Ciprofloxacin 2 Mg/Ml Solution For Infusion
PACKAGE LEAFLET: INFORMATION FOR THE USER Ciprofloxacin 2 mg/ml Solution for Infusion
Ciprofloxacin
Read all of this leaflet carefully before you start taking this medicine.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor or pharmacist.
- This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.
- If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.
The name of your medicine is Ciprofloxacin 2mg/ml Solution for Infusion.
In the rest of this leaflet Ciprofloxacin 2mg/ml solution for infusion is called Ciprofloxacin.
In this leaflet:
1. What Ciprofloxacin is and what it is used for
2. Before you are given Ciprofloxacin
3. Howto use Ciprofloxacin
4. Possible side-effects
5. How to store Ciprofloxacin
6. Further information
WHAT CIPROFLOXACIN IS AND WHAT IT IS USED FOR
Ciprofloxacin is an antibiotic belonging to the fluoroquinolone family. The active substance is ciprofloxacin. Ciprofloxacin works by killing bacteria that cause infections. It only works with specific strains of bacteria. Adults
Ciprofloxacin is used in adults to treat the following bacterial infections:
• respiratory tract infections
• long lasting or recurring ear or sinus infections
• urinaiy tract infections
• infections of the testicles
• genital organ infections in women
• gastro-intestinal tract infections and intra-abdominal infections
• skin and soft tissue infections
• bone and joint infections
• to treat infections in patients with a very low white blood cell count (neutropenia)
• to prevent infections in patients with a very low white blood cell count (neutropenia)
• anthrax inhalation exposure
If you have a severe infection or one that is caused by more than one type of bacterium, you may be given additional antibiotic treatment in addition to Ciprofloxacin.
Children and Adolescents
Ciprofloxacin is used in children and adolescents, under specialist medical supervision, to treat the following bacterial infections:
• lung and bronchial infections in children and adolescents suffering from cystic fibrosis
• complicated urinary tract infections, including infections that have reached the kidneys (pyelonephritis)
• anthrax inhalation exposure
Ciprofloxacin may also be used to treat other specific severe infections in children and adolescents when your doctor considered this necessary.
BEFORE YOU ARE GIVEN CIPROFLOXACIN
You must not be given Ciprofloxacin If you are:
• allergic (hypersensitive) to the active substance, to other quinolone drugs or to any of the other ingredients of Ciprofloxacin (see section 6)
• taking tizanidine (see Section 2: Taking other medicines)
Take special care with Ciprofloxacin Before taking Ciprofloxacin:
Tell your doctor if you:
• have ever had kidney problems because your treatment may need to be adjusted
• suffer from epilepsy or other neurological conditions
• have a histoiy of tendon problems during previous treatment with antibiotics such as Ciprofloxacin
• have myasthenia gravis (a type of muscle weakness)
Heart problems
Caution should be taken when using this kind of medicine, if you were born with or have family history of prolonged QT interval (seen on ECG, electrical recording of the heart), have salt imbalance in the blood (especially low level of potassium or magnesium in the blood), have a very slow heart rhythm (called ‘bradycardia'), have a weak heart (heart failure), have a history of heart attack (myocardial infarction), you are female or elderly or you are taking other medicines that result in abnormal ECG changes (see section Taking other medicines).
While under treatment with Ciprofloxacin:
Tell your doctor immediately, if any of the following occurs during treatment with Ciprofloxacin. Your doctor will decide whether treatment with Ciprofloxacin needs to be stopped.
• Severe, sudden allergic reaction (an anaphylactic reaction/shock, angio-oedema). Even with the first dose, there is a rare chance that you may experience a severe allergic reaction with the following symptoms: tightness in the chest, feeling dizzy, feeling sick or faint, or experience dizziness on standing. If this happens, tell your doctor immediately since the administration of Ciprofloxacin will have to be stopped.
• Pain and swelling in the joints, and tendinitis may occur occasionally, particularly if you are elderly and are also being treated with corticosteroids. At the first sign of any pain or inflammation Ciprofloxacin will have to be stopped, rest the painful area. Avoid any unnecessary exercise as this might increase the risk of a tendon rupture.
• If you suffer from epilepsy or other neurological conditions such as cerebral ischemia or stroke, you may experience side effects associated with the central nervous system. If this happens, stop taking Ciprofloxacin and contact your doctor immediately.
• You may experience psychiatric reactions after first administration of ciprofloxacin. If you suffer from depression or psychosis, your symptoms may become worse under treatment with Ciprofloxacin. If this happens, stop taking Ciprofloxacin and contact your doctor immediately.
• You may experience symptoms of neuropathy such as pain, burning, tingling, numbness and/or weakness. If this happens, stop taking Ciprofloxacin and contact your doctor immediately.
• Diarrhoea may develop while you are on antibiotics, including Ciprofloxacin, or even several weeks after you have stopped using them. If it becomes severe or persistent or you notice that your stool contains blood or mucus tell your doctor immediately. Ciprofloxacin treatment will have to be stopped immediately, as this can be life-threatening. Do not take medicines that stop or slow down bowel movements.
• Tell the doctor or laboratory staff that you are taking Ciprofloxacin if you have to provide a blood or urine sample.
• Ciprofloxacin may cause liver damage. If you notice any symptoms such as loss of appetite, jaundice (yellowing of the skin), dark urine, itching, or tenderness of the stomach, Ciprofloxacin must be stopped immediately.
• Ciprofloxacin may cause a reduction in the number of white blood cells and your resistance to infection may be decreased. If you experience an infection with symptoms such as fever and serious deterioration of your general
condition, or fever with local infection symptoms such as sore throat/pharynx/mouth or urinary problems you should see your doctor immediately. A blood test will be taken to check possible reduction of white blood cells (agranulocytosis). It is important to inform your doctor about your medicine.
• Tell your doctor if you or a member of your family is known to have a deficiency in glucose-6- phosphate dehydrogenase (G6PD), since you may experience a risk of anemia with ciprofloxacin.
• Your skin becomes more sensitive to sunlight or ultraviolet (UV) light under treatment with Ciprofloxacin. Avoid exposure to strong sunlight or artificial UV light such as sunbeds.
If your eyesight becomes impaired or if your eyes seem to be otherwise affected, consult an eye specialist immediately (see section 4).
Taking other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.
You must tell your doctor if you are taking other medicines that can alter your heart rhythm: medicines that belong to the group of anti-arrhythmics (e.g. quinidine, hydroquinidine, disopyramide, amiodarone, sotalol, dofetilide, ibutilide), tricyclic antidepressants, some antimicrobials (that belong to the group of macrolides), some antipsychotics.
Do not use Ciprofloxacin together with tizanidine, because this may cause side effects such as low blood pressure and sleepiness (see Section 2: "You must not be given Ciprofloxacin if you are").
The following medicines are known to interact with Ciprofloxacin in your body. Using Ciprofloxacin together with these medicines can influence the therapeutic effect of these medicines. It can also increase the probability of experiencing side effects.
Tell your doctor if you are taking:
• warfarin or other oral anti-coagulants (to thin the blood)
• probenecid (for gout)
• methotrexate (for certain types of cancer, psoriasis, rheumatoid arthritis)
• theophylline (for breathing problems)
• tizanidine (for muscle spasticity in multiple sclerosis)
• clozapine (an antipsychotic)
• ropinirole (for Parkinson’s disease)
• phenytoin (for epilepsy)
Ciprofloxacin may increase the levels of the following medicines in your blood:
• pentoxifylline (for circulatory disorders)
• caffeine
Taking Ciprofloxacin with food and drink
Food and drink does not affect your treatment with Ciprofloxacin.
Pregnancy and breastfeeding
It is preferable to avoid the use of Ciprofloxacin during pregnancy. Tell your doctor if you are planning to get pregnant.
Do not take Ciprofloxacin during breast feeding because ciprofloxacin is excreted in breast milk and can be harmful for your child.
Driving and using machines
Ciprofloxacin may make you feel less alert. Some neurological adverse events can occur. Therefore, make sure you know how you react to Ciprofloxacin before driving a vehicle or operating machinery. If in doubt, talk to your doctor.
Important information about some of the ingredients of Ciprofloxacin
If you are on a low sodium diet, it is important to know how much sodium is in your medicine.
Each of 100 ml (millilitres) of this medicine contains 15.4 millimoles (mmol) of sodium.
Each of 200ml contains 30.8 mmol of sodium.
Your doctor will explain to you exactly how much Ciprofloxacin you will be given as well as how often and for how long. This will depend on the type of infection you have and how bad it is.
Tell your doctor if you suffer from kidney problems because your dose may need to be adjusted.
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Technical Information Leaflet Ciprofloxacin 2 mg/ml Solution for Infusion Ciprofloxacin
This leaflet provides Technical Information for the healthcare professional. There is a separate Patient Information Leaflet.
1. NAME OF THE MEDICINAL PRODUCT
QUALITATIVE AND QUANTITATIVE COMPOSITION
1 ml of solution for infusion contains 2 mg of ciprofloxacin. Excipients: Contains 30.8 mmol (707.70 mg) sodium per 200 ml of solution for infusion. For a full list of excipients, see section 6.1,
PHARMACEUTICAL FORM
Solution for infusion. Clear, yellowish, sterile and non-pyrogenic aqueous solution.
CLINICAL PARTICULARS
4.1 Therapeutic indications
Ciprofloxacin 2 mg/ml Solution for Infusion is indicated for the treatment of the following infections (see sections 4.4 and 5.1). Special attention should be paid to available information on resistance to ciprofloxacin before commencing therapy. 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
• Epididymo-orchitis including cases due to Neisseria gonorrhoeae
• Pelvic inflammatory disease including cases due to Neisseria gonorrhoeae
In the above genital tract infections when thought or known to be due to Neisseria gonorrhoeae it is particularly important to obtain local information on the prevalence of resistance to ciprofloxacin and to confirm susceptibility based on laboratory testing.
• Infections of the gastro-intestinal tract (e.g. travellers' diarrhoea)
• Intra-abdominal infections
• Infections of the skin and soft tissue caused by Gram-negative bacteria
• Malignant external otitis
• Infections of the bones and joints
• Treatment of infections in neutropenic patients
• Prophylaxis of infections in neutropenic patients
• Inhalation anthrax (post-exposure prophylaxis and curative treatment)
Children and adolescents
• Broncho-pulmonary infections in cystic fibrosis caused by Pseudomonas aeruginosa
• Complicated urinary tract infections and pyelonephritis
• 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. After intravenous initiation of treatment, the treatment can be switched to oral treatment with tablet or suspension if clinically indicated at the discretion of the physician. IV treatment should be followed by oral route as soon as possible. In severe cases or if the patient is unable to take tablets (e.g. patients on enteral nutrition), it is recommended to commence therapy with intravenous ciprofloxacin until a switch to oral administration is possible. Treatment of infections due to certain bacteria (e.g. Pseudomonas aeruginosa, Acinetobacter or Staphylococci) may require higher ciprofloxacin doses and co-administration with other appropriate antibacterial agents. Treatment of some infections (e.g. pelvic inflammatory disease, intra-abdominal infections, infections in neutropenic patients and infections of bones and joints) may require co-administration with other appropriate antibacterial agents depending on the pathogens involved.
Adults_
|
Indications |
Daily dose in mg |
Total duration of treatment (including switch to oral therapy as soon as possible) | |
|
Infections of the lower respiratory tract |
400 mg twice daily to 400 mg three times a day |
7 to 14 days | |
|
Infections of the upper respiratory tract |
Acute exacerbation of chronic sinusitis |
400 mg twice daily to 400 mg three times a day |
7 to 14 days |
|
Chronic suppurative otitis media |
400 mg twice daily to 400 mq three times a day |
7 to 14 days | |
|
Malignant external otitis |
400 mg three times a day |
28 days up to 3 months | |
|
Urinary tract infections |
Complicated and uncomplicated pyelonephritis |
400 mg twice daily to 400 mg three times a day |
7 to 21 days, it can be continued for longer than 21 days in some specific circumstances (such as abscesses) |
|
Prostatitis |
400 mg twice daily to 400 mq three times a day |
2 to 4 weeks (acute) | |
|
Genital tract infections |
Epididymo-orchitis and pelvic inflammatory diseases |
400 mg twice daily to 400 mg three times a day |
at least 14 days |
|
Infections of the gastro-intestinal tract and intraabdominal infections |
Diarrhoea caused by bacterial pathogens including Shigella spp. other than Shigella dysenteriae type 1 and empirical treatment of severe travellers’ diarrhoea |
400 mg twice daily |
1 day |
|
Diarrhoea caused by Shigella dysenteriae type 1 |
400 mg twice daily |
5 days | |
|
Diarrhoea caused by Vibrio cholerae |
400 mg twice daily |
3 days | |
|
Typhoid fever |
400 mg twice daily |
7 days | |
|
Intra-abdominal infections due to Gram-negative bacteria |
400 mg twice daily to 400 mq three times a day |
5 to 14 days | |
|
Infections of the skin and soft tissue |
400 mg twice daily to 400 mg three times a day |
7 to 14 days | |
|
Bone and joint infections |
400 mg twice daily to 400 mq three times a day |
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. |
400 mg twice daily to 400 mg three times a day |
Therapy should be continued over the entire period of neutropenia | |
|
Inhalation anthrax post-exposure prophylaxis and curative treatment for persons requiring parenteral treatment. Drug administration should begin as soon as possible after suspected or confirmed exposure. |
400 mg twice daily |
60 days from the confirmation of Bacillus anthracis exposure | |
Children and adolescents
|
Cystic fibrosis |
10 mg/kg body weight three times a day with a maximum of 400 mg per dose |
10 to 14 days |
|
Complicated urinary tract infections and pyelonephritis |
6 mg/kg body weight three times a day to 10 mg/kg body weight three times a day with a maximum of 400 mg per dose |
10 to 21 days |
|
Inhalation anthrax post-exposure curative treatment for persons requiring parenteral treatment. 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 400 mg per dose |
60 days from the confirmation of Bacillus anthracis exposure |
|
Other severe infections |
10 mg/kg body weight three times a day with a maximum of 400 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 |
Serum Creatinine |
Intravenous Dose |
|
[mL/min/1.73 m2] |
[pmol/L] |
[mg] |
|
>60 |
< 124 |
See Usual Dosage |
|
30-60 |
124 to 168 |
200-400 mg every 12 h |
|
<30 |
> 169 |
200-400 mg every 24 h |
|
Patients on haemodialysis |
> 169 |
200-400 mg every 24 h (after dialysis) |
|
Patients on peritoneal dialysis |
> 169 |
200-400 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: Ciprofloxacin 2 mg/ml Solution for Infusion should be checked visually prior to use. It must not be used if cloudy. Ciprofloxacin should be administered by intravenous infusion. For children, the infusion duration is 60 minutes. In adult patients, infusion time is 60 minutes for 400 mg Ciprofloxacin 2 mg/ml Solution for Infusion and 30 minutes for 200 mg Ciprofloxacin 2 mg/ml Solution for Infusion. Slow infusion into a large vein will minimise patient discomfort and reduce the risk of venous irritation. The infusion solution can be infused either directly or after mixing with other compatible infusion solutions (see section 6.2).
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).
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 coadministered 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 5-17 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).
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:
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 these populations (See section 4.2 Elderly, section 4.5, section 4.8, section 4.9).
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: Crystal I uria 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 concomitantiy with ciprofloxacin should be monitored closely for clinical signs of overdose, and determination of serum concentrations (e.g. of theophylline) may be necessary (see section 4.5).
Methotrexate: The concomitant use of ciprofloxacin with methotrexate is not recommended (see section 4.5).
Interaction with tests: The in-vitro activity of ciprofloxacin against Mycobacterium tuberculosis might give false negative bacteriological test results in specimens from patients currently taking ciprofloxacin.
Injection Site Reaction: Local intravenous site reactions have been reported with the intravenous administration of ciprofloxacin. These reactions are more frequent if the infusion time is 30 minutes or less. These may appear as local skin reactions which resolve rapidly upon completion of the infusion. Subsequent intravenous administration is not contraindicated unless the reactions recur or worsen.
NaC! Load: In patients for whom sodium intake is of medical concern (patients with congestive heart failure, renal failure, nephritic syndrome, etc.), the additional sodium load should be taken into account.
Vision disorders: If vision becomes impaired or any effects on the eyes are experienced, an eye specialist should be consulted immediately (see section 4.8).
4.5 Interaction with other medicinal products and other forms of interaction
Effects of other medicinal products on ciprofloxacin:
Probenecid: Probenecid interferes with renal secretion of ciprofloxacin. Co-administration of probenecid and ciprofloxacin increases ciprofloxacin serum concentrations.
Effects of ciprofloxacin on other medicinal products:
Tizanidine: Tizanidine must not be administered together with ciprofloxacin (see section 4.3). In a clinical study with healthy subjects, there was an increase in serum tizanidine concentration (Cmax increase: 7-fold, range: 4 to 21-fold; AUC increase: 10-fold, range: 6 to 24-fold) when given concomitantiy 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 anti-coagulant activity in patients receiving antibacterial agents, including fluoroquinolones. The risk may vary with the underlying infection, age and general status of the patient so that the contribution of the fluoroquinolone to the increase in INR (international normalised ratio) is difficult to assess. It is recommended that the INR should be monitored frequently during and shortly after co-administration of ciprofloxacin with an oral anticoagulant agent.
Ropinirole: It was shown in a clinical study that concomitant use of ropinirole with ciprofloxacin, a moderate inhibitor of the CYP450 1A2 isozyme, results in an increase of Cmax and AUC of ropinirole by 60% and 84%, respectively. Monitoring of ropini role-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 coadministration with ciprofloxacin are advised (see section 4.4).
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).
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, diarrhoea, vomiting, transient increase in transaminases, rash, and injection and infusion site reactions. ADRs derived from clinical studies and post-marketing surveillance with Ciprofloxacin 2 mg/ml Solution for Infusion (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.
Treatment usually lasts between 5 and 21 days, but may be longer for severe infections.
Your doctor will give you each dose by slow infusion through a vein into your bloodstream.
For children, the infusion duration is 60 minutes. In adult patients, infusion time is 60 minutes for 400 mg Ciprofloxacin and 30 minutes for 200 mg Ciprofloxacin. Administering the infusion slowly helps prevent immediate side effects occurring. Remember to drink plenty of fluids while you are taking Ciprofloxacin.
If you stop your course of Ciprofloxacin
• It is important that you finish the course of treatment even if you begin to feel better after a few days. If you stop using this medicine too soon your infection may not be completely cured and the symptoms of the infection may return or get worse. You might also develop resistance to the antibiotic.
If you have any more questions about the use of this product, ask your doctor or pharmacist.
Like all medicines Ciprofloxacin can cause side-effects, although not everybody gets them.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, tell your doctor or pharmacist.
Common side effects (between 1 and 10 in every 100 people are likely to get these);
• nausea, diarrhoea, vomiting
• joint pains in children
• local reaction at the injection site, rash
• temporary increased amounts of substances in the blood (transaminases)
Uncommon side effects (between 1 and 10 in every 1,000 people are likely to get these):
• fungal superinfections
• a high concentration of eosinophils, a type of white blood cell, increased or decreased amounts of a blood doting factor (thrombocytes)
• loss of appetite (anorexia)
• hyperactivity, agitation, confusion, disorientation, hallucinations _
• headache, dizziness, sleeping problems, taste disorders, pins and needles, unusual sensitivity to stimuli of the senses, seizures (see Section 2; Take spedal care with Ciprofloxacin), Giddiness
• eyesight problems
• loss of hearing
• rapid heartbeat (tachycardia)
• expansion of the blood vessels (vasodilation), low blood pressure
• abdominal pain, digestive problems such as stomach upset (indigestion/heartbum), wind
• liver disorders, increased amounts of one substance in the blood (bilirubin), jaundice (cholestatic icterus)
• itching, hives
• joint pain in adults
• poor kidney function, kidney failure
• pains in your muscles and bones, feeling unwell (asthenia), fever, fluid retention
• increase in blood alkaline phosphatase (a certain substance in the blood)
Rare side effects (between 1 and 10 in every 10,000 people are likely to get these):
• inflammation of the bowel (colitis) linked to antibiotic use (can be fatal in rare cases) (see Section 2: Take spedal care with Ciprofloxacin)
• changes to the blood count (leukopenia, leukocytosis, neutropenia, anaemia), a drop in the number of red and white blood cells and platelets (pancytopenia), which may be fatal, bonemarrow depression which may also be fatal (see
Section 2: Take special care with Ciprofloxacin)
• allergic reaction, allergic swelling (oedema), rapid swelling of the skin and mucous membranes (angiooedema), severe allergic reaction (anaphylactic shock) which can be life-threatening (see Section 2: Take spedal care with Ciprofloxadn)
• increased blood sugar (hyperglycemia) _
• anxiety reaction, strange dreams, depression, mental disturbances (psychotic reactions) (see Section 2: Take spedal care with Ciprofloxacin)
• decreased skin sensitivity, tremor, migraine, disorder of sense of smell (olfactory disorders)
• tinnitus, impaired hearing
• fainting, inflammation of the blood vessel (vasculitis)
• shortness of breath induding asthmatic symptoms
• pancreatitis
• hepatitis, death of liver cells (liver necrosis) very rarely leading to life-threatening liver failure
• sensitivity to light (see Section 2: Take spedal care with Ciprofloxacin), small, pin-point bleeding under the skin (petechiae) _
• muscle pain, inflammation of the joints, increased musde tone, cramping, tendon rupture - especially of the large tendon at the back of the ankle (Achilles tendon) (see Section 2: Take special care with Ciprofloxacin)
• blood or crystals in the urine (see Section 2: Take spedal care with Ciprofloxacin), urinary tract inflammation
• excessive sweating
• abnormal levels of a dotting factor (prothromibin) increased levels of the enzyme amylase
Very rare side effects (less than 1 in every 10,000 people are likely to get these):
• a spedal type of reduced red blood cell count (haemolytic anaemia); a dangerous drop in a type of white blood cells (agranulocytosis)
• severe allergic reaction (anaphylactic reaction, anaphyladic shock, serum sickness) which can be fatal (see Section 2: Take special care with Ciprofloxacin)
• disturbed coordination, unsteady walk (gait disturbance), pressure on the brain (intracranial pressure)
• visual colour distortions
• various skin eruptions or rashes (e.g. the potentially fatal Stevens-Johnson syndrome or toxic epidermal necrolysis)
• muscle weakness, tendon inflammation, worsening of the symptoms of myasthenia gravis (see Section 2: Take special care with Ciprofloxacin)
Frequency not known (cannot be estimated from the available data)
• troubles associated with the nervous system such as pain, burning, tingling, numbness and/ or weakness in extremities
Heart problems
Not known: Abnormal fast heart rhythm, life-threatening irregular heart rhythm, alteration of the heart rhythm (called ‘prolongation of QT interval’, seen on ECG, electrical activity of the heart).
Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This indudes any possible side effects not listed in this leaflet. You can also report side effects directly via:
For UK: Yellow Card Scheme, Website: www.mhra.gov.uk/vellowcard.
For IE: HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie: E-mail: medsafety@hpra.ie.
By reporting side effects you can help provide more information on the safety of this medicine.
Your doctor, nurse or pharmacist will usually store your medicine for you.
Keep out of the reach and sight of children.
Do not use your medidne after the expiry date which is stated on the carton after "EXP": The expiry date refers to the last day of that month.
Medianes should not be disposed of via wastewater or household waste. These measures will help to protect the environment.
Store below 25°C. Do not put your medidne in the fridge or in the freezer as crystals may form if the medicine gets too cold. If you see crystals in your medicine, do not use the medicine and tell your doctor, nurse or pharmacist immediately. Always keep your medicine in the outer carton to protect it from light because it is sensitive to light.
Open it and use it straight away. This is a single dose container. Since Ciprofloxacin 2 mg/ml Solution for Infusion is light-sensitive, the bags or bottles should always be stored in the cardboard outer container. No special precautions are required during the normal 60 minute infusion period. If the product is inadvertently removed from the outer carton, the stability of the product is maintained for a period of up to one day in daylight.
Your medicine should not be mixed with certain other medicines that may also be given by infusion. Please ask your doctor, nurse or pharmacist if you want any more information about this.
Give any leftover medicine to your doctor, nurse or pharmacist. If you do this, it will help protect the environment. Do not put it down the drain or in the dustbin.
6. FURTHER INFORMATION
What Ciprofloxacin contains
The active medicine is Ciprofloxacin (as lactate).
Each 100 ml contains 200 mg (milligram) of ciprofloxacin. Each 200 ml contains 400 mg of ciprofloxacin.
The other ingredients are Lactic acid, Sodium Chloride, Hydrochloric Acid (for pH adjustment) and Water for Injections.
What Ciprofloxacin looks like and contents of the pack
Solution for infusion.
This means it is ready to give to you in a plastic bag or bottle as an intravenous or IV infusion (drip).
Each bag or bottle of Ciprofloxacin contains 100 ml or 200 ml of your medicine.
100 ml bags come in boxes of 10.
100 ml bottles come in boxes of 10.
100 ml bottles come in boxes of 1.
200 ml bags come in boxes of 5.
200 ml bottles come in boxes of 5.
200 ml bottles come in boxes of 1.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder: Noridem Enterprises Ltd, Evagorou and Makariou Mitsi Building 3, Office 115, 1065 Nicosia, Cyprus. Manufacturer: DEMO S.A., 218t km National Road Athens-Lamia, 14568 Krioneri, Athens, Greece.
This medicinal product is authorised in the Member States of the EEA under the following names:
United Kingdom: Ciprofloxacin 2 mg/ml Solution for Infusion Ireland: Ciprofloxacin 2 mg/ml Solution for Infusion
Spain: Ciprofloxacino KERN PHARMA 2 mg/ml soludbn para perfusidn EFG Greece: Ciprofloxacin/Noridem, AidAupa yia feyxuan 2 mg/ml Austria: Ciprofloxacin Noridem 2 mg/ml Infusionslosung Germany: Ciprofloxacin 2mg/ml Infusionslosung
This leaflet was last revised in 10/2014
If this leaflet is difficult to see or read, please contact the following address for help:
Fannin Limited, Fannin House, South County Business Park, Leopardstown, Dublin 18, Ireland Tel +353-1-2907000.
|
System Organ Class |
Common & 1/100 to <1/10 |
Uncommon a 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 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 /angioedema |
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 and torsades de pointes (reported predominantly in patients with risk factors for QT prolongation), ECG QT prolonged (see section 4.4 and 4.9). | |||
|
Vascular Disorders |
Vasodilatation Hypotension Syncope |
Vasculitis | |||
|
Respiratory, Thoracic and Mediastinal Disorders |
Dyspnoea (including asthmatic condition) | ||||
|
Gastrointestinal Disorders |
Nausea Diarrhoea |
Vomiting Gastrointestinal and abdominal pains Dyspepsia Flatulence |
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-threateninq) | ||
|
Musculoskeletal, Connective Tissue and Bone Disorders |
Musculoskeletal 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 |
Injection and infusion site reactions (only intravenous administration) |
Asthenia Fever |
Oedema Sweating (hyperhidrosis) | ||
|
Investigations |
Increase in blood alkaline phosphatase |
Prothrombin level abnormal Increased amylase |
* 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). The following undesirable effects have a higher frequency category
|
Common |
Vomiting, Transient increase in transaminases, Rash |
|
Uncommon |
Thrombocytopenia, Thrombocytaemia, Confusion and disorientation, Hallucinations, Par- and dysaesthesia, Seizures, Vertigo, Visual disturbances, Hearing loss, Tachycardia, Vasodilatation, Hypotension, Transient hepatic impairment, Cholestatic icterus, Renal failure, Oedema |
|
Rare |
Pancytopenia, Bone marrow depression, Anaphylactic shock, Psychotic reactions, Migraine, Olfactory nerve disorders, Hearing impaired, Vasculitis, Pancreatitis, Liver necrosis, Petechiae, Tendon rupture |
Paediatric patients: The incidence of arthropathy, mentioned above, is referring to data collected in studies with adults. In children, arthropathy is reported to occur commonly (see section 4.4).
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:
For UK: Yellow Card Scheme, Website: fwww.mhra.aov.uk/vellowcard).
For IE: HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie: E-mail: medsafetv@hpra.ie.
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 interval prolongation. Apart from routine emergency measures, it is recommended to monitor renal function, including urinary pH and acidify, if required, to prevent crystalluria. Patients should be kept well hydrated. Only a small quantity of ciprofloxacin (<10%) is eliminated by haemodialysis or peritoneal dialysis.
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 Moraxella catarrhalis |
S £0.5 mq/L |
R > 0.5 mq/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-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 ($), Staphylococcus spp. *(2)
Aerobic Gram-negative micro-organisms; Acinetobacter baumannii+. Burkholderia cepacia +*, Campylobacter spp.+* Citrobacter freundii*, Enterobacter aerogenes, Enterobacter cloacae *, Escherichia coli*, Klebsiella oxytoca, Klebsiella pneumoniae*, Monganella morganii*, Neisseria gononiioeae*, Proteus mirabilis*, Proteus vulgaris*, Providencia spp., Pseudomonas aeruginosa*, Pseudomonas fluorescens, Serratia marcescens*_
Anaerobic micro-organisms: Peptostreptococcus spp., Propionibacterium acnes
INHERENTLY RESISTANT ORGANISMS
Aerobic Gram-positive micro-organisms: Actinomyces, Enteroccus faecium, Listeria monocytogenes
Aerobjc_GramMTegatiye_micK>grganismsj. Stenotrophomonas maltophilia
Anaerobic micro-organisms: Excepted as listed above
Other micro-organisms: Mycoplasma genitalium, Ureaplasma urealitycum
* Clinical efficacy has been demonstrated for susceptible isolates in approved clinical indications + Resistance rate £ 50% in one or more EU countries
($): 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) : Methidllin-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 an intravenous infusion of ciprofloxacin the mean maximum serum concentrations were achieved at the end of infusion. Pharmacokinetics of ciprofloxacin were linear over the dose range up to 400 mg administered intravenously. Comparison of the pharmacokinetic parameters for a twice a day and three times a day intravenous dose regimen indicated no evidence of drug accumulation for ciprofloxacin and its metabolites. A 60-minute intravenous infusion of 200 mg ciprofloxacin or the oral administration of 250 mg ciprofloxacin, both given every 12 hours, produced an equivalent area under the serum concentration time curve (AUC). A 60-minute intravenous infusion of 400 mg ciprofloxacin every 12 hours was bioequivalent to a 500 mg oral dose every 12 hours with regard to AUC. The 400 mg intravenous dose administered over 60 minutes every 12 hours resulted in a Cmax similar to that observed with a 750 mg oral dose. A 60-minute infusion of 400 mg ciprofloxacin every 8 hours is equivalent with respect to AUC to 750 mg oral regimen given every 12 hours.
Distribution: Protein binding of ciprofloxadn is low (20-30%). Ciprofloxacin is present in plasma largely in a nonionised 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: desethylenedprofloxacin (M 1), sulphociprofloxacin (M 2), oxodprofloxacin (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.
|
Excretion of ciprofloxacin (% of dose) | ||
|
Intravenous Administration | ||
|
Urine |
Faeces | |
|
Ciprofloxacin |
61.5 |
15.2 |
|
Metabolites (M1-M4) |
9.5 |
2.6 |
Renal dearance 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 dprofloxacin 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 photo mutagenic 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: Lactic acid (E270), Sodium chloride, Hydrochloric Acid (E507) for pH adjustment, Water for injections.
6.2 Incompatibilities: Ciprofloxacin 2 mg/ml Solution for Infusion is incompatible with injection solutions (e.g. penicillins, heparin solutions) which are chemically or physically unstable at pH of 3.9 -4.5. Unless compatibility is proven, the infusion should always be administered separately. This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
6.3 Shelf life: Unopened: Two years. Single dose container. From a microbiological point of view, the product should be used immediately once opened (see section 6.4).
6.4 Special precautions for storage:
Polypropylene bag: Unopened: Store below 25°C. Keep the bag in the outer carton in order to protect from light. Do not refrigerate or freeze.
Polypropylene bottles: Unopened: Store below 25°C. Keep the bottles in the outer carton in order to protect from light. Do not refrigerate or freeze. Since Ciprofloxacin 2 mg/ml Solution for Infusion is light-sensitive, the bags and bottles should always be stored in the cardboard outer container. No special precautions are required during the normal 60 minute infusion period. Do not refrigerate or freeze Ciprofloxacin 2 mg/ml Solution for Infusion. If the product is inadvertently refrigerated, crystals may form. Do not use if crystals are present. These crystals will, however, redissolve at room temperature and do not adversely affect the quality of the product.
6.5 Nature and contents of container:
100 ml polypropylene bags: Plastic bags of polypropylene of 100 ml, with rubber (type I) closures, and Aluminium caps with plastic flip-top covers. The bags are placed in cartons. Boxes of 10 bags.
100 ml polypropylene bottles: Plastic bottles of polypropylene of 100 ml, with a molded plastic cap, a rubber (type II) gasket and a pull ring. Each bottle is placed in a metalized plastic pouch. The bottles are placed in carton boxes. Boxes of 10 bottles.
Plastic bottles of polypropylene of 100 ml, with a molded plastic cap, a rubber (type II) gasket and a pull ring. Each bottle is enclosed in an individual carton box. Boxes of 1 bottle.
200ml polypropylene bags: Plastic bags of polypropylene of 200 ml, with rubber (type I) closures, and Aluminium caps with plastic flip-top covers. The bags are placed in cartons. Boxes of 5 bags.
200 ml polypropylene bottles: Plastic bottles of polypropylene of 200 ml, with a molded plastic cap, a rubber (type II) gasket and a pull ring. Each bottle is placed in a metal ized plastic pouch. The bottles are placed in carton boxes. Boxes of 5 bottles.
Plastic bottles of polypropylene of 200 ml, with a molded plastic cap, a rubber (type II) gasket and a pull ring. Each bottle is enclosed in an individual carton box. Boxes of 1 bottle.
6.6 Special precautions for disposal and other handling:
□
Intravenous infusion: Ciprofloxacin should not be mixed with other drug products which are chemically or physically unstable at pH of 3.9 - 4 .5 (see section 6.2). The solution should be clear. Do not use if particles are present. Ciprofloxacin is compatible with the following commonly used infusion fluids: Ringer’s solution, Ringer lactate solution, 0.9% Sodium chloride solution, Dextrose 5% and Dextrose 10% solutions, Fructose 10% solution Sodium chloride 0.45% + Dextrose 5% solution and Sodium chloride 0.225% + Dextrose 5% solution. All solutions are stable for 48 hours below 25°C, with the only exception of the mixture of Ciprofloxacin with Ringer solution, which is stable for 12 hours below 25°C. Unless compatibility is proven, the infusion solution should always be administered separately. Since the infusion solution is photosensitive, the infusion bags and infusion bottles should be removed from the box only immediately before use. In daylight conditions complete efficacy is guaranteed for a period of three days. Any unused solution should be disposed of in accordance with local requirements.
MARKETING AUTHORISATION HOLDER
Noridem Enterprises Ltd., Evagorou & Makariou, Mitsi Building 3, Office 115, 1065 Nicosia, Cyprus.
8. MARKETING AUTHORISATION NUMBER
PL 24598/0009-001 PA 1122/005-001
Staphylococcus spp. - breakpoints for ciprofloxacin relate to high dose therapy.
* Non-species-related breakpoints have been determined mainly on the basis of PK/PD data and are independent of MIC distributions of specific species. They are for use only for species that have not been given a species-specific breakpoint and not for those species where susceptibility testing is not recommended. The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.
Groupings of relevant species according to ciprofloxacin susceptibility (for Streptococcus species see section 4.4)._