Ciprofloxacin 750 Mg Film-Coated Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Ciprofloxacin 750 mg film coated tablets.
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 873.0mg ciprofloxacin hydrochloride equivalent to 750mg ciprofloxacin.
For a full list of Excipients, see section 6.1
3 PHARMACEUTICAL FORM
Film coated tablets.
Off-white, round, biconvex, film coated tablets with CP/750 on one side and on the other.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Ciprofloxacin 750mg 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.
Consideration should be given to official guidance on the appropriate use of antibacterial agents.
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
• Gonococcal uretritis and cervicitis due to susceptible Neisseria gonorrhoeae
• Epididymo-orchitis including cases due to Neisseria gonorrhoeae
• Pelvic inflammatory disease including cases due to Neisseria gonorrhoeae In the above genital tract infections when thought or known to be due to Neisseria gonorrhoeae it is particularly important to obtain local information on the prevalence of resistance to ciprofloxacin and to confirm susceptibility based on laboratory testing.
• Infections of the gastro-intestinal tract (e.g. travellers' diarrhoea)
• Intra-abdominal infections
• Infections of the skin and soft tissue caused by Gram-negative bacteria
• Malignant external otitis
• Infections of the bones and joints
• Treatment of infections in neutropenic patients
• Prophylaxis of infections in neutropenic patients
Ciprofloxacin may be used in the management of neutropenic patients with fever that is suspected to be due to a bacterial infection
• Prophylaxis of invasive infections due to Neisseria meningitidis
• Inhalation anthrax (post-exposure prophylaxis and curative treatment) Children and adolescents
• Broncho-pulmonary infections in cystic fibrosis caused by Pseudomonas aeruginosa
• Complicated urinary tract infections and pyelonephritis
• 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).
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 coadministration with other appropriate antibacterial agents. Treatment of some infections (e.g. pelvic inflammatory disease, intraabdominal 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
|
(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 |
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-orchitisand 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 |
500 mg twice daily |
5 days | |
|
dysenteriae type 1 | |||
|
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 | |
|
Treatment of infections or prophylaxis of infections in neutropenic patients Ciprofloxacin should be coadministered 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 | |
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 postexposure prophylaxis and curative treatment for |
10 mg/kg body weight twice daily to 15 mg/kg body weight twice daily |
60 days from the confirmation of Bacillus anthracis exposure |
|
persons able to receive treatment by oral route when clinically appropriate. Drug administration should begin as soon as possible after suspected or confirmed exposure. |
with a maximum of 500 mg per dose. | |
|
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 [pmol/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. calciumfortified 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 (see section 6.1).
• Concomitant administration of ciprofloxacin and tizanidine (see section 4.5).
4.4 Special warnings and precautions for use
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 ifciprofloxacin 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) unlesss 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 fluoroquinolones.
The single dose of ciprofloxacin that may be used in uncomplicated cystitis in premenopausal 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 postsurgical 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.
Padiatric 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 jointrelated clinical signs and symptoms) by Day +42 of 7.2% and 4.6%.
Respectively, an incidence of drug-related arthropathy by 1-year follow-up was 9.0% and 5.7%. The increase of suspected drug-related arthropathy cases over time was not statistically significant between groups. Treatment should be initiated only after a careful benefit/risk evaluation, due to possible adverse events related to joints and/or surrounding tissue.
Broncho-pulmonary infections in cystic fibrosis
Clinical trials have included children and adolescents aged 5 17 years. More limited experience is available in treating children between 1 and 5 years of age.
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 (especially Achilles tendon), sometimes bilateral, may occur with ciprofloxacin, as soon as the first 48 hours of treatment. The risk of tendinopathy may be increased in elderly patients or in patients concomitantly treated with corticosteroids (see section 4.8).
At any sign of tendinitis (e.g. painful swelling, inflammation), ciprofloxacin treatment should be discontinued. Care should be taken to keep the affected limb at rest. Ciprofloxacin should be used with caution in patients with myasthenia gravis (see section 4.8).
Vision disorders:
If vision impaired or any effects on the eyes are experienced, an eyes 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. Ciprofloxacin should be used with caution in patients with CNS disorders which may be predisposed to seizure. If seizures occur ciprofloxacin should be discontinued (see section 4.8). Psychiatric reactions may occur even after the first administration of ciprofloxacin. In rare cases, depression or psychosis can progress to self-endangering behaviour. In these cases, ciprofloxacin should be discontinued.
Cases of polyneuropathy (based on neurological symptoms such as pain, burning, sensory disturbances or muscle weakness, alone or in combination) have been reported in patients receiving ciprofloxacin. Ciprofloxacin should be discontinued in patients experiencing symptoms of neuropathy, including pain, burning, tingling, numbness, and/or weakness in order to prevent the development of an irreversible condition (see section 4.8).
Cardiac disorders
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 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 the populations. (See section 4.2 Elderly, section 4.5, section 4.8 and section 4.9)
Hypoglycemia
As 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 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 excreated unchanged via renal pathway dose adjusted 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, ropinirole, tizanidine). Coadministration 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.
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 the QT interval (e.g. class IA and III anti-arrhythmics, 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.
Metaclopramide:
Metaclopramide 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:
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 conccentration 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 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-administered of ciprofoxacin with a vitamin K antagonist (e.g., warfarin, acenocoumarol, phenprocoumon, or fluindione).
Duloxetine
In clinical studies, it was demonstrated that concomitant use of suloxetine 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 expeced upon concomitant administration (see section 4.4)
Oral anticoagulants
Simultaneous administration of ciprofloxacin with warfarin may augment its anticoagulant effects. There have been many reports of increases in oral anticoagulant activity in patients receiving antibacterial agents, including fluoroquinolones. The risk may vary with the underlying infection, age and general status of the patient so that the contribution of the fluoroquinolone to the increase in INR (international normalised ratio) is difficult to assess. It is recommended that the INR should be monitored frequently during and shortly after co-administration of ciprofloxacin with an oral anticoagulant agent.
Ropinirole
It was shown in a clinical study that concomitant use of ropinirole with ciprofloxacin, a moderate inhibitor of the CYP450 1A2 isozyme, results in an increase of Cmax and AUC of ropinirole by 60% and 84%, respectively. Monitoring of ropinirole-related side effects and dose adjustment as appropriate is recommended during and shortly after co-administration with ciprofloxacin (see section 4.4).
Lidocaine
It was demonstrated in healthy subjects that concomitant use of lidocaine containing medical products with ciprofloxacin, a moderate inhibitor of CYP450 1A2 isozyme, reduces clearance of intravenous lidocaine by 22%. Although llidocaine 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 co-administration with ciprofloxacin are advised (see section 4.4).
Sildenafil
Cmax and AUC of sildenafil were increased approximately twofold in healthy subects 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 benifits.
4.6 Fertility, 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 |
Antibiotic associated colitis (very rarely with possible fatal outcome) (see section 4.4) | |||
|
Blood and Lymphatic System |
Eosinophilia |
Leukopenia Anaemia Neutropenia |
Haemolytic anaemia Agranulocytosis |
|
Disorders |
Leukocytosis Thrombocytopenia Thrombocytaemia |
Pancytopenia (lifethreatening) Bone marrow depression (lifethreatening) | |||
|
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 |
Anorexia |
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, ECG QT prolongation, torsades de pointes * (reported predominantly in patients with risk factors for QT prolongation) | |||
|
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 |
Pancreatitis | ||
|
Hepatobiliary Disorders |
Increase in transaminases Increased bilirubin |
Hepatic impairment Cholestaticicterus 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) | |
|
Musculoskeletal, |
Musculoskeletal |
Myalgia Arthritis |
Muscular |
|
Connective Tissue and Bone Disorders |
pain (e.g. extremity pain, back pain, chest pain) Arthralgia |
Increased muscle tone and cramping |
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 |
Prothrombin Level abnormal Increased amylase |
International normalised ratio increased (in patients treated with Vitamin K antagonists) |
* These events were reported during the post-marketing period and were observed predominantly among patients with further risk factors for QT prolongation (see section 4.4 and section 4.9).
Paediatric patients
The incidence of arthropathy, mentioned above, is referring to data collected in studies with adults. In children, arthropathy is reported to occur commonly (see section 4.4).
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
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.
In the event of overdose, symptomatic treatment should be implemented. ECG monitoring should be undertaken, because of the possibility of QT intervalprolongation.
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.
5 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.
PK/PD relationship:
Efficacy mainly depends on the relation between the maximum concentration in serum (Cmax) and the minimum inhibitory concentration (MIC) of ciprofloxacin for a bacterial pathogen and the relation between the area under the curve (AUC) and the MIC.
Mechanism of resistance:
In-vitro resistance to ciprofloxacin can be acquired through a stepwise process by target site mutations in both DNA gyrase and topoisomerase IV. The degree of cross-resistance between ciprofloxacin and other fluoroquinolones that results is variable. Single mutations may not result in clinical resistance, but multiple mutations generally result in clinical resistance to many or all active substances within the class.
Impermeability and/or active substance efflux pump mechanisms of resistance may have a variable effect on susceptibility to fluoroquinolones, which depends on the physiochemical properties of the various active substances within the class and the affinity of transport systems for each active substance. All in-vitro mechanisms of resistance are commonly observed in clinical isolates. Resistance mechanisms that inactivate other antibiotics such as permeation barriers (common in Pseudomonas aeruginosa) and efflux mechanisms may affect susceptibility to ciprofloxacin.
Plasmid-mediated resistance encoded by qnr-genes has been reported. Spectrum of antibacterial activity:
Breakpoints separate susceptible strains from strains with intermediate susceptibility and the latter from resistant strains:
EUCAST Recommendations
|
Microorganisms |
Susceptible |
Resistant |
|
Enterobacteria |
S ^ 0.5 mg/L |
R > 1 mg/L |
|
Pseudomonas |
S ^ 0.5 mg/L |
R > 1 mg/L |
|
Acinetobacter |
S ^ 1 mg/L |
R > 1 mg/L |
|
Staphylococcus spp.1 |
S ^ 1 mg/L |
R > 1 mg/L |
|
Haemophilus influenzae and |
S ^ 0.5 mg/L |
R > 0.5 mg/L |
|
Moraxella catarrhalis | ||
|
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 therapy. |
relate to high dose | |
|
* 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.
Metabolism
Low concentrations of four metabolites have been reported, which were identified as: desethyleneciprofloxacin (M 1), sulphociprofloxacin (M 2), oxociprofloxacin (M 3) and formylciprofloxacin (M 4). The metabolites display in-vitro antimicrobial activity but to a lower degree than the parent compound.
Ciprofloxacin is known to be a moderate inhibitor of the CYP 450 1A2 isoenzymes.
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.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
- Lactose monohydrate
- Sodium starch glycollate
- Povidone
- Sodium stearyl fumarate
- Methocel E5 premium
- Opadry Y-1-7000 White (Containing Hypromellose, Polyethylene glycol, and Titanium dioxide)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
Do not store above 25°C.
6.5 Nature and contents of container
Blister strips in cardboard outers comprising:
PVC/Aluminium blister strips
Pack size: 10 and 20 tablets
6.6 Special precautions for disposal
Not applicable.
7 MARKETING AUTHORISATION HOLDER
Special Concept Development (UK) Limited,
Unit 1-7 Colonial Way,
Watford, Hertfordshire,
WD24 4YR United Kingdom.
8 MARKETING AUTHORISATION NUMBER(S)
PL 36722/0041
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
14/04/2010
10 DATE OF REVISION OF THE TEXT
05/09/2016