- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
Adults• Lower respiratory tract infections due to Gram-negative bacteria- exacerbations of chronic obstructive pulmonary disease- broncho-pulmonary infections in cystic fibrosis or in bronchiectasis- pneumonia• Chronic suppurative otitis media• Acute exacerbation of chronic sinusitis especially if these are caused by Gram-negative bacteria• Urinary tract infections• Genital tract infections- gonococcal uretritis 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• Infections of the gastro-intestinal tract (e.g. travellers' diarrhoea)• Intra-abdominal infections• Infections of the skin and soft tissue caused by Gram-negative bacteria• Malignant external otitis• Infections of the bones and joints• Prophylaxis of invasive infections due to Neisseria meningitidis• 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.
Children and adolescents• Broncho-pulmonary infections in cystic fibrosis caused by Pseudomonas aeruginosa• Complicated urinary tract infections and pyelonephritis• Inhalation anthrax (post-exposure prophylaxis and curative treatment)Ciprofloxacin may also be used to treat severe infections in children and adolescents when this is considered to be necessary.Treatment should be initiated only by physicians who are experienced in the treatment of cystic fibrosis and/or severe infections in children and adolescents (see sections 4.4 and 5.1).
PosologyThe 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.
|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 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 meningitidis||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|
|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 patientsElderly patients should receive a dose selected according to the severity of the infection and the patient's creatinine clearance.
Patients with renal and hepatic impairmentRecommended 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|
Method of administrationTablets 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.
Severe infections and mixed infections with Gram-positive and anaerobic pathogensCiprofloxacin 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 infectionsGonococcal 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 infectionsResistance 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 fluoroquinolones.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 infectionsThere are limited data on the efficacy of ciprofloxacin in the treatment of post-surgical intra-abdominal infections.
Travellers' diarrhoeaThe choice of ciprofloxacin should take into account information on resistance to ciprofloxacin in relevant pathogens in the countries visited.
Infections of the bones and jointsCiprofloxacin should be used in combination with other antimicrobial agents depending on the results of the microbiological documentation.
Inhalational anthraxUse 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 populationThe use of ciprofloxacin in children and adolescents should follow available official guidance. Ciprofloxacin treatment should be initiated only by physicians who are experienced in the treatment of cystic fibrosis and/or severe infections in children and adolescents.Ciprofloxacin has been shown to cause arthropathy in weight-bearing joints of immature animals. Safety data from a randomised double-blind study on ciprofloxacin use in children (ciprofloxacin: n=335, mean age = 6.3 years; comparators: n=349, mean age = 6.2 years; age range = 1 to 17 years) revealed an incidence of suspected drug-related arthropathy (discerned from joint-related clinical signs and symptoms) by Day +42 of 7.2% and 4.6%. Respectively, an incidence of drug-related arthropathy by 1-year follow-up was 9.0% and 5.7%. The increase of suspected drug-related arthropathy cases over time was not statistically significant between groups. Treatment should be initiated only after a careful benefit/risk evaluation, due to possible adverse events related to joints and/or surrounding tissue.
Broncho-pulmonary infections in cystic fibrosisClinical 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 pyelonephritisCiprofloxacin 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 infectionsOther 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.
HypersensitivityHypersensitivity 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 SystemCiprofloxacin should generally not be used in patients with a history of tendon disease/disorder related to quinolone treatment. Nevertheless, in very rare instances, after microbiological documentation of the causative organism and evaluation of the risk/benefit balance, ciprofloxacin may be prescribed to these patients for the treatment of certain severe infections, particularly in the event of failure of the standard therapy or bacterial resistance, where the microbiological data may justify the use of ciprofloxacin.Tendinitis and tendon rupture (especially Achilles tendon), sometimes bilateral, may occur with ciprofloxacin, even within the first 48 hours of treatment. Inflammation and ruptures of tendon may occur even up to several months after discontinuation of ciprofloxacin therapy. The risk of tendinopathy may be increased in elderly patients or in patients concomitantly treated with corticosteroids (see section 4.8).At any sign of tendinitis (e.g. painful swelling, inflammation), ciprofloxacin treatment should be discontinued. Care should be taken to keep the affected limb at rest. Ciprofloxacin should be used with caution in patients with myasthenia gravis, because symptoms can be exacerbated (see section 4.8).
PhotosensitivityCiprofloxacin 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 SystemCiprofloxacin 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 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.Cases of polyneuropathy (based on neurological symptoms such as pain, burning, sensory disturbances or muscle weakness, alone or in combination) have been reported in patients receiving ciprofloxacin. Ciprofloxacin should be discontinued in patients experiencing symptoms of neuropathy, including pain, burning, tingling, numbness, and/or weakness in order to prevent the development of an irreversible condition (see section 4.8).
Cardiac disordersCaution 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 anti-arrhythmics, 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).
HypoglycemiaAs with other quinolones, hypoglycemia has been reported most often in diabetic patients, predominantly in the elderly population. In all diabetic patients, careful monitoring of blood glucose is recommended (see section 4.8).
Gastrointestinal SystemThe 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 systemCrystalluria 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 functionSince 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 systemCases 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 deficiencyHaemolytic 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.
ResistanceDuring 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 P450Ciprofloxacin 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). 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).
MethotrexateThe concomitant use of ciprofloxacin with methotrexate is not recommended (see section 4.5).
Interaction with testsThe in-vitro activity of ciprofloxacin against Mycobacterium tuberculosis might give false negative bacteriological test results in specimens from patients currently taking ciprofloxacin.
Effects of other products on ciprofloxacin:
Drugs known to prolong QT intervalCiprofloxacin, like other fluoroquinolones, should be used with caution in patients receiving drugs known to prolong QT interval (e.g. Class IA and III anti-arrhythmics, tricyclic antidepressants, macrolides, antipsychotics) (see section 4.4).
Chelation Complex FormationThe 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 ProductsDietary 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.
ProbenecidProbenecid interferes with renal secretion of ciprofloxacin. Co-administration of probenecid and ciprofloxacin increases ciprofloxacin serum concentrations.
MetoclopramideMetoclopramide 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.
OmeprazoleConcomitant 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:
TizanidineTizanidine 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.
MethotrexateRenal 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).
TheophyllineConcurrent 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 derivativesOn concurrent administration of ciprofloxacin and caffeine or pentoxifylline (oxpentifylline), raised serum concentrations of these xanthine derivatives were reported.
PhenytoinSimultaneous administration of ciprofloxacin and phenytoin may result in increased or reduced serum levels of phenytoin such that monitoring of drug levels is recommended.
CyclosporinA 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 antagonistsSimultaneous 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 ciprofloxacin to 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).
DuloxetineIn 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).
RopiniroleIt 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).
LidocaineIt 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.
ClozapineFollowing concomitant administration of 250 mg ciprofloxacin with clozapine for 7 days, serum concentrations of clozapine and N-desmethylclozapine were increased by 29% and 31%, respectively. Clinical surveillance and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised (see section 4.4).
SildenafilCmax 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.
PregnancyThe 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-feedingCiprofloxacin is excreted in breast milk. Due to the potential risk of articular damage, ciprofloxacin should not be used during breast-feeding.
|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 the available data)|
|Infections and Infestations||Mycotic super-infections||Antibiotic associated colitis (very rarely with possible fatal outcome) (see section 4.4)|
|Blood and Lymphatic System Disorders||Eosinophilia||Leukopenia Anaemia Neutropenia Leukocytosis Thrombocytopenia Thrombocytaemia||Haemolytic anaemia Agranulocytosis Pancytopenia (life-threatening) Bone marrow depression (life-threatening)|
|Immune System Disorders||Allergic reaction Allergic oedema / angiooedema||Anaphylactic reaction Anaphylactic shock (life-threatening) (see section 4.4) Serum sickness-like reaction|
|Metabolism and Nutrition Disorders||Decreased appetite||Hyperglycaemia Hypoglycaemia (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)|
|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)|
|Gastro-intestinal Disorders||Nausea Diarrhoea||Vomiting Gastro-intestinal and abdominal pains Dyspepsia Flatulence||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 life-threatening) Toxic epidermal necrolysis (potentially life-threatening)||Acute generalised exanthematous pustulosis (AGEP)|
|Musculo-skeletal and Connective Tissue Disorders||Musculo-skeletal pain (e.g. extremity pain, back pain, chest pain) Arthralgia||Myalgia Arthritis Increased muscle tone and cramping||Muscular weakness Tendinitis Tendon rupture (predominantly Achilles tendon) (see section 4.4) 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 normalised ratio increased (in patients treated with Vitamin K antagonists)|
Paediatric populationThe incidence of arthropathy, mentioned above, is referring to data collected in studies with adults. In children, arthropathy is reported to occur commonly (see section 4.4).
Reporting of suspected adverse reactionsReporting 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 Website: www.mhra.gov.uk/yellowcard.
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 relationshipEfficacy 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 resistanceIn-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 activityBreakpoints separate susceptible strains from strains with intermediate susceptibility and the latter from resistant strains:
|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|
|COMMONLY SUSCEPTIBLE SPECIES|
|Aerobic Gram-positive micro-organismsBacillus anthracis (1)|
|Aerobic Gram-negative micro-organismsAeromonas spp. Brucella spp. Citrobacter koseriFrancisella tularensisHaemophilus ducreyiHaemophilus influenzae*Legionella spp. Moraxella catarrhalis*Neisseria meningitidisPasteurella spp. Salmonella spp.*Shigella spp.*Vibrio spp. Yersinia pestis|
|Other micro-organismsChlamydia trachomatis ($) Chlamydia pneumoniae ($) Mycoplasma hominis ($) Mycoplasma pneumoniae ($)|
|SPECIES FOR WHICH ACQUIRED RESISTANCE MAY BE A PROBLEM|
|Aerobic Gram-positive micro-organismsEnterococcus faecalis ($) Staphylococcus spp.* (2)|
|Aerobic Gram-negative micro-organismsAcinetobacter baumannii+Burkholderia cepacia+*Campylobacter spp.+*Citrobacter freundii*Enterobacter aerogenesEnterobacter cloacae*Escherichia coli*Klebsiella oxytocaKlebsiella pneumoniae*Morganella morganii*Neisseria gonorrhoeae*Proteus mirabilis*Proteus vulgaris*Providencia spp. Pseudomonas aeruginosa*Pseudomonas fluorescensSerratia marcescens*|
|Anaerobic micro-organismsPeptostreptococcus spp. Propionibacterium acnes|
|INHERENTLY RESISTANT ORGANISMS|
|Aerobic Gram-positive micro-organismsActinomycesEnteroccus faeciumListeria monocytogenes|
|Aerobic Gram-negative micro-organismsStenotrophomonas maltophilia|
|Anaerobic micro-organismsExcepted as listed above|
|Other micro-organismsMycoplasma genitaliumUreaplasma urealitycum|
|* Clinical efficacy has been demonstrated for susceptible isolates in approved clinical indications + Resistance rate ≥ 50% in one or more EU countries ($): 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.|
AbsorptionFollowing 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.
DistributionProtein 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.
BiotransformationLow 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.
EliminationCiprofloxacin 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)|
Paediatric patientsThe 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%.
Articular tolerabilityAs 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.
Tablet coreCellulose microcrystalline,Crospovidone,Maize starch,Magnesium stearate,Silica colloidal anhydrous.
Film-coatHypromellose,Macrogol 4000,Titanium dioxide (E171).
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