- Approval Id
- c7d2e02a8feb1a5c
- Drug Approval Emc Name
- Ciprofloxacin 250mg film-coated tablets
- Drug Name
- Ciprofloxacin 250mg film-coated tablets
- Company Name
- Aurobindo Pharma - Milpharm Ltd.
- Company Address
- Odyssey Business Park, Ares Block, West End Road, South Ruislip, Middlesex, HA4 6QD
- Company Website
- http://www.aurobindo.com
- Company Telephone
- + 44 (0)208 845 8811
- Company Medical Info Email
- medinfo@aurobindo.com
- Company Customer Care Direct Line
- +44 (0)208 845 8811
- Company Medical Info Fax
- +44 (0)208 845 8795
- Atc Code
- J01MA02
- Legal Category
- Prescription only medicine
- Authorisation Holder
- Milpharm Limited
Ares Block, Odyssey Business Park
West End Road
Ruislip HA4 6QD
United Kingdom
- Authorisation Number
- PL 16363/0427
- Authorisation Date
- 24/06/2015
- Instruction Authorisation Holder
- Milpharm Limited
Ares Block, Odyssey Business Park
West End Road
Ruislip HA4 6QD
United Kingdom
- Instruction Authorisation Number
- PL 16363/0427
- Instruction Authorisation Date
- 24/06/2015
- Instruction Composition
- Each film-coated tablet contains 250 mg ciprofloxacin (as hydrochloride).
For the full list of excipients, see section 6.1.
- Instruction Dosage Form
- Film-coated tablet.
White to off white, round shaped (diameter 11.1 mm), film coated tablets, with a score line on one side and debossed with 'F' and '23' with a score line in between on the other side. The tablet can be divided into equal doses.
- Instruction Clinical Particulars
- 4.1 Therapeutic indications
Because of the risk of prolonged, disabling and potentially irreversible serious adverse drug reactions (see section 4.4 and section 4.8) this product must only be prescribed when other antibiotics that are commonly recommended for the infection are inappropriate. This applies to all indications listed below. Situations where other antibiotics are considered to be inappropriate are where:
• there is resistance to other first-line antibiotics recommended for the infection;
• other first-line antibiotics are contraindicated in an individual patient;
• other first-line antibiotics have caused side effects requiring treatment to be stopped;
• treatment with other first-line antibiotics has failed.
Ciprofloxacin film-coated tablets are indicated for the treatment of the following infections (see sections 4.4 and 5.1). Special attention should be paid to available information on resistance to ciprofloxacin before commencing therapy.
\*\*\*Adults\*\*\*
• Lower respiratory tract infections due to Gram-negative bacteria
- pneumonia
- broncho-pulmonary infections in cystic fibrosis or in bronchiectasis
• Chronic suppurative otitis media
• Acute exacerbation of chronic sinusitis especially if these are caused by Gram-negative bacteria
• Acute pyelonephritis
• Complicated urinary tract infections
• Bacterial prostatitis
• Genital tract infections
| | |
| --- | --- |
| | - gonococcal urethritis and cervicitis due to susceptible \*Neisseria gonorrhoeae\* - epididymo-orchitis including cases due to susceptible \*Neisseria gonorrhoeae\* - pelvic inflammatory disease including cases due to susceptible \*Neisseria gonorrhoeae\* |
• Intra-abdominal infections
• Infections of the skin and soft tissue caused by Gram-negative bacteria
• Infections of the bones and joints
• Inhalation anthrax (post-exposure prophylaxis and curative treatment)
Ciprofloxacin may be used in the management of neutropenic patients with fever that is suspected to be due to a bacterial infection.
In \*\*exacerbations of chronic obstructive pulmonary disease\*\* Ciprofloxacin should be used only when it is considered inappropriate to use other antibacterial agents that are commonly recommended for the treatment of these infections.
In \*\*uncomplicated acute cystitis\*\* Ciprofloxacin should be used only when it is considered inappropriate to use other antibacterial agents that are commonly recommended for the treatment of these infections.
\*\*\*Children and adolescents\*\*\*
• Broncho-pulmonary infections due to \*Pseudomonas aeruginosa\* in patients with cystic fibrosis
• Complicated urinary tract infections and acute pyelonephritis
• Inhalation anthrax (post-exposure prophylaxis and curative treatment)
Ciprofloxacin may also be used to treat severe infections in children and adolescents when this is considered to be necessary.
Treatment should be initiated only by physicians who are experienced in the treatment of cystic fibrosis and/or severe infections in children and adolescents (see sections 4.4 and 5.1).
Consideration should be given to official guidance on the appropriate use of antibacterial agents.4.2 Posology and method of administration
\*\*Posology\*\*
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.
Treatment of infections due to certain bacteria (e.g. \*Pseudomonas\* \*aeruginosa\*, \*Acinetobacter\* or \*Staphylococci\*) may require higher ciprofloxacin doses and co-administration with other appropriate antibacterial agents.
Treatment of some infections (e.g. pelvic inflammatory disease, intra-abdominal infections, infections in neutropenic patients and infections of bones and joints) may require co-administration with other appropriate antibacterial agents depending on the pathogens involved.
\*\*\*Adults\*\*\*
| | | | |
| --- | --- | --- | --- |
| \*\*Indications\*\* | | \*\*Daily dose in mg\*\* | \*\*Total duration of treatment (potentially including initial parenteral treatment with ciprofloxacin)\*\* |
| Infections of the lower respiratory tract | | 500 mg twice daily to 750 mg twice daily | 7 to 14 days |
| Infections of the upper respiratory tract | Acute exacerbation of chronic sinusitis | 500 mg twice daily to 750 mg twice daily | 7 to 14 days |
| Chronic suppurative otitis media | 500 mg twice daily to 750 mg twice daily | 7 to 14 days |
| Malignant external otitis | 750 mg twice daily | 28 days up to 3 months |
| Urinary tract infections (see section 4.4) | Uncomplicated cystitis | 250 mg twice daily to 500 mg twice daily | 3 days |
| In pre-menopausal women, 500 mg single dose may be used | |
| Complicated cystitis, Uncomplicated pyelonephritis | 500 mg twice daily | 7 days |
| Complicated pyelonephritis | 500 mg twice daily to 750 mg twice daily | at least 10 days, it can be continued for longer than 21 days in some specific circumstances (such as abscesses) |
| Prostatitis | 500 mg twice daily to 750 mg twice daily | 2 to 4 weeks (acute) to 4 to 6 weeks (chronic) |
| Genital tract infections | Gonococcal uretritis and cervicitis | 500 mg as a single dose | 1 day (single dose) |
| Epididymo-orchitis and pelvic inflammatory diseases | 500 mg twice daily to 750 mg twice daily | 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 | 500 mg twice daily | 1 day |
| Diarrhoea caused by \*Shigella dysenteriae\* type 1 | 500 mg twice daily | 5 days |
| Diarrhoea caused by \*Vibrio cholerae\* | 500 mg twice daily | 3 days |
| Typhoid fever | 500 mg twice daily | 7 days |
| Intra-abdominal infections due to Gram-negative bacteria | 500 mg twice daily to 750 mg twice daily | 5 to 14 days |
| Infections of the skin and soft tissue | | 500 mg twice daily to 750 mg twice daily | 7 to 14 days |
| Bone and joint infections | | 500 mg twice daily to 750 mg twice daily | max. of 3 months |
| Neutropenic patients with fever that is suspected to be due to a bacterial infection. Ciprofloxacin should be co-administered with appropriate antibacterial agent(s) in accordance to official guidance. | | 500 mg twice daily to 750 mg twice daily | Therapy should be continued over the entire period of neutropenia |
| Prophylaxis of invasive infections due to \*Neisseria meningitides\* | | 500 mg as a single dose | 1 day (single dose) |
| Inhalation anthrax post-exposure prophylaxis and curative treatment for persons able to receive treatment by oral route when clinically appropriate. Drug administration should begin as soon as possible after suspected or confirmed exposure. | | 500 mg twice daily | 60 days from the confirmation of \*Bacillus anthracis\* exposure |
\*\*\*Paediatric population\*\*\*
| | | |
| --- | --- | --- |
| \*\*Indications\*\* | \*\*Daily dose in mg\*\* | \*\*Total duration of treatment (potentially including initial parenteral treatment with ciprofloxacin)\*\* |
| Cystic fibrosis | 20 mg/kg body weight twice daily with a maximum of 750 mg per dose. | 10 to 14 days |
| Complicated urinary tract infections and pyelonephritis | 10 mg/kg body weight twice daily to 20 mg/kg body weight twice daily with a maximum of 750 mg per dose. | 10 to 21 days |
| Inhalation anthrax post-exposure prophylaxis and curative treatment for persons able to receive treatment by oral route when clinically appropriate. Drug administration should begin as soon as possible after suspected or confirmed exposure. | 10 mg/kg body weight twice daily to 15 mg/kg body weight twice daily with a maximum of 500 mg per dose. | 60 days from the confirmation of \*Bacillus anthracis\* exposure |
| Other severe infections | 20 mg/kg body weight twice daily with a maximum of 750 mg per dose. | According to the type of infections |
\*\*\*Elderly patients\*\*\*
\*Elderly\* patients should receive a dose selected according to the severity of the infection and the patient's creatinine clearance.
\*\*\*Patients with 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]\*\* | \*\*Oral Dose [mg]\*\* |
| > 60 | < 124 | See Usual Dosage. |
| 30-60 | 124 to 168 | 250-500 mg every 12 h |
| <30 | > 169 | 250-500 mg every 24 h |
| Patients on haemodialysis | > 169 | 250-500 mg every 24 h (after dialysis) |
| Patients on peritoneal dialysis | > 169 | 250-500 mg every 24 h |
In patients with impaired liver function no dose adjustment is required.
Dosing in children with impaired renal and/or hepatic function has not been studied.
\*Method of administration\*
Tablets are to be swallowed unchewed with fluid. They can be taken independent of mealtimes. If taken on an empty stomach, the active substance is absorbed more rapidly. Ciprofloxacin tablets should not be taken with dairy products (e.g. milk, yoghurt) or mineral-fortified fruit-juice (e.g. calcium-fortified orange juice) (see section 4.5).
In severe cases or if the patient is unable to take tablets (e.g. patients on enteral nutrition), it is recommended to commence therapy with intravenous ciprofloxacin until a switch to oral administration is possible.4.3 Contraindications
• Hypersensitivity to the active substance, to other quinolones or to any of the excipients listed in section 6.1.
• Concomitant administration of ciprofloxacin and tizanidine (see section 4.5).4.4 Special warnings and precautions for use
The use of ciprofloxacin should be avoided in patients who have experienced serious adverse reactions in the past when using quinolone or fluoroquinolone containing products (see section 4.8). Treatment of these patients with ciprofloxacin should only be initiated in the absence of alternative treatment options and after careful benefit/risk assessment (see also section 4.3).
\*\*\*Prolonged, disabling and potentially irreversible serious adverse drug reactions\*\*\*
Cases of prolonged (continuing for months or years), disabling and potentially irreversible serious adverse drug reactions affecting different, sometimes multiple, body systems (including musculoskeletal, nervous, psychiatric and senses) have been reported in patients receiving quinolones and fluoroquinolones irrespective of their age and pre-existing risk factors. There are no pharmacological treatments established to be effective treatments of the symptoms of long lasting or disabling side effects associated with fluoroquinolones. Ciprofloxacin should be discontinued immediately at the first signs or symptoms of any serious adverse reaction and patients should be advised to contact their prescriber for advice, so that symptoms can be appropriately investigated and to avoid further exposure which could potentially worsen adverse reactions
\*\*\*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.
\*\*\*Genital tract infections\*\*\*
Gonococcal uretritis, cervicitis, epididymo-orchitis and pelvic inflammatory diseases may be caused by fluoroquinolone-resistant Neisseria gonorrhoeae \*isolates\*.
Therefore, ciprofloxacin should be administered for the treatment of gonococcal uretritis or cervicitis only if ciprofloxacin-resistant \*Neisseria gonorrhoeae\* can be excluded.
For epididymo-orchitis and pelvic inflammatory diseases, empirical ciprofloxacin should only be considered in combination with another appropriate antibacterial agent (e.g. a cephalosporin) unless ciprofloxacin resistant \*Neisseria gonorrhoeae\* can be excluded. If clinical improvement is not achieved after 3 days of treatment, the therapy should be reconsidered.
\*\*Urinary tract infections\*\*
Resistance to fluoroquinolones of \*Escherichia coli\* – the most common pathogen involved in urinary tract infections – varies across the European Union. Prescribers are advised to take into account the local prevalence of resistance in \*Escherichia coli\* to quinolones.
The single dose of ciprofloxacin that may be used in uncomplicated cystitis in pre-menopausal women is expected to be associated with lower efficacy than the longer treatment duration. This is all the more to be taken into account as regards the increasing resistance level of \*Escherichia coli\* to quinolones.
\*\*\*Intra-abdominal infections\*\*\*
There are limited data on the efficacy of ciprofloxacin in the treatment of post-surgical intra-abdominal infections.
\*\*\*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.
\*\*\*Paediatric population\*\*\*
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 (see section 4.8)..
\*\*\*Broncho-pulmonary infections in cystic fibrosis\*\*\*
Clinical trials have included children and adolescents aged 5-17 years. More limited experience is available in treating children between 1 and 5 years of age.
\*\*\*Complicated urinary tract infections and pyelonephritis\*\*\*
Ciprofloxacin treatment of urinary tract infections should be considered when other treatments cannot be used, and should be based on the results of the microbiological documentation.
Clinical trials have included children and adolescents aged 1-17 years.
\*\*\*Other specific severe infections\*\*\*
Other severe infections in accordance with official guidance, or after careful benefit-risk evaluation when other treatments cannot be used, or after failure to conventional therapy and when the microbiological documentation can justify a ciprofloxacin use.
The use of ciprofloxacin for specific severe infections other than those mentioned above has not been evaluated in clinical trials and the clinical experience is limited. Consequently, caution is advised when treating patients with these infections.
\*\*\*Hypersensitivity\*\*\*
Hypersensitivity and allergic reactions, including anaphylaxis and anaphylactoid reactions, may occur following a single dose (see section 4.8) and may be life-threatening. If such reaction occurs, ciprofloxacin should be discontinued and an adequate medical treatment is required.
\*\*\*Musculoskeletal System\*\*\*
Ciprofloxacin should generally not be used in patients with a history of tendon disease/disorder related to quinolone treatment. Nevertheless, in very rare instances, after microbiological documentation of the causative organism and evaluation of the risk/benefit balance, ciprofloxacin may be prescribed to these patients for the treatment of certain severe infections, particularly in the event of failure of the standard therapy or bacterial resistance, where the microbiological data may justify the use of ciprofloxacin.
\*\*\*Tendinitis and tendon rupture\*\*\*
Tendinitis and tendon rupture (especially but not limited to Achilles tendon), sometimes bilateral, may occur as early as within 48 hours of starting treatment with quinolones and fluoroquinolones and have been reported to occur even up to several months after discontinuation of treatment. The risk of tendinitis and tendon rupture is increased in older patients, patients with renal impairment, patients with solid organ transplants, and those treated concurrently with corticosteroids. Therefore, concomitant use of corticosteroids should be avoided.
At the first sign of tendinitis (e.g. painful swelling, inflammation) the treatment with ciprofloxacin should be discontinued and alternative treatment should be considered. The affected limb(s) should be appropriately treated (e.g. immobilisation). Corticosteroids should not be used if signs of tendinopathy occur.
Ciprofloxacin should be used with caution in patients with myasthenia gravis, because symptoms can be exacerbated (see section 4.8).
\*\*\*Vision disorders\*\*\*
If vision becomes impaired or any effects on the eyes are experienced, an eye specialist should be consulted immediately.
\*\*\*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\*\*\*
Ciprofloxacin like other quinolones are known to trigger seizures or lower the seizure threshold. Cases of status epilepticus have been reported. Ciprofloxacin should be used with caution in patients with CNS disorders which may be predisposed to seizure. If seizures occur ciprofloxacin should be discontinued (see section 4.8). Psychiatric reactions may occur even after the first administration of ciprofloxacin. In rare cases, depression or psychosis can progress to suicidal ideations/thoughts culminating in attempted suicide or completed suicide. In the occurrence of such cases, ciprofloxacin should be discontinued.
\*\*\*Peripheral neuropathy\*\*\*
Cases of sensory or sensorimotor polyneuropathy resulting in paraesthesia, hypaesthesia, dysesthesia, or weakness have been reported in patients receiving quinolones and fluoroquinolones. Patients under treatment with ciprofloxacin should be advised to inform their doctor prior to continuing treatment if symptoms of neuropathy such as pain, burning, tingling, numbness, or weakness develop in order to prevent the development of potentially irreversible condition (see section 4.8).
\*\*\*Cardiac disorders\*\*\*
Caution should be taken when using fluoroquinolones, including ciprofloxacin, in patients with known risk factors for prolongation of the QT interval such as, for example:
• congenital long QT syndrome
• concomitant use of drugs that are known to prolong the QT interval (e.g. Class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics)
• uncorrected electrolyte imbalance (e.g. hypokalaemia, hypomagnesaemia)
• cardiac disease (e.g. heart failure, myocardial infarction, bradycardia)
Elderly patients and women may be more sensitive to QTc-prolonging medications. Therefore, caution should be taken when using fluoroquinolones, including ciprofloxacin, in these populations. (See section 4.2 Elderly patients, section 4.5, section 4.8, section 4.9).
\*\*\*Dysglycaemia\*\*\*
As with all quinolones, disturbances in blood glucose, including both hypoglycaemia and hyperglycaemia have been reported, usually in diabetic patients receiving concomitant treatment with an oral hypoglycaemic agent (e.g., glibenclamide) or with insulin. Cases of hypoglycaemic coma have been reported. In diabetic patients, careful monitoring of blood glucose is recommended (see section 4.8).
\*\*\*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.
\*\*\*Impaired renal function\*\*\*
Since ciprofloxacin is largely excreted unchanged via renal pathway dose adjustment is needed in patients with impaired renal function as described in section 4.2 to avoid an increase in adverse drug reactions due to accumulation of ciprofloxacin.
\*\*\*Hepatobiliary system\*\*\*
Cases of hepatic necrosis and life-threatening hepatic failure have been reported with ciprofloxacin (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, olanzapine, ropinirole, tizanidine, duloxetine, \*\*agomelatine\*\*). 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.
Aortic aneurysm and dissection, and heart valve regurgitation/incompetence
Epidemiologic studies report an increased risk of aortic aneurysm and dissection, particularly in elderly patients, and of aortic and mitral valve regurgitation after intake of fluoroquinolones. Cases of aortic aneurysm and dissection, sometimes complicated by rupture (including fatal ones), and of regurgitation/incompetence of any of the heart valves have been reported in patients receiving fluoroquinolones (see section 4.8).
Therefore, fluoroquinolones should only be used after careful benefit-risk assessment and after consideration of other therapeutic options in patients with positive family history of aneurysm disease, or congenital heart valve disease, or in patients diagnosed with pre-existing aortic aneurysm and/or aortic dissection, or heart valve disease, or in presence of other risk factors or conditions predisposing
- for aortic aneurysm and dissection and heart valve regurgitation/incompetence (e.g. connective tissue disorders such as Marfan syndrome, Ehlers-Danlos syndrome, Turner syndrome, Behcet's disease, hypertension, rheumatoid arthritis) or additionally
- for aortic aneurysm and dissection (e.g. vascular disorders such as Takayasu arteritis or giant cell arteritis, or known atherosclerosis, or Sjögren's syndrome) or additionally
- for heart valve regurgitation/incompetence (e.g. infective endocarditis).
The risk of aortic aneurysm and dissection, and their rupture may also be increased in patients treated concurrently with systemic corticosteroids.
In case of sudden abdominal, chest or back pain, patients should be advised to immediately consult a physician in an emergency department.
Patients should be advised to seek immediate medical attention in case of acute dyspnoea, new onset of heart palpitations, or development of oedema of the abdomen or lower extremities.
\*\*\*Sodium\*\*\*
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.4.5 Interaction with other medicinal products and other forms of interaction
\*\*\*Effects of other products on ciprofloxacin:\*\*\*
\*\*\*Drugs known to prolong QT interval\*\*\*
Ciprofloxacin, like other fluoroquinolones, should be used with caution in patients receiving drugs known to prolong QT interval (e.g. Class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) (see section 4.4).
\*\*\*Chelation Complex Formation\*\*\*
The simultaneous administration of ciprofloxacin (oral) and multivalent cation-containing drugs and mineral supplements (e.g. calcium, magnesium, aluminium, iron), polymeric phosphate binders (e.g. sevelamer or lanthanum carbonate), sucralfate or antacids, and highly buffered drugs (e.g. didanosine tablets) containing magnesium, aluminium, or calcium reduces the absorption of ciprofloxacin. Consequently, ciprofloxacin should be administered either 1-2 hours before or at least 4 hours after these preparations. The restriction does not apply to antacids belonging to the class of H2 receptor blockers.
\*\*\*Food and Dairy Products\*\*\*
Dietary calcium as part of a meal does not significantly affect absorption. However, the concurrent administration of dairy products or mineral-fortified drinks alone (e.g. milk, yoghurt, calcium-fortified orange juice) with ciprofloxacin should be avoided because absorption of ciprofloxacin may be reduced.
\*\*\*Probenecid\*\*\*
Probenecid interferes with renal secretion of ciprofloxacin. Co-administration of probenecid and ciprofloxacin increases ciprofloxacin serum concentrations.
\*\*\*Metoclopramide\*\*\*
Metoclopramide accelerates the absorption of ciprofloxacin (oral) resulting in a shorter time to reach maximum plasma concentrations. No effect was seen on the bioavailability of ciprofloxacin.
\*\*\*Omeprazole\*\*\*
Concomitant administration of ciprofloxacin and omeprazole containing medicinal products results in a slight reduction of Cmax and AUC of ciprofloxacin.
\*\*\*Effects of ciprofloxacin on other medicinal products\*\*:\*
\*Agomelatine\*
In clinical studies, it was demonstrated that fluvoxamine, as a strong inhibitor of the CYP450 1A2 isoenzyme, markedly inhibits the metabolism of agomelatine resulting in a 60-fold increase of agomelatine exposure. Although no clinical data are available for a possible interaction with ciprofloxacin, a moderate inhibitor of CYP450 1A2, similar effects can be expected upon concomitant administration \*\*(\*\*see 'Cytochrome P450' in section 4.4).
\*\*\*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.
\*\*\*Methotrexate\*\*\*
Renal tubular transport of methotrexate may be inhibited by concomitant administration of ciprofloxacin, potentially leading to increased plasma levels of methotrexate and increased risk of methotrexate-associated toxic reactions. The concomitant use is not recommended (see section 4.4).
\*\*\*Theophylline\*\*\*
Concurrent administration of ciprofloxacin and theophylline can cause an undesirable increase in serum theophylline concentration. This can lead to theophylline-induced side effects that may rarely be life threatening or fatal. During the combination, serum theophylline concentrations should be checked and the theophylline dose reduced as necessary (see section 4.4).
\*\*\*Other xanthine derivatives\*\*\*
On concurrent administration of ciprofloxacin and caffeine or pentoxifylline (oxpentifylline), raised serum concentrations of these xanthine derivatives were reported.
\*\*\*Phenytoin\*\*\*
Simultaneous administration of ciprofloxacin and phenytoin may result in increased or reduced serum levels of phenytoin such that monitoring of drug levels is recommended.
\*\*\*Cyclosporin\*\*\*
A transient rise in the concentration of serum creatinine was observed when ciprofloxacin and cyclosporin containing medicinal products were administered simultaneously. Therefore, it is frequently (twice a week) necessary to control the serum creatinine concentrations in these patients.
\*\*\*Vitamin K antagonists\*\*\*
Simultaneous administration of ciprofloxacin \*\*with a vitamin K antagonist\*\* may augment its anti-coagulant effects. The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacinto the increase in INR (international normalised ratio) is difficult to assess. The INR should be monitored frequently during and shortly after co-administration of ciprofloxacin with a vitamin K antagonist (e.g., warfarin, acenocoumarol, phenprocoumon, or fluindione).
\*\*\*Duloxetine\*\*\*
In clinical studies, it was demonstrated that concomitant use of duloxetine with strong inhibitors of the CYP450 1A2 isozyme such as fluvoxamine, may result in an increase of AUC and Cmax of duloxetine. Although no clinical data are available on a possible interaction with ciprofloxacin, similar effects can be expected upon concomitant administration (see section 4.4).
\*\*\*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).
\*\*\*Lidocaine\*\*\*
It was demonstrated in healthy subjects that concomitant use of lidocaine containing medicinal products with ciprofloxacin, a moderate inhibitor of CYP450 1A2 isozyme, reduces clearance of intravenous lidocaine by 22%. Although lidocaine treatment was well tolerated, a possible interaction with ciprofloxacin associated with side effects may occur upon concomitant administration.
\*\*\*Clozapine\*\*\*
Following concomitant administration of 250 mg ciprofloxacin with clozapine for 7 days, serum concentrations of clozapine and N-desmethylclozapine were increased by 29% and 31%, respectively. Clinical surveillance and appropriate adjustment of clozapine dosage during and shortly after coadministration with ciprofloxacin are advised (see section 4.4).
\*Sildenafil\*
Cmax and AUC of sildenafil were increased approximately twofold in healthy subjects after an oral dose of 50 mg given concomitantly with 500 mg ciprofloxacin. Therefore, caution should be used prescribing ciprofloxacin concomitantly with sildenafil taking into consideration the risks and the benefits.
\*Zolpidem\*
Co-administration of ciprofloxacin may increase blood levels of zolpidem, concurrent use is not recommended.4.6 Pregnancy and lactation
\*\*\*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.
\*\*\*Breast-feeding\*\*\*
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
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
The most commonly reported adverse drug reactions (ADRs) are nausea and diarrhoea.
ADRs derived from clinical studies and post-marketing surveillance with Ciprofloxacin (oral, intravenous, and sequential therapy) sorted by categories of frequency are listed below. The frequency analysis takes into account data from both oral and intravenous administration of ciprofloxacin.
| | | | | | |
| --- | --- | --- | --- | --- | --- |
| \*\*System Organ Class\*\* | \*\*Common\*\* ≥ 1/100 to < 1/10 | \*\*Uncommon\*\* ≥ 1/1 000 to < 1/100 | \*\*Rare\*\* ≥ 1/10 000 to < 1/1 000 | \*\*Very Rare\*\* < 1/10 000` | \*\*Frequency not known\*\* (cannot be estimated from available data) |
| \*\*Infections and Infestations\*\* | | Mycotic superinfections | | | |
| \*\*Blood and Lymphatic System Disorders\*\* | | Eosinophilia | Leukopenia Anaemia Neutropenia Leukocytosis Thrombocytopenia Thrombocytaemia | Haemolytic anaemia Agranulocytosis Pancytopenia (lifethreatening) Bone marrow depression (life threatening) | |
| \*\*Immune System Disorders\*\* | | | Allergic reaction Allergic oedema / angiooedema | Anaphylactic reaction Anaphylactic shock (lifethreatening) (see section 4.4) Serum sickness like reaction | |
| \*\*Endocrine disorders\*\* | | | | | Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) |
| \*\*Metabolism and Nutrition Disorders\*\* | | Decreased appetite | Hyperglycaemia Hypoglycaemia (see section 4.4) | | Hypoglycaemic coma (see section 4.4) |
| \*\*Psychiatric Disorders\\*\*\* | | Psychomotor hyperactivity / agitation | Confusion and disorientation Anxiety reaction Abnormal dreams Depression(potentially culminating in suicidal ideations/thoughts or suicide attempts and completed suicide) (see section 4.4) Hallucinations | Psychotic reactions (potentially culminating in suicidal ideations/ thoughts or suicide attempts and completed suicide) (see section 4.4) | Mania, incl. hypomania |
| \*\*Nervous System Disorders\\*\*\* | | Headache Dizziness Sleep disorders Taste disorders | Par- and Dysaesthesia Hypoaesthesia Tremor Seizures (including status epilepticus see section 4.4) Vertigo | Migraine Disturbed coordination Gait disturbance Olfactory nerve disorders Intracranial hypertension and pseudotumor cerebri | Peripheral neuropathy and polyneuropathy (see section 4.4) |
| \*\*Eye Disorders\\*\*\* | | | Visual disturbances(e.g. diplopia) | Visual colour distortions | |
| \*\*Ear and Labyrinth Disorders\\*\*\* | | | Tinnitus, Hearing loss / Hearing impaired | | |
| \*\*Cardiac Disorders\\*\\*\*\* | | | Tachycardia | | Ventricular arrhythmia and torsades de pointes (reported predominantly in patients with risk factors for QT prolongation), ECG QT prolonged (see sections 4.4 and 4.9) |
| \*\*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 | Antibiotic associated colitis (very rarely with possible fatal outcome) (see section 4.4) | Pancreatitis | |
| \*\*Hepatobiliary Disorders\*\* | | Increase in transaminases Increased bilirubin | Hepatic impairment Cholestatic icterus Hepatitis | Liver necrosis (very rarely progressing to life-threatening hepatic failure) (see section 4.4) | |
| \*\*Skin and Subcutaneous Tissue Disorders\*\* | | Rash, Pruritus Urticaria | Photosensitivity reactions (see section 4.4) | Petechiae Erythema multiforme Erythema nodosum Stevens- Johnson Syndrome (potentially lifethreatening) Toxic epidermal necrolysis (potentially life- threatening) | Acute generalised exanthematous pustulosis (AGEP), Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) |
| \*\*Musculoskeletal and Connective Tissue Disorders\\*\*\* | | Musculoskeletal pain (e.g. extremity pain, back pain, chest pain), Arthralgia | Myalgia, Arthritis Increased muscle tone and cramping Tendinitis Tendon rupture (predominantly Achilles tendon) (see section 4.4) | Muscular weakness Exacerbation of symptoms of myasthenia gravis (see section 4.4) | |
| \*\*Renal and Urinary Disorders\*\* | | Renal impairment | Renal failure Haematuria Crystalluria (see section 4.4) Tubulointerstitial nephritis | | |
| \*\*General Disorders and Administration Site Conditions\\*\*\* | | Asthenia Fever | Oedema, Sweating (hyperhidrosis) | | |
| \*\*Investigations\*\* | | Increase in blood alkaline phosphatase | Increased amylase | | International normalized ratio increased (in patients treated with Vitamin K antagonists) |
\\* Cases of prolonged (up to months or years), disabling and potentially irreversible serious drug reactions affecting several, sometimes multiple, system organ classes and senses (including reactions such as tendonitis, tendon rupture, arthralgia, pain in extremities, gait disturbance, neuropathies associated with paraesthesia, , fatigue, psychiatric symptoms, memory impairment, , and impairment of hearing, vision, taste and smell) have been reported in association with the use of quinolones and fluoroquinolones in some cases irrespective of pre-existing risk factors (see Section 4.4). A range of psychiatric symptoms may occur as part of these side effects, which may include, but are not necessarily limited to, sleep disorders, anxiety, panic attacks, confusion, or depression. There are no pharmacological treatments established to be effective treatments of the symptoms of long lasting or disabling side effects associated with fluoroquinolones. The frequency of these prolonged, disabling and potentially irreversible serious drug reactions cannot be estimated with precision using available data, but the reporting incidence from adverse drug reaction reports indicates the frequency is at minimum between 1/1,000 and 1/10,000 (corresponding to the Rare frequency category).
\\*\\* Cases of aortic aneurysm and dissection, sometimes complicated by rupture (including fatal ones), and of regurgitation/incompetence of any of the heart valves have been reported in patients receiving fluoroquinolones (see section 4.4).
\*\*\*Paediatric population\*\*\*
The incidence of arthropathy (arthralgia, arthritis), mentioned above, is referring to data collected in studies with adults. In children, arthropathy is reported to occur commonly (see section 4.4).
\*\*\*\*Reporting of suspected adverse reactions\*\*\*\*
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.4.9 Overdose
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, e.g. ventricular emptying followed by medical carbon it is recommended to monitor renal function, including urinary pH and acidify, if required, to prevent crystalluria. Patients should be kept well hydrated. Calcium or magnesium containing antacids may theoretically reduce the absorption of ciprofloxacin in overdoses.
Only a small quantity of ciprofloxacin (<10%) is eliminated by haemodialysis or peritoneal dialysis.
In the event of overdose, symptomatic treatment should be implemented. ECG monitoring should be undertaken, because of the possibility of QT interval prolongation.
- Instruction Pharmacology
- 5.1 Pharmacodynamic properties
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.
\*\*\*Pharmacokinetic /Pharmacodynamic 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:
\*\*\*EUCAST Recommendations\*\*\*
| | | |
| --- | --- | --- |
| \*\*Microorganisms\*\* | \*\*Susceptible\*\* | \*\*Resistant\*\* |
| \*Enterobacteriaceae\* | S ≤ 0.5 mg/L | R > 1 mg/ L |
| \*Pseudomonas spp.\* | S ≤ 0.5 mg/L | R > 1 mg/ L |
| \*Acinetobacter spp.\* | S ≤ 1 mg/L | R > 1 mg/ L |
| \*Staphylococcus\* spp.1 | S ≤ 1 mg/L | R >1 mg/L |
| \*Haemophilus influenzae\* and \*Moraxella catarrhalis\* | S ≤ 0.5 mg/L | R > 0.5 mg/L |
| \*Neisseria gonorrhoeae\* | S ≤0.03 mg/L | R > 0.06 mg/L |
| \*Neisseria meningitidis\* | S ≤0.03 mg/L | R > 0.06 mg/L |
| Non-species-related breakpoints\*\*\\*\*\* | S ≤0.5 mg/L | R > 1 mg/ L |
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.
Groupings of relevant species according to ciprofloxacin susceptibility (for Streptococcus species see section 4.4)
| |
| --- |
| \*\*COMMONLY SUSCEPTIBLE SPECIES\*\* |
| \*\*Aerobic Gram-positive micro-organisms\*\* \*Bacillus anthracis (1)\* |
| \*\*Aerobic Gram-negative micro-organisms\*\* \*Aeromonas spp.\* \*Brucella spp.\* \*Citrobacter koseri\* \*Francisella tularensis\* \*Haemophilus ducreyi\* \*Haemophilus influenzae\\*\* \*Legionella spp.\* \*Moraxella catarrhalis\\*\* \*Neisseria meningitidis\* \*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\*\* |
| \*\*Aerobic Gram-positive micro-organisms\*\* \*Enterococcus faecalis ($)\* \*Staphylococcus spp. \\*(2)\* |
| \*\*Aerobic Gram-negative micro-organisms\*\* \*Acinetobacter baumannii+\* \*Burkholderia cepacia+\\*\* \*Campylobacter spp.+\\*\* \*Citrobacter freundii\\*\* \*Enterobacter aerogenes\* \*Enterobacter cloacae\\*\* \*Escherichia coli\\*\* \*Klebsiella oxytoca\* \*Klebsiella pneumoniae\\*\* \*Morganella morganii\\*\* \*Neisseria gonorrhoeae\\*\* \*Proteus mirabilis\\*\* \*Proteus vulgaris\\*\* \*Providencia spp.\* \*Pseudomonas aeruginosa\\*\* \*Pseudomonas fluorescens\* \*Serratia marcescens\\*\* |
| \*\*Anaerobic micro-organisms\*\* \*Peptostreptococcus spp.\* \*Propionibacterium acnes\* |
| \*\*INHERENTLY RESISTANT ORGANISMS\*\* |
| \*\*Aerobic Gram-positive micro-organisms\*\* \*Actinomyces\* \*Enteroccus faecium\* \*Listeria monocytogenes\* |
| \*\*Aerobic Gram-negative micro-organisms\*\* \*Stenotrophomonas maltophilia\* |
| \*\*Anaerobic micro-organisms\*\* \*Excepted as listed above\* |
| \*\*Other micro-organisms\*\* \*Mycoplasma genitalium\* \*Ureaplasma urealitycum\* |
| \\* Clinical efficacy has been demonstrated for susceptible isolates in approved clinical indications + Resistance rate ≥ 50% in one or more EU countries ($): 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\*\*\*
Following oral administration of single doses of 250 mg, 500 mg, and 750 mg of ciprofloxacin tablets, ciprofloxacin is absorbed rapidly and extensively, mainly from the small intestine, reaching maximum serum concentrations 1-2 hours later.
Single doses of 100-750 mg produced dose-dependent maximum serum concentrations (Cmax) between 0.56 and 3.7 mg/L. Serum concentrations increase proportionately with doses up to 1000 mg.
The absolute bioavailability is approximately 70-80%.
A 500 mg oral dose given every 12 hours has been shown to produce an area under the serum concentration-time curve (AUC) equivalent to that produced by an intravenous infusion of 400 mg ciprofloxacin given over 60 minutes every 12 hours.
\*\*\*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.
\*\*\*Biotransformation\*\*\*
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. The serum elimination half-life in subjects with normal renal function is approximately 4-7 hours.
| | | |
| --- | --- | --- |
| \*\*Excretion of ciprofloxacin (% of dose)\*\* | | |
| | \*\*Oral Administration\*\* | |
| \*\*Urine\*\* | \*\*Faeces\*\* |
| Ciprofloxacin | 44.7 | 25.0 |
| Metabolites (M1-M4) | 11.3 | 7.5 |
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.
\*\*\*Paediatric patients\*\*\*
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
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.
- Instruction Pharmaceutical Particulars
- 6.1 List of excipients
\*Tablet core:\*
Cellulose microcrystalline
Sodium starch glycolate (Type A)
Povidone (K 30)
Silica, colloidal anhydrous
Magnesium stearate
\*Film coating:\*
Hypromellose
Titanium dioxide (E 171)
Macrogol 4006.2 Incompatibilities
Not applicable.6.3 Shelf life
4 years.6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.6.5 Nature and contents of container
Ciprofloxacin film-coated tablets are available in PVC/PVdC-Aluminum foil blister pack.
\*\*Pack sizes:\*\* 1, 8, 10, 14, 16, 20, 50 and 100 film-coated tablets
Not all pack sizes may be marketed.6.6 Special precautions for disposal and other handling
Any unused product or waste material should be disposed of in accordance with local requirements.
- Instruction Content
- ## Composition
Each film-coated tablet contains 250 mg ciprofloxacin (as hydrochloride).
For the full list of excipients, see section 6.1.
## Pharmaceutical Form
Film-coated tablet.
White to off white, round shaped (diameter 11.1 mm), film coated tablets, with a score line on one side and debossed with 'F' and '23' with a score line in between on the other side. The tablet can be divided into equal doses.
## Clinical Particulars
4.1 Therapeutic indications
Because of the risk of prolonged, disabling and potentially irreversible serious adverse drug reactions (see section 4.4 and section 4.8) this product must only be prescribed when other antibiotics that are commonly recommended for the infection are inappropriate. This applies to all indications listed below. Situations where other antibiotics are considered to be inappropriate are where:
• there is resistance to other first-line antibiotics recommended for the infection;
• other first-line antibiotics are contraindicated in an individual patient;
• other first-line antibiotics have caused side effects requiring treatment to be stopped;
• treatment with other first-line antibiotics has failed.
Ciprofloxacin film-coated tablets are indicated for the treatment of the following infections (see sections 4.4 and 5.1). Special attention should be paid to available information on resistance to ciprofloxacin before commencing therapy.
\*\*\*Adults\*\*\*
• Lower respiratory tract infections due to Gram-negative bacteria
- pneumonia
- broncho-pulmonary infections in cystic fibrosis or in bronchiectasis
• Chronic suppurative otitis media
• Acute exacerbation of chronic sinusitis especially if these are caused by Gram-negative bacteria
• Acute pyelonephritis
• Complicated urinary tract infections
• Bacterial prostatitis
• Genital tract infections
| | |
| --- | --- |
| | - gonococcal urethritis and cervicitis due to susceptible \*Neisseria gonorrhoeae\* - epididymo-orchitis including cases due to susceptible \*Neisseria gonorrhoeae\* - pelvic inflammatory disease including cases due to susceptible \*Neisseria gonorrhoeae\* |
• Intra-abdominal infections
• Infections of the skin and soft tissue caused by Gram-negative bacteria
• Infections of the bones and joints
• Inhalation anthrax (post-exposure prophylaxis and curative treatment)
Ciprofloxacin may be used in the management of neutropenic patients with fever that is suspected to be due to a bacterial infection.
In \*\*exacerbations of chronic obstructive pulmonary disease\*\* Ciprofloxacin should be used only when it is considered inappropriate to use other antibacterial agents that are commonly recommended for the treatment of these infections.
In \*\*uncomplicated acute cystitis\*\* Ciprofloxacin should be used only when it is considered inappropriate to use other antibacterial agents that are commonly recommended for the treatment of these infections.
\*\*\*Children and adolescents\*\*\*
• Broncho-pulmonary infections due to \*Pseudomonas aeruginosa\* in patients with cystic fibrosis
• Complicated urinary tract infections and acute pyelonephritis
• Inhalation anthrax (post-exposure prophylaxis and curative treatment)
Ciprofloxacin may also be used to treat severe infections in children and adolescents when this is considered to be necessary.
Treatment should be initiated only by physicians who are experienced in the treatment of cystic fibrosis and/or severe infections in children and adolescents (see sections 4.4 and 5.1).
Consideration should be given to official guidance on the appropriate use of antibacterial agents.4.2 Posology and method of administration
\*\*Posology\*\*
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.
Treatment of infections due to certain bacteria (e.g. \*Pseudomonas\* \*aeruginosa\*, \*Acinetobacter\* or \*Staphylococci\*) may require higher ciprofloxacin doses and co-administration with other appropriate antibacterial agents.
Treatment of some infections (e.g. pelvic inflammatory disease, intra-abdominal infections, infections in neutropenic patients and infections of bones and joints) may require co-administration with other appropriate antibacterial agents depending on the pathogens involved.
\*\*\*Adults\*\*\*
| | | | |
| --- | --- | --- | --- |
| \*\*Indications\*\* | | \*\*Daily dose in mg\*\* | \*\*Total duration of treatment (potentially including initial parenteral treatment with ciprofloxacin)\*\* |
| Infections of the lower respiratory tract | | 500 mg twice daily to 750 mg twice daily | 7 to 14 days |
| Infections of the upper respiratory tract | Acute exacerbation of chronic sinusitis | 500 mg twice daily to 750 mg twice daily | 7 to 14 days |
| Chronic suppurative otitis media | 500 mg twice daily to 750 mg twice daily | 7 to 14 days |
| Malignant external otitis | 750 mg twice daily | 28 days up to 3 months |
| Urinary tract infections (see section 4.4) | Uncomplicated cystitis | 250 mg twice daily to 500 mg twice daily | 3 days |
| In pre-menopausal women, 500 mg single dose may be used | |
| Complicated cystitis, Uncomplicated pyelonephritis | 500 mg twice daily | 7 days |
| Complicated pyelonephritis | 500 mg twice daily to 750 mg twice daily | at least 10 days, it can be continued for longer than 21 days in some specific circumstances (such as abscesses) |
| Prostatitis | 500 mg twice daily to 750 mg twice daily | 2 to 4 weeks (acute) to 4 to 6 weeks (chronic) |
| Genital tract infections | Gonococcal uretritis and cervicitis | 500 mg as a single dose | 1 day (single dose) |
| Epididymo-orchitis and pelvic inflammatory diseases | 500 mg twice daily to 750 mg twice daily | 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 | 500 mg twice daily | 1 day |
| Diarrhoea caused by \*Shigella dysenteriae\* type 1 | 500 mg twice daily | 5 days |
| Diarrhoea caused by \*Vibrio cholerae\* | 500 mg twice daily | 3 days |
| Typhoid fever | 500 mg twice daily | 7 days |
| Intra-abdominal infections due to Gram-negative bacteria | 500 mg twice daily to 750 mg twice daily | 5 to 14 days |
| Infections of the skin and soft tissue | | 500 mg twice daily to 750 mg twice daily | 7 to 14 days |
| Bone and joint infections | | 500 mg twice daily to 750 mg twice daily | max. of 3 months |
| Neutropenic patients with fever that is suspected to be due to a bacterial infection. Ciprofloxacin should be co-administered with appropriate antibacterial agent(s) in accordance to official guidance. | | 500 mg twice daily to 750 mg twice daily | Therapy should be continued over the entire period of neutropenia |
| Prophylaxis of invasive infections due to \*Neisseria meningitides\* | | 500 mg as a single dose | 1 day (single dose) |
| Inhalation anthrax post-exposure prophylaxis and curative treatment for persons able to receive treatment by oral route when clinically appropriate. Drug administration should begin as soon as possible after suspected or confirmed exposure. | | 500 mg twice daily | 60 days from the confirmation of \*Bacillus anthracis\* exposure |
\*\*\*Paediatric population\*\*\*
| | | |
| --- | --- | --- |
| \*\*Indications\*\* | \*\*Daily dose in mg\*\* | \*\*Total duration of treatment (potentially including initial parenteral treatment with ciprofloxacin)\*\* |
| Cystic fibrosis | 20 mg/kg body weight twice daily with a maximum of 750 mg per dose. | 10 to 14 days |
| Complicated urinary tract infections and pyelonephritis | 10 mg/kg body weight twice daily to 20 mg/kg body weight twice daily with a maximum of 750 mg per dose. | 10 to 21 days |
| Inhalation anthrax post-exposure prophylaxis and curative treatment for persons able to receive treatment by oral route when clinically appropriate. Drug administration should begin as soon as possible after suspected or confirmed exposure. | 10 mg/kg body weight twice daily to 15 mg/kg body weight twice daily with a maximum of 500 mg per dose. | 60 days from the confirmation of \*Bacillus anthracis\* exposure |
| Other severe infections | 20 mg/kg body weight twice daily with a maximum of 750 mg per dose. | According to the type of infections |
\*\*\*Elderly patients\*\*\*
\*Elderly\* patients should receive a dose selected according to the severity of the infection and the patient's creatinine clearance.
\*\*\*Patients with 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]\*\* | \*\*Oral Dose [mg]\*\* |
| > 60 | < 124 | See Usual Dosage. |
| 30-60 | 124 to 168 | 250-500 mg every 12 h |
| <30 | > 169 | 250-500 mg every 24 h |
| Patients on haemodialysis | > 169 | 250-500 mg every 24 h (after dialysis) |
| Patients on peritoneal dialysis | > 169 | 250-500 mg every 24 h |
In patients with impaired liver function no dose adjustment is required.
Dosing in children with impaired renal and/or hepatic function has not been studied.
\*Method of administration\*
Tablets are to be swallowed unchewed with fluid. They can be taken independent of mealtimes. If taken on an empty stomach, the active substance is absorbed more rapidly. Ciprofloxacin tablets should not be taken with dairy products (e.g. milk, yoghurt) or mineral-fortified fruit-juice (e.g. calcium-fortified orange juice) (see section 4.5).
In severe cases or if the patient is unable to take tablets (e.g. patients on enteral nutrition), it is recommended to commence therapy with intravenous ciprofloxacin until a switch to oral administration is possible.4.3 Contraindications
• Hypersensitivity to the active substance, to other quinolones or to any of the excipients listed in section 6.1.
• Concomitant administration of ciprofloxacin and tizanidine (see section 4.5).4.4 Special warnings and precautions for use
The use of ciprofloxacin should be avoided in patients who have experienced serious adverse reactions in the past when using quinolone or fluoroquinolone containing products (see section 4.8). Treatment of these patients with ciprofloxacin should only be initiated in the absence of alternative treatment options and after careful benefit/risk assessment (see also section 4.3).
\*\*\*Prolonged, disabling and potentially irreversible serious adverse drug reactions\*\*\*
Cases of prolonged (continuing for months or years), disabling and potentially irreversible serious adverse drug reactions affecting different, sometimes multiple, body systems (including musculoskeletal, nervous, psychiatric and senses) have been reported in patients receiving quinolones and fluoroquinolones irrespective of their age and pre-existing risk factors. There are no pharmacological treatments established to be effective treatments of the symptoms of long lasting or disabling side effects associated with fluoroquinolones. Ciprofloxacin should be discontinued immediately at the first signs or symptoms of any serious adverse reaction and patients should be advised to contact their prescriber for advice, so that symptoms can be appropriately investigated and to avoid further exposure which could potentially worsen adverse reactions
\*\*\*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.
\*\*\*Genital tract infections\*\*\*
Gonococcal uretritis, cervicitis, epididymo-orchitis and pelvic inflammatory diseases may be caused by fluoroquinolone-resistant Neisseria gonorrhoeae \*isolates\*.
Therefore, ciprofloxacin should be administered for the treatment of gonococcal uretritis or cervicitis only if ciprofloxacin-resistant \*Neisseria gonorrhoeae\* can be excluded.
For epididymo-orchitis and pelvic inflammatory diseases, empirical ciprofloxacin should only be considered in combination with another appropriate antibacterial agent (e.g. a cephalosporin) unless ciprofloxacin resistant \*Neisseria gonorrhoeae\* can be excluded. If clinical improvement is not achieved after 3 days of treatment, the therapy should be reconsidered.
\*\*Urinary tract infections\*\*
Resistance to fluoroquinolones of \*Escherichia coli\* – the most common pathogen involved in urinary tract infections – varies across the European Union. Prescribers are advised to take into account the local prevalence of resistance in \*Escherichia coli\* to quinolones.
The single dose of ciprofloxacin that may be used in uncomplicated cystitis in pre-menopausal women is expected to be associated with lower efficacy than the longer treatment duration. This is all the more to be taken into account as regards the increasing resistance level of \*Escherichia coli\* to quinolones.
\*\*\*Intra-abdominal infections\*\*\*
There are limited data on the efficacy of ciprofloxacin in the treatment of post-surgical intra-abdominal infections.
\*\*\*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.
\*\*\*Paediatric population\*\*\*
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 (see section 4.8)..
\*\*\*Broncho-pulmonary infections in cystic fibrosis\*\*\*
Clinical trials have included children and adolescents aged 5-17 years. More limited experience is available in treating children between 1 and 5 years of age.
\*\*\*Complicated urinary tract infections and pyelonephritis\*\*\*
Ciprofloxacin treatment of urinary tract infections should be considered when other treatments cannot be used, and should be based on the results of the microbiological documentation.
Clinical trials have included children and adolescents aged 1-17 years.
\*\*\*Other specific severe infections\*\*\*
Other severe infections in accordance with official guidance, or after careful benefit-risk evaluation when other treatments cannot be used, or after failure to conventional therapy and when the microbiological documentation can justify a ciprofloxacin use.
The use of ciprofloxacin for specific severe infections other than those mentioned above has not been evaluated in clinical trials and the clinical experience is limited. Consequently, caution is advised when treating patients with these infections.
\*\*\*Hypersensitivity\*\*\*
Hypersensitivity and allergic reactions, including anaphylaxis and anaphylactoid reactions, may occur following a single dose (see section 4.8) and may be life-threatening. If such reaction occurs, ciprofloxacin should be discontinued and an adequate medical treatment is required.
\*\*\*Musculoskeletal System\*\*\*
Ciprofloxacin should generally not be used in patients with a history of tendon disease/disorder related to quinolone treatment. Nevertheless, in very rare instances, after microbiological documentation of the causative organism and evaluation of the risk/benefit balance, ciprofloxacin may be prescribed to these patients for the treatment of certain severe infections, particularly in the event of failure of the standard therapy or bacterial resistance, where the microbiological data may justify the use of ciprofloxacin.
\*\*\*Tendinitis and tendon rupture\*\*\*
Tendinitis and tendon rupture (especially but not limited to Achilles tendon), sometimes bilateral, may occur as early as within 48 hours of starting treatment with quinolones and fluoroquinolones and have been reported to occur even up to several months after discontinuation of treatment. The risk of tendinitis and tendon rupture is increased in older patients, patients with renal impairment, patients with solid organ transplants, and those treated concurrently with corticosteroids. Therefore, concomitant use of corticosteroids should be avoided.
At the first sign of tendinitis (e.g. painful swelling, inflammation) the treatment with ciprofloxacin should be discontinued and alternative treatment should be considered. The affected limb(s) should be appropriately treated (e.g. immobilisation). Corticosteroids should not be used if signs of tendinopathy occur.
Ciprofloxacin should be used with caution in patients with myasthenia gravis, because symptoms can be exacerbated (see section 4.8).
\*\*\*Vision disorders\*\*\*
If vision becomes impaired or any effects on the eyes are experienced, an eye specialist should be consulted immediately.
\*\*\*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\*\*\*
Ciprofloxacin like other quinolones are known to trigger seizures or lower the seizure threshold. Cases of status epilepticus have been reported. Ciprofloxacin should be used with caution in patients with CNS disorders which may be predisposed to seizure. If seizures occur ciprofloxacin should be discontinued (see section 4.8). Psychiatric reactions may occur even after the first administration of ciprofloxacin. In rare cases, depression or psychosis can progress to suicidal ideations/thoughts culminating in attempted suicide or completed suicide. In the occurrence of such cases, ciprofloxacin should be discontinued.
\*\*\*Peripheral neuropathy\*\*\*
Cases of sensory or sensorimotor polyneuropathy resulting in paraesthesia, hypaesthesia, dysesthesia, or weakness have been reported in patients receiving quinolones and fluoroquinolones. Patients under treatment with ciprofloxacin should be advised to inform their doctor prior to continuing treatment if symptoms of neuropathy such as pain, burning, tingling, numbness, or weakness develop in order to prevent the development of potentially irreversible condition (see section 4.8).
\*\*\*Cardiac disorders\*\*\*
Caution should be taken when using fluoroquinolones, including ciprofloxacin, in patients with known risk factors for prolongation of the QT interval such as, for example:
• congenital long QT syndrome
• concomitant use of drugs that are known to prolong the QT interval (e.g. Class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics)
• uncorrected electrolyte imbalance (e.g. hypokalaemia, hypomagnesaemia)
• cardiac disease (e.g. heart failure, myocardial infarction, bradycardia)
Elderly patients and women may be more sensitive to QTc-prolonging medications. Therefore, caution should be taken when using fluoroquinolones, including ciprofloxacin, in these populations. (See section 4.2 Elderly patients, section 4.5, section 4.8, section 4.9).
\*\*\*Dysglycaemia\*\*\*
As with all quinolones, disturbances in blood glucose, including both hypoglycaemia and hyperglycaemia have been reported, usually in diabetic patients receiving concomitant treatment with an oral hypoglycaemic agent (e.g., glibenclamide) or with insulin. Cases of hypoglycaemic coma have been reported. In diabetic patients, careful monitoring of blood glucose is recommended (see section 4.8).
\*\*\*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.
\*\*\*Impaired renal function\*\*\*
Since ciprofloxacin is largely excreted unchanged via renal pathway dose adjustment is needed in patients with impaired renal function as described in section 4.2 to avoid an increase in adverse drug reactions due to accumulation of ciprofloxacin.
\*\*\*Hepatobiliary system\*\*\*
Cases of hepatic necrosis and life-threatening hepatic failure have been reported with ciprofloxacin (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, olanzapine, ropinirole, tizanidine, duloxetine, \*\*agomelatine\*\*). 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.
Aortic aneurysm and dissection, and heart valve regurgitation/incompetence
Epidemiologic studies report an increased risk of aortic aneurysm and dissection, particularly in elderly patients, and of aortic and mitral valve regurgitation after intake of fluoroquinolones. Cases of aortic aneurysm and dissection, sometimes complicated by rupture (including fatal ones), and of regurgitation/incompetence of any of the heart valves have been reported in patients receiving fluoroquinolones (see section 4.8).
Therefore, fluoroquinolones should only be used after careful benefit-risk assessment and after consideration of other therapeutic options in patients with positive family history of aneurysm disease, or congenital heart valve disease, or in patients diagnosed with pre-existing aortic aneurysm and/or aortic dissection, or heart valve disease, or in presence of other risk factors or conditions predisposing
- for aortic aneurysm and dissection and heart valve regurgitation/incompetence (e.g. connective tissue disorders such as Marfan syndrome, Ehlers-Danlos syndrome, Turner syndrome, Behcet's disease, hypertension, rheumatoid arthritis) or additionally
- for aortic aneurysm and dissection (e.g. vascular disorders such as Takayasu arteritis or giant cell arteritis, or known atherosclerosis, or Sjögren's syndrome) or additionally
- for heart valve regurgitation/incompetence (e.g. infective endocarditis).
The risk of aortic aneurysm and dissection, and their rupture may also be increased in patients treated concurrently with systemic corticosteroids.
In case of sudden abdominal, chest or back pain, patients should be advised to immediately consult a physician in an emergency department.
Patients should be advised to seek immediate medical attention in case of acute dyspnoea, new onset of heart palpitations, or development of oedema of the abdomen or lower extremities.
\*\*\*Sodium\*\*\*
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.4.5 Interaction with other medicinal products and other forms of interaction
\*\*\*Effects of other products on ciprofloxacin:\*\*\*
\*\*\*Drugs known to prolong QT interval\*\*\*
Ciprofloxacin, like other fluoroquinolones, should be used with caution in patients receiving drugs known to prolong QT interval (e.g. Class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) (see section 4.4).
\*\*\*Chelation Complex Formation\*\*\*
The simultaneous administration of ciprofloxacin (oral) and multivalent cation-containing drugs and mineral supplements (e.g. calcium, magnesium, aluminium, iron), polymeric phosphate binders (e.g. sevelamer or lanthanum carbonate), sucralfate or antacids, and highly buffered drugs (e.g. didanosine tablets) containing magnesium, aluminium, or calcium reduces the absorption of ciprofloxacin. Consequently, ciprofloxacin should be administered either 1-2 hours before or at least 4 hours after these preparations. The restriction does not apply to antacids belonging to the class of H2 receptor blockers.
\*\*\*Food and Dairy Products\*\*\*
Dietary calcium as part of a meal does not significantly affect absorption. However, the concurrent administration of dairy products or mineral-fortified drinks alone (e.g. milk, yoghurt, calcium-fortified orange juice) with ciprofloxacin should be avoided because absorption of ciprofloxacin may be reduced.
\*\*\*Probenecid\*\*\*
Probenecid interferes with renal secretion of ciprofloxacin. Co-administration of probenecid and ciprofloxacin increases ciprofloxacin serum concentrations.
\*\*\*Metoclopramide\*\*\*
Metoclopramide accelerates the absorption of ciprofloxacin (oral) resulting in a shorter time to reach maximum plasma concentrations. No effect was seen on the bioavailability of ciprofloxacin.
\*\*\*Omeprazole\*\*\*
Concomitant administration of ciprofloxacin and omeprazole containing medicinal products results in a slight reduction of Cmax and AUC of ciprofloxacin.
\*\*\*Effects of ciprofloxacin on other medicinal products\*\*:\*
\*Agomelatine\*
In clinical studies, it was demonstrated that fluvoxamine, as a strong inhibitor of the CYP450 1A2 isoenzyme, markedly inhibits the metabolism of agomelatine resulting in a 60-fold increase of agomelatine exposure. Although no clinical data are available for a possible interaction with ciprofloxacin, a moderate inhibitor of CYP450 1A2, similar effects can be expected upon concomitant administration \*\*(\*\*see 'Cytochrome P450' in section 4.4).
\*\*\*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.
\*\*\*Methotrexate\*\*\*
Renal tubular transport of methotrexate may be inhibited by concomitant administration of ciprofloxacin, potentially leading to increased plasma levels of methotrexate and increased risk of methotrexate-associated toxic reactions. The concomitant use is not recommended (see section 4.4).
\*\*\*Theophylline\*\*\*
Concurrent administration of ciprofloxacin and theophylline can cause an undesirable increase in serum theophylline concentration. This can lead to theophylline-induced side effects that may rarely be life threatening or fatal. During the combination, serum theophylline concentrations should be checked and the theophylline dose reduced as necessary (see section 4.4).
\*\*\*Other xanthine derivatives\*\*\*
On concurrent administration of ciprofloxacin and caffeine or pentoxifylline (oxpentifylline), raised serum concentrations of these xanthine derivatives were reported.
\*\*\*Phenytoin\*\*\*
Simultaneous administration of ciprofloxacin and phenytoin may result in increased or reduced serum levels of phenytoin such that monitoring of drug levels is recommended.
\*\*\*Cyclosporin\*\*\*
A transient rise in the concentration of serum creatinine was observed when ciprofloxacin and cyclosporin containing medicinal products were administered simultaneously. Therefore, it is frequently (twice a week) necessary to control the serum creatinine concentrations in these patients.
\*\*\*Vitamin K antagonists\*\*\*
Simultaneous administration of ciprofloxacin \*\*with a vitamin K antagonist\*\* may augment its anti-coagulant effects. The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacinto the increase in INR (international normalised ratio) is difficult to assess. The INR should be monitored frequently during and shortly after co-administration of ciprofloxacin with a vitamin K antagonist (e.g., warfarin, acenocoumarol, phenprocoumon, or fluindione).
\*\*\*Duloxetine\*\*\*
In clinical studies, it was demonstrated that concomitant use of duloxetine with strong inhibitors of the CYP450 1A2 isozyme such as fluvoxamine, may result in an increase of AUC and Cmax of duloxetine. Although no clinical data are available on a possible interaction with ciprofloxacin, similar effects can be expected upon concomitant administration (see section 4.4).
\*\*\*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).
\*\*\*Lidocaine\*\*\*
It was demonstrated in healthy subjects that concomitant use of lidocaine containing medicinal products with ciprofloxacin, a moderate inhibitor of CYP450 1A2 isozyme, reduces clearance of intravenous lidocaine by 22%. Although lidocaine treatment was well tolerated, a possible interaction with ciprofloxacin associated with side effects may occur upon concomitant administration.
\*\*\*Clozapine\*\*\*
Following concomitant administration of 250 mg ciprofloxacin with clozapine for 7 days, serum concentrations of clozapine and N-desmethylclozapine were increased by 29% and 31%, respectively. Clinical surveillance and appropriate adjustment of clozapine dosage during and shortly after coadministration with ciprofloxacin are advised (see section 4.4).
\*Sildenafil\*
Cmax and AUC of sildenafil were increased approximately twofold in healthy subjects after an oral dose of 50 mg given concomitantly with 500 mg ciprofloxacin. Therefore, caution should be used prescribing ciprofloxacin concomitantly with sildenafil taking into consideration the risks and the benefits.
\*Zolpidem\*
Co-administration of ciprofloxacin may increase blood levels of zolpidem, concurrent use is not recommended.4.6 Pregnancy and lactation
\*\*\*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.
\*\*\*Breast-feeding\*\*\*
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
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
The most commonly reported adverse drug reactions (ADRs) are nausea and diarrhoea.
ADRs derived from clinical studies and post-marketing surveillance with Ciprofloxacin (oral, intravenous, and sequential therapy) sorted by categories of frequency are listed below. The frequency analysis takes into account data from both oral and intravenous administration of ciprofloxacin.
| | | | | | |
| --- | --- | --- | --- | --- | --- |
| \*\*System Organ Class\*\* | \*\*Common\*\* ≥ 1/100 to < 1/10 | \*\*Uncommon\*\* ≥ 1/1 000 to < 1/100 | \*\*Rare\*\* ≥ 1/10 000 to < 1/1 000 | \*\*Very Rare\*\* < 1/10 000` | \*\*Frequency not known\*\* (cannot be estimated from available data) |
| \*\*Infections and Infestations\*\* | | Mycotic superinfections | | | |
| \*\*Blood and Lymphatic System Disorders\*\* | | Eosinophilia | Leukopenia Anaemia Neutropenia Leukocytosis Thrombocytopenia Thrombocytaemia | Haemolytic anaemia Agranulocytosis Pancytopenia (lifethreatening) Bone marrow depression (life threatening) | |
| \*\*Immune System Disorders\*\* | | | Allergic reaction Allergic oedema / angiooedema | Anaphylactic reaction Anaphylactic shock (lifethreatening) (see section 4.4) Serum sickness like reaction | |
| \*\*Endocrine disorders\*\* | | | | | Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) |
| \*\*Metabolism and Nutrition Disorders\*\* | | Decreased appetite | Hyperglycaemia Hypoglycaemia (see section 4.4) | | Hypoglycaemic coma (see section 4.4) |
| \*\*Psychiatric Disorders\\*\*\* | | Psychomotor hyperactivity / agitation | Confusion and disorientation Anxiety reaction Abnormal dreams Depression(potentially culminating in suicidal ideations/thoughts or suicide attempts and completed suicide) (see section 4.4) Hallucinations | Psychotic reactions (potentially culminating in suicidal ideations/ thoughts or suicide attempts and completed suicide) (see section 4.4) | Mania, incl. hypomania |
| \*\*Nervous System Disorders\\*\*\* | | Headache Dizziness Sleep disorders Taste disorders | Par- and Dysaesthesia Hypoaesthesia Tremor Seizures (including status epilepticus see section 4.4) Vertigo | Migraine Disturbed coordination Gait disturbance Olfactory nerve disorders Intracranial hypertension and pseudotumor cerebri | Peripheral neuropathy and polyneuropathy (see section 4.4) |
| \*\*Eye Disorders\\*\*\* | | | Visual disturbances(e.g. diplopia) | Visual colour distortions | |
| \*\*Ear and Labyrinth Disorders\\*\*\* | | | Tinnitus, Hearing loss / Hearing impaired | | |
| \*\*Cardiac Disorders\\*\\*\*\* | | | Tachycardia | | Ventricular arrhythmia and torsades de pointes (reported predominantly in patients with risk factors for QT prolongation), ECG QT prolonged (see sections 4.4 and 4.9) |
| \*\*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 | Antibiotic associated colitis (very rarely with possible fatal outcome) (see section 4.4) | Pancreatitis | |
| \*\*Hepatobiliary Disorders\*\* | | Increase in transaminases Increased bilirubin | Hepatic impairment Cholestatic icterus Hepatitis | Liver necrosis (very rarely progressing to life-threatening hepatic failure) (see section 4.4) | |
| \*\*Skin and Subcutaneous Tissue Disorders\*\* | | Rash, Pruritus Urticaria | Photosensitivity reactions (see section 4.4) | Petechiae Erythema multiforme Erythema nodosum Stevens- Johnson Syndrome (potentially lifethreatening) Toxic epidermal necrolysis (potentially life- threatening) | Acute generalised exanthematous pustulosis (AGEP), Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) |
| \*\*Musculoskeletal and Connective Tissue Disorders\\*\*\* | | Musculoskeletal pain (e.g. extremity pain, back pain, chest pain), Arthralgia | Myalgia, Arthritis Increased muscle tone and cramping Tendinitis Tendon rupture (predominantly Achilles tendon) (see section 4.4) | Muscular weakness Exacerbation of symptoms of myasthenia gravis (see section 4.4) | |
| \*\*Renal and Urinary Disorders\*\* | | Renal impairment | Renal failure Haematuria Crystalluria (see section 4.4) Tubulointerstitial nephritis | | |
| \*\*General Disorders and Administration Site Conditions\\*\*\* | | Asthenia Fever | Oedema, Sweating (hyperhidrosis) | | |
| \*\*Investigations\*\* | | Increase in blood alkaline phosphatase | Increased amylase | | International normalized ratio increased (in patients treated with Vitamin K antagonists) |
\\* Cases of prolonged (up to months or years), disabling and potentially irreversible serious drug reactions affecting several, sometimes multiple, system organ classes and senses (including reactions such as tendonitis, tendon rupture, arthralgia, pain in extremities, gait disturbance, neuropathies associated with paraesthesia, , fatigue, psychiatric symptoms, memory impairment, , and impairment of hearing, vision, taste and smell) have been reported in association with the use of quinolones and fluoroquinolones in some cases irrespective of pre-existing risk factors (see Section 4.4). A range of psychiatric symptoms may occur as part of these side effects, which may include, but are not necessarily limited to, sleep disorders, anxiety, panic attacks, confusion, or depression. There are no pharmacological treatments established to be effective treatments of the symptoms of long lasting or disabling side effects associated with fluoroquinolones. The frequency of these prolonged, disabling and potentially irreversible serious drug reactions cannot be estimated with precision using available data, but the reporting incidence from adverse drug reaction reports indicates the frequency is at minimum between 1/1,000 and 1/10,000 (corresponding to the Rare frequency category).
\\*\\* Cases of aortic aneurysm and dissection, sometimes complicated by rupture (including fatal ones), and of regurgitation/incompetence of any of the heart valves have been reported in patients receiving fluoroquinolones (see section 4.4).
\*\*\*Paediatric population\*\*\*
The incidence of arthropathy (arthralgia, arthritis), mentioned above, is referring to data collected in studies with adults. In children, arthropathy is reported to occur commonly (see section 4.4).
\*\*\*\*Reporting of suspected adverse reactions\*\*\*\*
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.4.9 Overdose
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, e.g. ventricular emptying followed by medical carbon it is recommended to monitor renal function, including urinary pH and acidify, if required, to prevent crystalluria. Patients should be kept well hydrated. Calcium or magnesium containing antacids may theoretically reduce the absorption of ciprofloxacin in overdoses.
Only a small quantity of ciprofloxacin (<10%) is eliminated by haemodialysis or peritoneal dialysis.
In the event of overdose, symptomatic treatment should be implemented. ECG monitoring should be undertaken, because of the possibility of QT interval prolongation.
## Pharmacological Properties
5.1 Pharmacodynamic properties
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.
\*\*\*Pharmacokinetic /Pharmacodynamic 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:
\*\*\*EUCAST Recommendations\*\*\*
| | | |
| --- | --- | --- |
| \*\*Microorganisms\*\* | \*\*Susceptible\*\* | \*\*Resistant\*\* |
| \*Enterobacteriaceae\* | S ≤ 0.5 mg/L | R > 1 mg/ L |
| \*Pseudomonas spp.\* | S ≤ 0.5 mg/L | R > 1 mg/ L |
| \*Acinetobacter spp.\* | S ≤ 1 mg/L | R > 1 mg/ L |
| \*Staphylococcus\* spp.1 | S ≤ 1 mg/L | R >1 mg/L |
| \*Haemophilus influenzae\* and \*Moraxella catarrhalis\* | S ≤ 0.5 mg/L | R > 0.5 mg/L |
| \*Neisseria gonorrhoeae\* | S ≤0.03 mg/L | R > 0.06 mg/L |
| \*Neisseria meningitidis\* | S ≤0.03 mg/L | R > 0.06 mg/L |
| Non-species-related breakpoints\*\*\\*\*\* | S ≤0.5 mg/L | R > 1 mg/ L |
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.
Groupings of relevant species according to ciprofloxacin susceptibility (for Streptococcus species see section 4.4)
| |
| --- |
| \*\*COMMONLY SUSCEPTIBLE SPECIES\*\* |
| \*\*Aerobic Gram-positive micro-organisms\*\* \*Bacillus anthracis (1)\* |
| \*\*Aerobic Gram-negative micro-organisms\*\* \*Aeromonas spp.\* \*Brucella spp.\* \*Citrobacter koseri\* \*Francisella tularensis\* \*Haemophilus ducreyi\* \*Haemophilus influenzae\\*\* \*Legionella spp.\* \*Moraxella catarrhalis\\*\* \*Neisseria meningitidis\* \*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\*\* |
| \*\*Aerobic Gram-positive micro-organisms\*\* \*Enterococcus faecalis ($)\* \*Staphylococcus spp. \\*(2)\* |
| \*\*Aerobic Gram-negative micro-organisms\*\* \*Acinetobacter baumannii+\* \*Burkholderia cepacia+\\*\* \*Campylobacter spp.+\\*\* \*Citrobacter freundii\\*\* \*Enterobacter aerogenes\* \*Enterobacter cloacae\\*\* \*Escherichia coli\\*\* \*Klebsiella oxytoca\* \*Klebsiella pneumoniae\\*\* \*Morganella morganii\\*\* \*Neisseria gonorrhoeae\\*\* \*Proteus mirabilis\\*\* \*Proteus vulgaris\\*\* \*Providencia spp.\* \*Pseudomonas aeruginosa\\*\* \*Pseudomonas fluorescens\* \*Serratia marcescens\\*\* |
| \*\*Anaerobic micro-organisms\*\* \*Peptostreptococcus spp.\* \*Propionibacterium acnes\* |
| \*\*INHERENTLY RESISTANT ORGANISMS\*\* |
| \*\*Aerobic Gram-positive micro-organisms\*\* \*Actinomyces\* \*Enteroccus faecium\* \*Listeria monocytogenes\* |
| \*\*Aerobic Gram-negative micro-organisms\*\* \*Stenotrophomonas maltophilia\* |
| \*\*Anaerobic micro-organisms\*\* \*Excepted as listed above\* |
| \*\*Other micro-organisms\*\* \*Mycoplasma genitalium\* \*Ureaplasma urealitycum\* |
| \\* Clinical efficacy has been demonstrated for susceptible isolates in approved clinical indications + Resistance rate ≥ 50% in one or more EU countries ($): 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\*\*\*
Following oral administration of single doses of 250 mg, 500 mg, and 750 mg of ciprofloxacin tablets, ciprofloxacin is absorbed rapidly and extensively, mainly from the small intestine, reaching maximum serum concentrations 1-2 hours later.
Single doses of 100-750 mg produced dose-dependent maximum serum concentrations (Cmax) between 0.56 and 3.7 mg/L. Serum concentrations increase proportionately with doses up to 1000 mg.
The absolute bioavailability is approximately 70-80%.
A 500 mg oral dose given every 12 hours has been shown to produce an area under the serum concentration-time curve (AUC) equivalent to that produced by an intravenous infusion of 400 mg ciprofloxacin given over 60 minutes every 12 hours.
\*\*\*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.
\*\*\*Biotransformation\*\*\*
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. The serum elimination half-life in subjects with normal renal function is approximately 4-7 hours.
| | | |
| --- | --- | --- |
| \*\*Excretion of ciprofloxacin (% of dose)\*\* | | |
| | \*\*Oral Administration\*\* | |
| \*\*Urine\*\* | \*\*Faeces\*\* |
| Ciprofloxacin | 44.7 | 25.0 |
| Metabolites (M1-M4) | 11.3 | 7.5 |
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.
\*\*\*Paediatric patients\*\*\*
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
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.
## Pharmaceutical Particulars
6.1 List of excipients
\*Tablet core:\*
Cellulose microcrystalline
Sodium starch glycolate (Type A)
Povidone (K 30)
Silica, colloidal anhydrous
Magnesium stearate
\*Film coating:\*
Hypromellose
Titanium dioxide (E 171)
Macrogol 4006.2 Incompatibilities
Not applicable.6.3 Shelf life
4 years.6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.6.5 Nature and contents of container
Ciprofloxacin film-coated tablets are available in PVC/PVdC-Aluminum foil blister pack.
\*\*Pack sizes:\*\* 1, 8, 10, 14, 16, 20, 50 and 100 film-coated tablets
Not all pack sizes may be marketed.6.6 Special precautions for disposal and other handling
Any unused product or waste material should be disposed of in accordance with local requirements.
