1. Name Of The Medicinal Product
Ciproxin 750 mg film-coated tablets
2. Qualitative And Quantitative Composition
Each film-coated tablet contains 750 mg ciprofloxacin (as hydrochloride).
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Film-coated tablet.
Oblong, nearly white to slightly yellowish tablets marked with “CIP 750” on one side and “BAYER” on the reverse side.
4. Clinical Particulars
4.1 Therapeutic Indications
Ciproxin 750 mg 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
• 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
• 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
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
|
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
|
|
Treatment of infections or prophylaxis of infections in neutropenic patients
Ciprofloxacin should be co-administered with appropriate antibacterial agent(s) in accordance to official guidance.
|
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
|
|
Children and adolescents
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
|
Geriatric patients
Geriatric patients should receive a dose selected according to the severity of the infection and the patient's creatinine clearance.
Renal and hepatic impairment
Recommended starting and maintenance doses for patients with impaired renal function:
Creatinine Clearance
[mL/min/1.73 m²]
|
Serum Creatinine
[µmol/L]
|
Oral Dose
[mg]
|
> 60
|
< 124
|
See Usual Dosage.
|
30
|
124 to 168
|
250
|
< 30
|
> 169
|
250
|
Patients on haemodialysis
|
> 169
|
250
|
Patients on peritoneal dialysis
|
> 169
|
250
|
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 (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
Epididymo-orchitis and pelvic inflammatory diseases may be caused by fluoroquinolone-resistant Neisseria gonorrhoeae. Ciprofloxacin should be co-administered with another appropriate antibacterial agent unless ciprofloxacin-resistant Neisseria gonorrhoeae can be excluded. If clinical improvement is not achieved after 3 days of treatment, the therapy should be reconsidered.
Intra-abdominal infections
There are limited data on the efficacy of ciprofloxacin in the treatment of post-surgical intra-abdominal infections.
Travellers' diarrhoea
The choice of ciprofloxacin should take into account information on resistance to ciprofloxacin in relevant pathogens in the countries visited.
Infections of the bones and joints
Ciprofloxacin should be used in combination with other antimicrobial agents depending on the results of the microbiological documentation.
Inhalational anthrax
Use in humans is based on in-vitro susceptibility data and on animal experimental data together with limited human data. Treating physicians should refer to national and/or international consensus documents regarding the treatment of anthrax.
Children and adolescents
The use of ciprofloxacin in children and adolescents should follow available official guidance. Ciprofloxacin treatment should be initiated only by physicians who are experienced in the treatment of cystic fibrosis and/or severe infections in children and adolescents.
Ciprofloxacin has been shown to cause arthropathy in weight-bearing joints of immature animals. Safety data from a randomised double-blind study on ciprofloxacin use in children (ciprofloxacin: n=335, mean age = 6.3 years; comparators: n=349, mean age = 6.2 years; age range = 1 to 17 years) revealed an incidence of suspected drug-related arthropathy (discerned from joint-related clinical signs and symptoms) by Day +42 of 7.2% and 4.6%. Respectively, an incidence of drug-related arthropathy by 1-year follow-up was 9.0% and 5.7%. The increase of suspected drug-related arthropathy cases over time was not statistically significant between groups. Treatment should be initiated only after a careful benefit/risk evaluation, due to possible adverse events related to joints and/or surrounding tissue.
Broncho-pulmonary infections in cystic fibrosis
Clinical trials have included children and adolescents aged 5
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
Other specific severe infections
Other severe infections in accordance with official guidance, or after careful benefit-risk evaluation when other treatments cannot be used, or after failure to conventional therapy and when the microbiological documentation can justify a ciprofloxacin use.
The use of ciprofloxacin for specific severe infections other than those mentioned above has not been evaluated in clinical trials and the clinical experience is limited. Consequently, caution is advised when treating patients with these infections.
Hypersensitivity
Hypersensitivity and allergic reactions, including anaphylaxis and anaphylactoid reactions, may occur following a single dose (see section 4.8) and may be life-threatening. If such reaction occurs, ciprofloxacin should be discontinued and an adequate medical treatment is required.
Musculoskeletal System
Ciprofloxacin should generally not be used in patients with a history of tendon disease/disorder related to quinolone treatment. Nevertheless, in very rare instances, after microbiological documentation of the causative organism and evaluation of the risk/benefit balance, ciprofloxacin may be prescribed to these patients for the treatment of certain severe infections, particularly in the event of failure of the standard therapy or bacterial resistance, where the microbiological data may justify the use of ciprofloxacin.
Tendinitis and tendon rupture (especially Achilles tendon), sometimes bilateral, may occur with ciprofloxacin, as soon as the first 48 hours of treatment. The risk of tendinopathy may be increased in elderly patients or in patients concomitantly treated with corticosteroids (see section 4.8).
At any sign of tendinitis (e.g. painful swelling, inflammation), ciprofloxacin treatment should be discontinued. Care should be taken to keep the affected limb at rest.
Ciprofloxacin should be used with caution in patients with myasthenia gravis (see section 4.8).
Photosensitivity
Ciprofloxacin has been shown to cause photosensitivity reactions. Patients taking ciprofloxacin should be advised to avoid direct exposure to either extensive sunlight or UV irradiation during treatment (see section 4.8).
Central Nervous System
Quinolones are known to trigger seizures or lower the seizure threshold. Ciprofloxacin should be used with caution in patients with CNS disorders which may be predisposed to seizure. If seizures occur ciprofloxacin should be discontinued (see section 4.8). Psychiatric reactions may occur even after the first administration of ciprofloxacin. In rare cases, depression or psychosis can progress to self-endangering behaviour. In these cases, ciprofloxacin should be discontinued.
Cases of polyneuropathy (based on neurological symptoms such as pain, burning, sensory disturbances or muscle weakness, alone or in combination) have been reported in patients receiving ciprofloxacin. Ciprofloxacin should be discontinued in patients experiencing symptoms of neuropathy, including pain, burning, tingling, numbness, and/or weakness in order to prevent the development of an irreversible condition (see section 4.8).
Cardiac disorders
Since ciprofloxacin is associated with cases of QT prolongation (see section 4.8), caution should be exercised when treating patients at risk for torsades de pointes arrhythmia.
Gastrointestinal System
The occurrence of severe and persistent diarrhoea during or after treatment (including several weeks after treatment) may indicate an antibiotic-associated colitis (life-threatening with possible fatal outcome), requiring immediate treatment (see section 4.8). In such cases, ciprofloxacin should immediately be discontinued, and an appropriate therapy initiated. Anti-peristaltic drugs are contraindicated in this situation.
Renal and urinary system
Crystalluria related to the use of ciprofloxacin has been reported (see section 4.8). Patients receiving ciprofloxacin should be well hydrated and excessive alkalinity of the urine should be avoided.
Hepatobiliary system
Cases of hepatic necrosis and life-threatening hepatic failure have been reported with ciprofloxacin (see section 4.8). In the event of any signs and symptoms of hepatic disease (such as anorexia, jaundice, dark urine, pruritus, or tender abdomen), treatment should be discontinued.
Glucose-6-phosphate dehydrogenase deficiency
Haemolytic reactions have been reported with ciprofloxacin in patients with glucose-6-phosphate dehydrogenase deficiency. Ciprofloxacin should be avoided in these patients unless the potential benefit is considered to outweigh the possible risk. In this case,potential occurrence of haemolysis should be monitored.
Resistance
During or following a course of treatment with ciprofloxacin bacteria that demonstrate resistance to ciprofloxacin may be isolated, with or without a clinically apparent superinfection. There may be a particular risk of selecting for ciprofloxacin-resistant bacteria during extended durations of treatment and when treating nosocomial infections and/or infections caused by Staphylococcus and Pseudomonas species.
Cytochrome P450
Ciprofloxacin inhibits CYP1A2 and thus may cause increased serum concentration of concomitantly administered substances metabolised by this enzyme (e.g. theophylline, clozapine, ropinirole, tizanidine). Co-administration of ciprofloxacin and tizanidine is contra-indicated. Therefore, patients taking these substances concomitantly with ciprofloxacin should be monitored closely for clinical signs of overdose, and determination of serum concentrations (e.g. of theophylline) may be necessary (see section 4.5).
Methotrexate
The concomitant use of ciprofloxacin with methotrexate is not recommended (see section 4.5).
Interaction with tests
The in-vitro activity of ciprofloxacin against Mycobacterium tuberculosis might give false negative bacteriological test results in specimens from patients currently taking ciprofloxacin.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Effects of other products on ciprofloxacin:
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), 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
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.
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.
Oral anticoagulants
.Simultaneous administration of ciprofloxacin with warfarin may augment its anti-coagulant 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).
Clozapine
Following concomitant administration of 250 mg ciprofloxacin with clozapine for 7 days, serum concentrations of clozapine and N-desmethylclozapine were increased by 29% and 31%, respectively. Clinical surveillance and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised (see section 4.4).
4.6 Pregnancy And Lactation
Pregnancy
The data that are available on administration of ciprofloxacin to pregnant women indicates no malformative or feto/neonatal toxicity of ciprofloxacin. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. In juvenile and prenatal animals exposed to quinolones, effects on immature cartilage have been observed, thus, it cannot be excluded that the drug could cause damage to articular cartilage in the human immature organism / foetus (see section 5.3).
As a precautionary measure, it is preferable to avoid the use of ciprofloxacin during pregnancy.
Lactation
Ciprofloxacin is excreted in breast milk. Due to the potential risk of articular damage, ciprofloxacin should not be used during breast-feeding.
4.7 Effects On Ability To Drive And Use Machines
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 Ciproxin (oral, intravenous, and sequential therapy) sorted by categories of frequency are listed below. The frequency analysis takes into account data from both oral and intravenous administration of ciprofloxacin.
System Organ Class
|
Common
|
Uncommon
|
Rare
|
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 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
|
|
Anorexia
|
Hyperglycaemia
|
|
|
Psychiatric Disorders
|
|
Psychomotor hyperactivity / agitation
|
Confusion and disorientation
Anxiety reaction
Abnormal dreams
Depression
Hallucinations
|
Psychotic reactions (see section 4.4)
|
|
Nervous System Disorders
|
|
Headache
Dizziness
Sleep disorders
Taste disorders
|
Par- and Dysaesthesia
Hypoaesthesia
Tremor
Seizures (see section 4.4)
Vertigo
|
Migraine
Disturbed coordination
Gait disturbance
Olfactory nerve disorders
Intracranial hypertension
|
Peripheral neuropathy (see section 4.4)
|
Eye Disorders
|
|
|
Visual disturbances
|
Visual colour distortions
|
|
Ear and Labyrinth Disorders
|
|
|
Tinnitus
Hearing loss / Hearing impaired
|
|
|
Cardiac Disorders
|
|
|
Tachycardia
|
|
Ventricular arrhythmia, QT prolongation, torsades de pointes *
|
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
|
|
|
