypersensitivity to ciprofloxacin or any of the excipients, or other quinolone anti-infectives, or who have a history of quinolone-induced tendon disorder.
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) can occur.
· Hypersensitivity to the active substance, to other quinolones or to any of the excipients (see section 6.1).
· Concomitant administration of ciprofloxacin and tizanidine (see section 4.5).
4.4 Special warnings and precautions for use
In the event of hypersensitivity, which in some instances can occur after the first administration, therapy should be discontinued.
Ciprofloxacin should be used with caution in epileptics and patients with existing central nervous system disorders or a history of convulsive disorders and only if the benefits of treatment are considered to outweigh the risk of possible CNS side-effects. CNS side-effects have been reported after first administration of ciprofloxacin in some patients. Treatment should be discontinued if the side-effects, depression or psychoses lead to self-endangering behaviour (see also Section 4.8).
Crystalluria related to the use of ciprofloxacin has been reported. Patients receiving ciprofloxacin should be well hydrated and excessive alkalinity of the urine should be avoided.
Patients with a family history of or actual defects in glucose-6-phosphate dehydrogenase activity are prone to haemolytic reactions with quinolones, and so ciprofloxacin should be used with caution in these patients.
Tendon inflammation and rupture may occur with quinolone antibiotics. Such reactions have been observed particularly in older patients and in those treated concurrently with corticosteroids. At the first sign of pain or inflammation, patients should discontinue ciprofloxacin and rest the affected limbs.
Patients with pre-existent significant renal or hepatic disorders should be carefully monitored to detect any deterioration in function. It should only be administered with great caution to persons with renal insufficiency, or severe dehydration.
Eradication of infection due to Pseudomonas in persons with cystic fibrosis only occurs in a minority of cases, particularly after repeat courses of treatment with ciprofloxacin. Cyclical or alternating antibacterial therapies may help reduce the number of resistant strains.
There is a risk of pseudomembranous colitis with broad-spectrum antibiotics possibly leading to a fatal outcome. It is important to consider this in patients suffering from severe, persistent diarrhoea. With ciprofloxacin this effect has been reported rarely. If pseudomembranous colitis is suspected treatment with ciprofloxacin should be stopped and appropriate treatment given (e.g. oral vancomycin). Drugs that inhibit peristalsis must not be given.
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.
Laboratory tests may give abnormal findings if performed whilst patients are receiving ciprofloxacin e.g. increased alkaline phosphatase; increases in liver function tests e.g. transaminases and cholestatic jaundice, especially in patients with previous liver damage.
In patients for whom sodium intake is of medical concern (e.g. patients with congestive heart failure, renal failure, nephrotic syndrome), the sodium content of Ciproxin Solution for Infusion 2mg/ml, 100ml should be taken into account. Ciproxin Solution for Infusion 2mg/ml, 100ml contains 900mg/100ml sodium chloride equivalent to 154mmol sodium per litre. The sodium chloride content of the 100ml container is 900mg (15.4mmol sodium).
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 over the time was not statistically significant between groups. Treatment should only be initiated after a careful benefit/risk evaluation, due to possible adverse events related to joints and/or surrounding tissue.
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 (children aged 1 – 17 years) and for the use in inhalational anthrax (post-exposure) has not been evaluated in clinical trials and the clinical experience is limited. The use of ciprofloxacin should follow the official guidance.
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.
Streptococcal Infections (including Streptococcus pneumoniae)
Ciprofloxacin is not recommended for the treatment of streptococcal infections due to inadequate efficacy.
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.
Infections of the bones and joints
Ciprofloxacin should be used in combination with other antimicrobial agents depending on the results of the microbiological documentation.
Inhalational anthrax
Use in humans is based on in-vitro susceptibility data and on animal experimental data together with limited human data. Treating physicians should refer to national and /or international consensus documents regarding the treatment of anthrax.
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.
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.
Tendinitis and tendon rupture (especially Achilles tendon), sometimes bilateral, may occur with ciprofloxacin, as soon as the first 48 hours of treatment. The risk of tendinopathy may be increased in elderly patients or in patients concomitantly treated with corticosteroids (see section 4.8).
At any sign of tendinitis (e.g. painful swelling, inflammation), ciprofloxacin treatment should be discontinued. Care should be taken to keep the affected limb at rest.
Ciprofloxacin should be used with caution in patients with myasthenia gravis (see section 4.8).
Photosensitivity
Ciprofloxacin has been shown to cause photosensitivity reactions. Patients taking ciprofloxacin should be advised to avoid direct exposure to either extensive sunlight or UV irradiation during treatment (see section 4.8).
Central Nervous System
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
The in-vitro activity of ciprofloxacin against Mycobacterium tuberculosis might give false negative bacteriological test results in specimens from patients currently taking ciprofloxacin.
Injection Site Reaction
Local intravenous 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.
NaCl Load
In patients for whom sodium intake is of medical concern (patients with congestive heart failure, renal failure, nephrotic syndrome, etc.), the additional sodium load should be taken into account (for sodium chloride content, see section 2).
4.5 Interaction with other medicinal products and other forms of interaction
Probenecid interferes with renal secretion of ciprofloxacin. Co-administration of probenecid and ciprofloxacin increases the ciprofloxacin serum concentrations.
Concomitant administration of ciprofloxacin and omeprazole results in slight reduction of Cmax and AUC of ciprofloxacin.
In a crossover study, 10 healthy subjects were given ciprofloxacin 500mg or placebo twice daily for three days, at the end of which a single dose of tizanidine 4mg was given. There was an increase in tizanidine serum concentrations (Cmax increase: 7-fold, range: 4 to 21-fold; AUC increase: 10-fold, range: 6 to 24-fold) when given concomitantly with ciprofloxacin compared to placebo. Associated with the increased serum concentrations was a potentiated hypotensive and sedative effect. Tizanidine must not be administered together with ciprofloxacin (refer to Section 4.3).
Increased plasma levels of theophylline have been observed following concurrent administration with ciprofloxacin. It is recommended that the dose of theophylline should be reduced and plasma levels of theophylline monitored. The reaction between theophylline and ciprofloxacin is potentially life-threatening. Therefore, where monitoring of plasma levels is not possible, the use of ciprofloxacin should be avoided in patients receiving theophylline. Particular caution is advised in those patients with convulsive disorders.
Renal tubular transport of methotrexate may be inhibited by concomitant administration of ciprofloxacin potentially leading to increased plasma levels of methotrexate. This may increase the risk of methotrexate associated toxic reactions. Therefore, patients receiving methotrexate therapy should be carefully monitored when concomitant ciprofloxacin therapy is indicated.
Animal data have shown that high doses of quinolones in combination with some non-steroidal anti-inflammatory drugs, (e.g. fenbufen, but not acetylsalicylic acid) can lead to convulsions.
Transient increases in serum creatinine have been seen following concomitant administration of ciprofloxacin and ciclosporin. Therefore, monitoring of serum creatinine levels is advisable (twice a week).
Prolongation of bleeding time has been reported during concomitant administration of ciprofloxacin and oral anti-coagulants.
The simultaneous administration of quinolones and glibenclamide can on occasion potentiate the effect of glibenclamide resulting in hypoglycaemia.
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.
Ciprofloxacin inhibits CYP1A2 and thus may cause increased serum concentration of concomitantly administered substances metabolised by this enzyme (e.g. theophylline, clozapine, tacrine, ropinirole, tizanidine, duloxetine). Therefore, patients taking these substances concomitantly with ciprofloxacin should be monitored closely for clinical signs of overdose, and determination of serum concentrations, especially of theophylline, may be necessary.
Phenytoin levels may be altered when Ciproxin is used concomitantly.
Ciprofloxacin may interfere with estimations of urinary 17-ketosteroids, or vanillylmandelic acid.
Concomitant use with phenylpropionic acid-derived non-steroidal anti-inflammatory drugs may lead to toxicity, possibly because of renal effects.
Effects of other medicinal products on ciprofloxacin:
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 (Cmax 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.
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.
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.
Oral anticoagulants
Simultaneous administration of ciprofloxacin with warfarin may augment its anti-coagulant effects. There have been many reports of increases in oral anti-coagulant 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.
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 Cmax and AUC of ropinirole by 60% and 84%, respectively. Monitoring of ropinirole-related side effects and dose adjustment as appropriate is recommended during and shortly after co-administration with ciprofloxacin (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).
4.6 Pregnancy and lactation
Ciprofloxacin should not be used during pregnancy or in women at risk of pregnancy, nor during lactation.
Reproduction studies performed in mice, rats and rabbits using parenteral and oral administration did not reveal any evidence of teratogenicity, impairment of fertility or impairment of peri-/post-natal development. However, as with other quinolones, ciprofloxacin has been shown to cause arthropathy in immature animals, and therefore its use during pregnancy or in women capable of child-bearing is not recommended. Studies have indicated that ciprofloxacin is secreted in breast milk. Administration to nursing mothers is thus not recommended.
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.
4.7 Effects on ability to drive and use machines
Ciprofloxacin could result in impairment of the patient's ability to drive or operate machinery, particularly 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.
4.8 Undesirable effects
Adverse drug reactions based on all clinical studies with ciprofloxacin (oral, parenteral) sorted by CIOMS III categories of frequency using MedDRA terminology are listed below. The most frequently reported adverse reactions are nausea, diarrhoea and injection and infusion site reactions (intravenous administration only).
Adverse drug reactions derived from post-marketing reports are included in the column frequency “not known”.
The most commonly reported adverse drug reactions (ADRs) are nausea, diarrhoea, vomiting, transient increase in transaminases, rash, and injection and infusion site reactions.
ADRs derived from clinical studies and post-marketing surveillance with Ciproxin (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.
Old Table:
Common
1% to < 10%
Uncommon
0.1% to < 1%
Rare
0.01% to < 0.1%
Very rare
< 0.01%
Not known
Infections and Infestations
Candida infections
Antibiotic associated colitis (very rarely with possible fatal outcome, refer to Section 4.4)
Blood and Lymphatic System Disorders
Eosinophilia
Leukopenia
Anaemia
Neutropenia
Leukocytosis
Thrombocytopenia
Thrombocythaemia
Haemolytic anaemia
Agranulocytosis
Pancytopenia (life-threatening)
Bone marrow depression (life-threatening)
Immune System Disorders
Allergic reaction
Allergic oedema / angiooedema
Anaphylactic reaction
Anaphylactic shock (life-threatening)
Serum sickness-like reaction
Metabolism and Nutrition Disorders
Anorexia
Hyperglycaemia
Psychiatric Disorders
Psychomotor hyperactivity / agitation
Confusion and disorientation
Anxiety reaction
Abnormal dreams
Depression
Hallucinations
Psychotic reactions (which may progress to self-endangering behaviour)
Nervous System Disorders
Headache
Dizziness
Sleep disorders
Taste disorders (usually reversible upon discontinuation of treatment)
Par- and Dysaesthesia
Hypoaesthesia
Tremor
Seizures
Vertigo
Somnolence
Migraine
Disturbed coordination
Smell disorders
Hyperaesthesia
Intracranial hypertension
Eye Disorders
Visual disturbances
Visual colour distortions
Ear and Labyrinth Disorders
Tinnitus
Hearing loss
Hearing impaired
Cardiac Disorders
Tachycardia
Vascular Disorders
Vasodilatation
Hypotension
Syncope
Vasculitis
Respiratory, Thoracic and Mediastinal Disorders
Dyspnoea (including asthmatic condition)
Gastrointestinal Disorders
Nausea
Diarrhoea
Vomiting
Gastrointestinal and abdominal pains
Dyspepsia
Flatulence
Dysphagia
Pancreatitis
Hepato-biliary Disorders
Transient increase in transaminases
Increased bilirubin
Transient hepatic impairment
Jaundice
Hepatitis (non infective)
Liver necrosis (very rarely progressing to life-threatening hepatic failure)
Skin and Subcutaneous Tissue Disorders
Rash
Pruritus
Urticaria
Photosensitivity reactions
Unspecific blistering
Petechiae
Erythema multiforme minor
Erythema nodosum
Stevens-Johnson syndrome
Toxic epidermal necrolysis.
Musculoskeletal, Connective Tissue and Bone Disorders
Arthralgia
Myalgia
Arthritis
Increased muscle tone and cramping
Muscular weakness
Tendonitis
Tendon rupture (predominantly Achilles tendon, refer to Section 4.4)
Exacerbation of symptoms of myasthenia gravis
Renal and Urinary Disorders
Renal impairment
Renal failure
Haematuria
Crystalluria
Tubulointerstitial nephritis
General Disorders and Administration Site Conditions
Injection and infusion site reactions (only intravenous administration)
Unspecific pain
Feeling unwell
Fever
Oedema
Sweating (hyperhidrosis)
Gait disturbance
Investigations
Transient increase in blood alkaline phosphatase
Prothrombin level abnormal
Increased amylase
Updated Table:
System Organ Class
≥ 1/100 to < 1/10
≥ 1/1 000 to < 1/100
≥ 1/10 000 to < 1/1 000
Very Rare
< 1/10 000
Frequency not known
(cannot be estimated from available data)
Mycotic superinfections
Antibiotic associated colitis (very rarely with possible fatal outcome) (see section 4.4)
Thrombocytaemia
Anaphylactic shock (life-threatening) (see section 4.4)
Psychotic reactions (see section 4.4)
Taste disorders
Seizures (see section 4.4)
Olfactory nerve disorders
Peripheral neuropathy (see section 4.4)
Hearing loss / Hearing impaired
Ventricular arrhythmia, QT prolongation, torsades de pointes *
Hepatobiliary Disorders
Increase in transaminases
Hepatic impairment
Cholestatic icterus
Hepatitis
Liver necrosis (very rarely progressing to life-threatening hepatic failure) (see section 4.4)
Photosensitivity reactions (see section 4.4)
Erythema multiforme
Stevens-Johnson syndrome (potentially life-threatening)
Toxic epidermal necrolysis (potentially life-threatening)
Musculoskeletal pain (e.g. extremity pain, back pain, chest pain)
Tendinitis
Tendon rupture (predominantly Achilles tendon) (see section 4.4)
Exacerbation of symptoms of myasthenia gravis (see section 4.4)
Renal failure Haematuria
Crystalluria (see section 4.4)
Asthenia
Increase in blood alkaline phosphatase
* 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).
The following undesirable effects have a higher frequency category in the subgroup of patients receiving intravenous or sequential (intravenous to oral) treatment:
Common:
Vomiting, transient increase in transaminases, rash
Uncommon:
Thrombocytopenia, thrombocythaemia, confusion and disorientation, hallucinations, par- and dysaesthesia, seizures, vertigo, visual disturbances, hearing loss, tachycardia, vasodilatation, hypotension, transient hepatic impairment, 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
The incidence of arthropathy, mentioned above, is referring to data collected in studies with adults. In children arthropathy is reported to occur commonly (See also 4.4 Special warning and precaution for use).
The following undesirable effects have a higher frequency category in the subgroups of patients receiving intravenous or sequential (intravenous to oral) treatment:
Vomiting, Transient increase in transaminases, Rash
Thrombocytopenia, Thrombocytaemia, Confusion and disorientation, Hallucinations, Par- and dysaesthesia, Seizures, Vertigo, Visual disturbances, Hearing loss, Tachycardia, Vasodilatation, Hypotension, Transient hepatic impairment, Cholestatic icterus, Renal failure, Oedema
Pancytopenia, Bone marrow depression, Anaphylactic shock, Psychotic reactions, Migraine, Olfactory nerve disorders, Hearing impaired, Vasculitis, Pancreatitis, Liver necrosis, Petechiae, Tendon rupture
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).
4.9 Overdose
Based on the limited information available in two cases of ingestion of over 18g of ciprofloxacin, reversible renal toxicity has occurred. Therefore, apart from routine emergency measures, it is recommended to monitor renal function, including urinary pH and acidify, if required, to prevent crystalluria. Patients must be kept well hydrated, and in the case of renal damage resulting in prolonged oliguria, dialysis should be initiated.
Serum levels of ciprofloxacin are reduced by dialysis.
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.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Fluoroquinolone antibacterials, ATC code: J01 MA 02.
Mechanism of action
As a fluoroquinolone antibacterial agent, ciprofloxacin acts on the bacterial enzymes DNA-gyrase and topoisomerase IV, which are required for bacterial DNA replication, transcription, repair, and recombination.
Mechanism of resistance
In vitro investigations have shown that resistance to ciprofloxacin is commonly due to mutations in bacterial topoisomerases and usually develops slowly and gradually ('multiple-step' type). Cross-resistance between fluoroquinolones may occur when the mechanism of resistance is due to mutations in bacterial gyrases. However, single mutations may not result in clinical resistance, but multiple mutations generally do result in clinical resistance to 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. Plasmid mediated resistance encoded by qnr-genes have been reported. Resistance mechanisms that inactivate penicillins, cephalosporins, aminoglycosides, macrolides, and tetracyclines do not interfere with the antibacterial activity of ciprofloxacin.
In vitro Susceptibility Data
In accordance to the guidance document CPMP/EWP/558/95 rev 1 EUCAST clinical MIC breakpoints for moxifloxacin are listed together with Clinical and Laboratory Standards Institute (CLSI, formerly NCCLS) interpretative criteria for the susceptibility testing of ciprofloxacin where breakpoints differ. CLSI disc breakpoints are also included since the majority of susceptibility testing in Europe is performed by this method.
Pharmacotherapeutic group: Fluoroquinolones, ATC code: J01MA02
Mechanism of action:
As a fluoroquinolone antibacterial agent, the bactericidal action of ciprofloxacin results from the inhibition of both type II topoisomerase (DNA-gyrase) and topoisomerase IV, required for bacterial DNA replication, transcription, repair and recombination.
PK/PD relationship:
Efficacy mainly depends on the relation between the maximum concentration in serum (Cmax) 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:
Table 2: EUCAST clinical MIC breakpoints for ciprofloxacin (excerpt from 2006-01-31 v2.2, www.escmid.org/sites/index_f.aspx?par=2.4)
Organism
Susceptible
(mg/L)
Resistant
Enterobacteriaceae
0.5
>1
Pseudomonas
Staphylococcus1
1
Streptococcus pneumoniae2
0.125
>2
Haemophilus influenzae and Moraxella catarrhalis3
>0.5
Neisseria gonorrhoeae
0.03
>0.06
Non-species related breakpoints4
1. Staphylococcus spp. - breakpoints for ciprofloxacin and ofloxacin relate to high dose therapy.
2. Streptococcus pneumoniae - wild-type S. pneumoniae are not considered susceptible to ciprofloxacin or ofloxacin and are therefore categorized as intermediate.
3. Strains with MIC values above the S/I breakpoint are very rare or not yet reported. The identification and antimicrobial susceptibility tests on any such isolate must be repeated and if the result is confirmed the isolate sent to a reference laboratory. Until there is evidence regarding clinical response for confirmed isolates with MIC above the current resistant breakpoint (in italics) they should be reported resistant. Haemophilus/Moraxella - fluoroquinolone low-level resistance (ciprofloxacin MIC:s of 0.125 - 0.5 mg/L) may occur in H. influenzae . There is no evidence that low-level resistance is of clinical importance in respiratory tract infections with H. influenzae.
4. Non-species related breakpoints have been determined mainly on the basis of PK/PD data and are independent of MIC distributions of specific species. They are for use only for species that have not been given a species-specific breakpoint and not for those species where susceptibility testing is not recommended (marked with -- or IE in the table).
Clinical and Laboratory Standards Institute™ (CLSI), formerly NCCLS breakpoints are presented in the table below for MIC testing (mg/L) or disc diffusion testing (zone diameter [mm]) using a 5-μg ciprofloxacin disc.
EUCAST Recommendations
Microorganisms
Enterobacteria
S £ 0.5 mg/L
R > 1 mg/L
Acinetobacter
S £ 1 mg/L
Staphylococcus spp.1
Haemophilus influenzae and
Moraxella catarrhalis
R > 0.5 mg/L
S £ 0.03 mg/L
R > 0.06 mg/L
Neisseria meningitidis
Non-species-related breakpoints*
1 Staphylococcus spp. - breakpoints for ciprofloxacin relate to high dose therapy.
* Non-species-related breakpoints have been determined mainly on the basis of PK/PD data and are independent of MIC distributions of specific species. They are for use only for species that have not been given a species-specific breakpoint and not for those species where susceptibility testing is not recommended.
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.
Table 3: Clinical and Laboratory Standards Institute™ (CLSI) MIC (mg/L) and disc diffusion breakpoints (mm) (M100-S16, 2006):
Intermediate
1 a
21 b
2 a
16-20 b
4 a
15 b
Pseudomonas aeruginosa and other non-Enterobacteriaceae
1a
21b
2a
16-20b
4a
15b
Staphylococcus spp.
Enterococcus spp.
Haemophilus spp.
1c
21d
-
Neisseria gonorrhoeae spp
0.06e
41e
0.12-0.5 e
28-40 e
1 e
27 e
a This interpretive standard is applicable only to broth dilution tests using CAMHB incubated in ambient air at 33 to 35°C (do not exceed 35°C) for 16 - 20 hours
b This interpretive standard is applicable only to disc diffusion tests using Mueller-Hinton agar incubated in ambient air at 33 to 35°C (do not exceed 35°C) for 16 - 18 hours
c This interpretive standard is applicable only to broth dilution susceptibility tests with Haemophilus influenzae and Haemophilus parainfluenzae using Haemophilus test medium (HTM) broth incubated in ambient air at 35°C ± 2 °C for 20 – 24 hours
d This interpretive standard is applicable only to disc diffusion tests with H. influenzae and H . parainfluenzae using HTM incubated in 5% CO2 at 35°C ± 2 °C for 16 - 18 hours
e This interpretive standard is applicable only to agar based susceptibility tests using GC agar and 1% defined growth supplement at 36 ±1°C (not to exceed 37°C) in 5% CO2 for 20 - 24 hours.
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 least some types of infections is questionable.
Table 4: Groupings of relevant species according to ciprofloxacin susceptibility
Groupings of relevant species according to ciprofloxacin susceptibility (for Streptococcus species see section 4.4)
Commonly susceptible species
COMMONLY SUSCEPTIBLE SPECIES
Aerobic Gram-positive micro-organisms
Bacillus anthracis
Bacillus anthracis (1)
Aerobic Gram-negative micro-organisms
Citrobacter freundii *
Haemophilus influenzae *
Moraxella catarrhalis *
Shigella spp.
Aeromonas spp.
Brucella spp.
Citrobacter koseri
Francisella tularensis
Haemophilus ducreyi
Haemophilus influenzae*
Legionella spp.
Moraxella catarrhalis*
Pasteurella spp.
Salmonella spp.*
Shigella spp. *
Vibrio spp.
Yersinia pestis
Anaerobic micro-organisms
Mobiluncus
Other micro-organisms
Chlamydia trachomatis ($)
Chlamydia pneumoniae ($)
Mycoplasma hominis ($)
Mycoplasma pneumoniae ($)
Species for which acquired resistance may be a problem
SPECIES FOR WHICH ACQUIRED RESISTANCE MAY BE A PROBLEM
Staphylococcus aureus (methicillin-susceptible) *
Streptococcus pneumoniae *
Enterococcus faecalis ($)
Staphylococcus spp. *(2)
Burkholderia cepacia +
Campylobacter spp.+ *
Enterobacter aerogenes
Enterobacter cloacae *
Escherichia coli *
Klebsiella oxytoca
Klebsiella pneumoniae *
Morganella morganii + *
Neisseria gonorrhoeae *
Proteus mirabilis + *
Proteus vulgaris *
Providencia spp.
Pseudomonas aeruginosa + *
Pseudomonas fluorescens +
Salmonella spp. *
Serratia marcescens + *
Acinetobacter baumannii+
Burkholderia cepacia +*
Campylobacter spp.+*
Citrobacter freundii*
Escherichia coli*
Klebsiella pneumoniae*
Morganella morganii*
Neisseria gonorrhoeae*
Proteus mirabilis*
Proteus vulgaris*
Pseudomonas aeruginosa*
Pseudomonas fluorescens
Serratia marcescens*
Inherently Resistant Organisms
Staphylococcus aureus (methicillin-resistant)
Stenotrophomonas maltophilia
*Clinical efficacy has been demonstrated for susceptible isolates in approved clinical indications
+ Resistance rate > 10% in most EU countries
Peptostreptococcus spp.
Propionibacterium acnes
INHERENTLY RESISTANT ORGANISMS
Actinomyces
Enteroccus faecium
Listeria monocytogenes
Excepted as listed above
Mycoplasma genitalium
Ureaplasma urealitycum
* Clinical efficacy has been demonstrated for susceptible isolates in approved clinical indications
+ Resistance rate ≥ 50% in one or more EU countries
($): Natural intermediate susceptibility in the absence of acquired mechanism of resistance
(1): Studies have been conducted in experimental animal infections due to inhalations of Bacillus anthracis spores; these studies reveal that antibiotics starting early after exposition avoid the occurrence of the disease if the treatment is made up to the decrease of the number of spores in the organism under the infective dose. The recommended use in human subjects is based primarily on in-vitro susceptibility and on animal experimental data together with limited human data. Two-month treatment duration in adults with oral ciprofloxacin given at the following dose, 500 mg bid, is considered as effective to prevent anthrax infection in humans. The treating physician should refer to national and /or international consensus documents regarding treatment of anthrax.
(2): Methicillin-resistant S. aureus very commonly express co-resistance to fluoroquinolones. The rate of resistance to methicillin is around 20 to 50% among all staphylococcal species and is usually higher in nosocomial isolates.
5.2 Pharmacokinetic properties
Absorption of oral doses of ciprofloxacin 250mg, 500mg and 750mg tablet formulation occurs rapidly, mainly from the small intestine, the half-life of absorption being 2-15 minutes. Plasma levels are dose-related and peak 0.5-2.0 hours after oral dosing. The AUC also increases dose proportionately after administration of both single and repeated oral (tablet) and intravenous doses. The pharmacokinetic profile of intravenous ciprofloxacin was shown to be linear over the dose range (100mg-400mg). Following intravenous administration of ciprofloxacin, the mean maximum plasma concentrations were achieved at the end of the infusion period. That is, for a 100mg or 200mg dose, 30 minutes, and for a 400mg dose, 60 minutes. Reported plasma levels at this time point were 1.8mg/l, 3.4mg/l and 3.9mg/l, respectively. The absolute bioavailability is approximately 70-80% and ciprofloxacin is subject to only slight first-pass metabolism.
Distribution of ciprofloxacin within tissues is wide and the volume of distribution high, though slightly lower in the elderly. Protein binding is low (between 19-40%). Ciprofloxacin is present in plasma largely in a non-ionised form.
Only 10-20% of a single oral or intravenous dose is eliminated as metabolites (which exhibit lower activity than the parent drug). Four different antimicrobially active metabolites have been reported, desethyleneciprofloxacin (M1), sulphociprofloxacin (M2), oxaciprofloxacin (M3) and formylciprofloxacin (M4). M2 and M3 account for one third each of metabolised substance and M1 is found in small amounts (1.3-2.6% of the dose). M4 has been found in very small quantities (<0.1% of the dose). M1-M3 have antimicrobial activity comparable to nalidixic acid and M4 found in the smallest quantity has antimicrobial activity similar to that of norfloxacin.
Elimination of ciprofloxacin and its metabolites occurs rapidly, primarily by the kidney. After single oral and intravenous doses of ciprofloxacin, 55% and 75% respectively are eliminated by the kidney and 39% and 14% in the faeces within 5 days. Renal elimination takes place mainly during the first 12 hours after dosing and renal clearance levels suggest that active secretion by the renal tubules occurs in addition to normal glomerular filtration. Renal clearance is between 0.18-0.3 l/h.kg and total body clearance between 0.48-0.60 l/h.kg. Approximately 1% of a ciprofloxacin dose is excreted via the biliary route. The elimination kinetics are linear and after repeated dosing at 12 hourly intervals, no further accumulation is detected after the distribution equilibrium is attained (at 4-5 half-lives). The elimination half-life of unchanged ciprofloxacin over a period of 24-48 hours post-dose is 3.1-5.1 hours. A total body clearance of approximately 35 l/h was observed after intravenous administration.
Some studies carried out with ciprofloxacin in severely renally impaired patients (serum creatinine >265 micromole/l or creatinine clearance <20ml/minute) demonstrated either a doubling of the elimination half-life, or fluctuations in half-life in comparison with healthy volunteers, whereas other studies showed no significant correlation between elimination half-life and creatinine clearance. However, it is recommended that in severely renally impaired patients, the total daily dose should be reduced by half, although monitoring of drug serum levels provides the most reliable basis for dose adjustment as necessary.
The data available to substantiate the pharmacokinetic data in children are limited. In a study in children Cmax and AUC were not age-dependent (above one year of age). No notable increase in Cmax and AUC upon multiple dosing (10 mg/kg three times daily) 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 and the bioavailability of the oral suspension ranges from 50 to 80%.
Inhalation anthrax: Ciprofloxacin serum concentrations achieved in humans serve as a surrogate endpoint reasonably likely to predict clinical benefit and provide the basis for the recommended doses.
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.
Comparison of the pharmacokinetic parameters for a twice a day and three times a day intravenous dose regimen indicated no evidence of drug accumulation for ciprofloxacin and its metabolites.
A 60-minute intravenous infusion of 200 mg ciprofloxacin or the oral administration of 250 mg ciprofloxacin, both given every 12 hours, produced an equivalent area under the serum concentration time curve (AUC).
A 60-minute intravenous infusion of 400 mg ciprofloxacin every 12 hours was bioequivalent to a 500 mg oral dose every 12 hours with regard to AUC.
The 400 mg intravenous dose administered over 60 minutes every 12 hours resulted in a Cmax similar to that observed with a 750 mg oral dose.
A 60-minute infusion of 400 mg ciprofloxacin every 8 hours is equivalent with respect to AUC to 750 mg oral regimen given every 12 hours.
Distribution
Protein binding of ciprofloxacin is low (20‑30%). Ciprofloxacin is present in plasma largely in a non-ionised form and has a large steady state distribution volume of 2‑3 L/kg body weight. 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) where total concentrations exceeding those of plasma concentrations are reached.
Metabolism
Low concentrations of four metabolites have been reported, which were identified as: desethyleneciprofloxacin (M 1), sulphociprofloxacin (M 2), oxociprofloxacin (M 3) and formylciprofloxacin (M 4). The metabolites display in-vitro antimicrobial activity but to a lower degree than the parent compound.
Ciprofloxacin is known to be a moderate inhibitor of the CYP 450 1A2 iso-enzymes.
Elimination
Ciprofloxacin is largely excreted unchanged both renally and, to a smaller extent, faecally.
Excretion of ciprofloxacin (% of dose)
Intravenous Administration
Urine
Faeces
61.5
15.2
Metabolites (M1-M4)
9.5
2.6
Renal clearance is between 180‑300 mL/kg/h and the total body clearance is between 480‑600 mL/kg/h. Ciprofloxacin undergoes both glomerular filtration and tubular secretion. Severely impaired renal function leads to increased half lives of ciprofloxacin of up to 12 h.
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.
The pharmacokinetic data in paediatric patients are limited.
In a study in children Cmax and AUC were not age-dependent (above one year of age). No notable increase in Cmax and AUC upon multiple dosing (10 mg/kg three times daily) was observed.
In 10 children with severe sepsis Cmax 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%.
5.3 Preclinical safety data
Following extensive oral and intravenous toxicology testing with ciprofloxacin, only two findings which may be considered relevant to the use of ciprofloxacin in man were observed. Crystalluria was noted in those species of animals which had a normally alkaline urine. Kidney damage without the presence of crystalluria was not observed. This effect is considered a secondary inflammatory foreign-body reaction, due to the precipitation of a crystalline complex of ciprofloxacin, magnesium and protein in the distal tubule system of the kidneys. This is considered not to be a problem in man, because the urine is normally acidic. However, to avoid the occurrence of crystalluria, patients should be well hydrated and excessive alkalinity of the urine avoided.
Articular tolerability studies
As reported for 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 caused severe articular changes at therapeutic doses after two weeks of treatment, which were still observed after 5 months. Additionally, because of the potential of arthropathy, the use of ciprofloxacin during pregnancy, in women capable of child bearing and in nursing mothers is not recommended.
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:
As reported for 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 caused severe articular changes at therapeutic doses after two weeks of treatment, which were still observed after 5 months.
6.1 List of excipients
Lactic Acid (0.01%),
Sodium Chloride
Concentrated Hydrochloric Acid
Water for Injections
Lactic acid solution 20 %,
Sodium chloride,
Hydrochloric acid concentrated,
Water for injections.
6.2 Incompatibilities
Ciproxin Solution for Infusion 2mg/ml, 100ml is incompatible with injection solutions (e.g. penicillins, heparin solutions) which are chemically or physically unstable at its pH of 3.9-4.5. Unless compatibility is proven, the infusion should always be administered separately. For compatible co-infusion solutions see Section 6.6.
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
Unless compatibility with other solutions/drugs has been confirmed, the infusion solution must always be administered separately. The visual signs of incompatibility are e.g. precipitation, clouding, and discoloration.
Incompatibility appears with all infusion solutions/drugs that are physically or chemically unstable at the pH of the solutions (e.g. penicillins, heparin solutions), especially in combination with solutions adjusted to an alkaline pH (pH of ciprofloxacin solutions: 3.9 – 4.5).
6.3 Shelf life
Four years.
Chemical and physical in-use stability has been demonstrated for a minimum of 24 hours when stored below 25°C.
From a microbiological point of view, unless the method of opening/reconstitution/dilution precludes the risk of microbial contamination, the product should be used immediately.
If not used immediately, in-use storage times and conditions are the responsibility of the user.
4 years
Chemical and physical in-use stability has been demonstrated for 24 hours at room temperature (15 °C to 25 °C). From a microbiological point of view, unless the method of opening and mixing with co-infusion solutions precludes the risk of microbial contamination, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user.
6.4 Special precautions for storage
Keep the bottle in the outer carton. No special precautions are required during the normal 30-60 minute infusion period. If the product is inadvertently removed from the outer carton, the stability of the product is maintained for a period of up to three days in daylight.
Do not refrigerate or freeze Ciproxin Solution for Infusion 2mg/ml, 100ml. If the product is inadvertently refrigerated, crystals may form. However, these will redissolve at room temperature and do not affect the product's characteristics.
Keep in the outer carton in order to protect from light. Do not refrigerate or freeze.
6.5 Nature and contents of container
Type II, internally siliconised, colourless glass infusion bottles with type I for infusion, matt grey PTFE-coated, siliconised chlorobutyl stoppers, containing 100ml of Ciproxin Solution for Infusion 2mg/ml, 100ml, with a cardboard outer.
One of the following primary packaging materials is used:
Colourless type 2 glass bottle inside siliconized with gray siliconized chlorobutyl (foil clad PTFE) or bromobutyl stopper
Pack sizes of 1, 5 or 40 bottles containing 100 mL of solution for infusion each.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
Ciproxin Solution for Infusion 2mg/ml, 100ml should be infused directly and be administered by short-term intravenous infusion over a period of 30-60 minutes. The product should not be mixed with other drug products which are chemically or physically unstable at its pH of 3.9-4.5 (see Section 6.2). However, Ciproxin Solution for Infusion 2mg/ml, 100ml has been shown to be compatible with Ringer's solution, 0.9% sodium chloride solution, 5% and 10% glucose solutions, glucose/saline and fructose 10% solution. Unless compatibility is proven, the infusion solution should always be administered separately.
The ciprofloxacin infusion solution is compatible with Ringer solution, Ringer lactate solution, 5 % and 10 % glucose solutions, and 5 % and 10 % fructose solutions. When ciprofloxacin infusion solutions are mixed with compatible infusion solutions, for microbial reasons and light sensitivity these solutions must be administered shortly after admixture.
As the infusion solution is sensitive to light, only remove the bottles from the folding box for use. In daylight the full efficacy of the solution is guaranteed over a period of 3 days.
For single use only.
At cool temperatures precipitation may occur, which will re-dissolve at room temperature (15°C – 25 °C).
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.
Any unused solution should be disposed of.
10. DATE OF REVISION OF THE TEXT
November 2007
September 2010
Correction to section 6.5.
Section 7:
Name and address of the MA holder has been changed from Bayer UK to
Bayer Limited, The Atrium, Blackthorn Road, Dublin 18.
Section 8:
The Product Authorisation Number has changed from PA 21/36/1 to PA 1410/28/6.
Section 10:
The date of revision of the text has been amended to January 2008.