Data Sheet
CIFRAN
Ciprofloxacin hydrochloride Ph. Eur. 250 mg, 500 mg and 750 mg film coated tablets
Presentation
Cifran 250 mg tablets: each tablet contains 291.79 mg ciprofloxacin hydrochloride, equivalent to 250 mg ciprofloxacin. Tablets are white to off-white, round, film-coated, embossed with '250' on one side and plain on the other side.
Cifran 500 mg tablets: each tablet contains 583.59 mg ciprofloxacin hydrochloride, equivalent to 500 mg ciprofloxacin. Tablets are white to off-white, caplet-shaped, film-coated, embossed with '500' on one side and plain on the other side.
Cifran 750 mg tablets: each tablet contains 875.39 mg ciprofloxacin hydrochloride, equivalent to 750 mg ciprofloxacin. Tablets are white to off-white, caplet-shaped, film-coated, embossed with '750' on one side and plain on the other side.
Uses
Actions
Ciprofloxacin is a synthetic broad spectrum antibacterial agent (ATCCODE: J 01 MA 02). Ciprofloxacin is effective in vitro against virtually all gram-negative pathogens, including Pseudomonas aeruginosa. It is also effective against gram-positive pathogen such as staphylococci and streptococci. Anaerobes are generally less susceptible.
Ciprofloxacin has a rapid bactericidal action, both in the proliferation phase and in the resting phase. During the proliferation phase of a bacterium a segmental twisting and untwisting of the chromosomes take place. An enzyme called DNA gyrase plays a decisive part in this process. Ciprofloxacin inhibits this DNA gyrase in a way that arrests the bacterial metabolism, since vital information can no longer be read from the bacterial chromosome.
Resistance to ciprofloxacin develops slowly and in stages (multiple-step type). Plasmid-mediated resistance development of the kind that occurs with β-lactam antibiotics, aminoglycosides, and tetracyclines has not been observed with ciprofloxacin. It is of clinical interest that plasmid-carrying bacteria are also completely sensitive to ciprofloxacin.
On account of its different mode of action, parallel resistance of other important, chemically different, active substance groups, such as β-lactam antibiotics, aminoglycosides, tetracyclines, macrolide or peptide antibiotics, sulphonamides, trimethoprim or nitrofuran derivatives, is generally not seen with Ciprofloxacin. In its indication area ciprofloxacin remains completely effective on pathogens resistant to the above-mentioned groups of antibiotics.
Parallel resistance is observed within the group of gyrase inhibitors. However, because of the high primary sensitivity to ciprofloxacin shown by most organisms parallel resistance is less pronounced with this drug. Ciprofloxacin is thus often still effective on pathogens that are already resistant to the less effective gyrase inhibitors.
Because of its chemical structure ciprofloxacin is completely effective on β-lactamase-forming bacteria.
Ciprofloxacin can be used in combination with other antibiotics. In vitro studies with usually sensitive pathogens, carried out using ciprofloxacin in combination with β-lactam antibiotics and aminoglycosides, have shown primarily additive or indifferent effects; synergistic increases in efficacy were relatively rare and antagonistic effects very rare.
Possible combination drugs include:
for pseudomonas: azlocillin, ceftazidime
for streptococci: mezlocillin, azlocillin, other effective β-lactam antibiotics
for staphylococci: β-lactam antibiotics, particularly isoxazolylpenicillins, vancomycin
for anaerobes: metronidazole, clindamycin
Pharmacokinetics
Absorption
Following oral administration of single doses of 250 mg, 500 mg, and 750 mg tablets ciprofloxacin is absorbed rapidly and extensively mainly from the small intestine, reaching maximum serum concentrations 1-2 hours later.
Mean ciprofloxacin serum concentrations (mg/L) after oral administration:
| Time from tablet intake (h) | 250 mg | 500 mg | 750 mg |
|---|---|---|---|
| 0.5 | 0.9 | 1.7 | 2.9 |
| 1.0 | 1.3 | 2.5 | 3.5 |
| 2.0 | 0.9 | 2.0 | 2.9 |
| 4.0 | 0.5 | 1.7 | 1.7 |
| 8.0 | 0.3 | 0.6 | 0.8 |
| 12.0 | 0.2 | 0.4 | 0.5 |
The absolute bioavailability is approximately 70-80%. Maximum serum
concentrations (Cmax) and total areas under serum concentration vs. time
curves (AUC) increased in proportion to dose.
Comparison of the pharmacokinetic parameters for a bid and tid i.v. dose regimen indicated no evidence of drug accumulation for ciprofloxacin and its metabolites.
A 60 minute i.v. infusion of 200 mg ciprofloxacin or the oral administration of 250 mg ciprofloxacin both given every 12 hours produced an equivalent are under the serum concentration curve (AUC).
Results of pharmacokinetic studies in paediatric cystic fibrosis patients have show dosages of 20 mg/kg bd orally or 10 mg/kg tid i.v. are recommended to achieve plasma concentration/time profiles comparable tot those achieved in the adult population at the currently recommended dosage regimens.
Distribution
The protein binding of ciprofloxacin is low (20-30%), and the substance is present in plasma largely in a non-ionised form. Ciprofloxacin can diffuse freely into the extravascular space. The large steady-state volume of distribution of 2-3 l/kg body weight shows that ciprofloxacin penetrates into tissues resulting in concentrations which clearly exceed the corresponding serum levels.
Bioavailability
Small concentrations of 4 metabolites have been reported. They were identified as desethyleneciprofloxacin (M 1), sulphociprofloxacin (M 2), oxociprofloxacin (M 3) and formylciprofloxacin (M 4). M 1 to M 3 display antibacterial activity comparable to or inferior to that of nalidixic acid. M 4, with the smallest quantity, is largely equivalent to norfloxacin in its antimicrobial activity.
Excretion
Ciprofloxacin is largely excreted unchanged both renally and, to a smaller extent, non-renally.
| 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 0.18-0.3 L/h/kg and the total body clearance
between 0.48-0.60 L/h/kg. Ciprofloxacin undergoes both glomerular filtration
and tubular secretion.
Non-renal clearance of ciprofloxacin is mainly due to active transintestinal secretion as well as metabolisation. 1% of the dose is eliminated via the biliary excretion route. Ciprofloxacin is present in the bile in high concentrations.
Indications
Adults
Uncomplicated and complicated infections caused by ciprofloxacin sensitive pathogens:
Infections of the lower respiratory tract. In the treatment of outpatients with pneumonia due to Pneumococcus ciprofloxacin should not be used as the drug of first choice. Ciprofloxacin can be regarded as a suitable treatment for pneumonias caused by Klebsiella, Enterobacter, Proteus, E. coli, Pseudomonas, Haemophilus, Branhamella, Legionella, and Staphylococcus.
Infections of the kidneys and/or the efferent urinary tract.
Infections of the genital organs, including adnexitis, gonorrhoea, prostatitis.
Infections of the abdominal cavity (e.g. infections of the gastrointestinal tract or of the biliary tract, peritonitis).
Infections of the skin and soft tissue.
Infections of the bones and joints.
Sepsis.
Inhalation anthrax (post exposure): To reduce the incidence or progression of disease following exposure to aerolized Bacillus anthracis. Ciprofloxacin serum concentrations achieved in humans serve as a surrogate endpoint reasonably likely to predict clinical benefit and provide the basis for this indication.
According to in vitro investigations, the following pathogens can be regarded as sensitive:
E. coli, Shigella, Salmonella, Citrobacter, Klebsiella, Enterobacter, Serratia, Hafnia, Edwardsiella, Proteus (indole-positive and indole-negative), Providencia, Morganella, Yersinia; Vibrio, Aeromonas, Plesiomonas, Pasteurella, Haemophilus, Campylobacter, Pseudomonas, Legionella, Neisseria, Moraxella, Acinetobacter, Brucella; Staphylococcus, Listeria, Corynebacterium, Chlamydia.
The following show varying degrees of sensitivity:
Gardnerella, Flavobacterium, Alcaligenes, Streptococcus agalactiae, Enterococcus faecalis, Streptococcus pyogenes, Streptococcus pneumoniae, Viridans group streptococci, Mycoplasma hominis, Mycobacterium tuberculosis, and Mycobacterium fortuitum.
The following are usually resistant:
Enterococcus faecium, Ureaplasma urealyticum, Nocardia asteroides. With a few exceptions anaerobes are moderately sensitive e.g. Peptococcus, Peptostreptococcus; to resistant e.g. Bacteroides.
Ciprofloxacin has been shown to be active against Bacillus anthracis both in vitro and by use of serum levels as a surrogate marker.
Ciprofloxacin is ineffective against Treponema pallidum.
Children
For the treatment of acute pulmonary exacerbation of cystic fibrosis associated with P. aeruginosa infection in paediatric patients aged 5-17 years. For the indication of inhalational anthrax (post-exposure), the risk-benefit assessment indicates that administration of ciprofloxacin to paediatric patients is appropriate. The use of ciprofloxacin for indications other than this is not recommended in children.
Dosage and Administration
Adults
Unless otherwise prescribed, the following guideline doses are recommended:
| Indication | Dose |
|---|---|
| Respiratory tract infection (according to severity and organism) | 500 mg to 1000 mg (1 g) |
| Urinary tract infections: | |
| - acute, uncomplicated | 250 mg to 500 mg |
| - complicated | 500 mg to 1000 mg (1 g) |
| Gonorrhoea | |
| - extragenital | 250 mg |
| - acute, uncomplicated | single dose 250 mg |
| Diarrhoea | 500 mg to 1000 mg (1 g) |
| Other infections (see Indications) | 1000 mg (1 g) |
| Particularly severe, life threatening infections, i.e. -Streptococcal pneumonia -Recurrent infections in cystic fibrosis -Bone and joint infections -Septicaemia -Peritonitis In particular when Pseudomonas, Staphylococcus or Streptococcus is present |
1500 mg (1.5 g) |
| Inhalation anthrax (post exposure) Drug administration should begin as soon as possible after suspected or confirmed exposure. |
1000 mg (1 g) |
Elderly
Elderly patients should receive a dose as low as possible depending on the severity of their illness and the creatinine clearance.
Children
Clinical and pharmacokinetic data support the use of ciprofloxacin in paediatric cystic fibrosis patients (aged 5-17 years) with acute pulmonary exacerbation associated with P. aeruginosa infection, at a dose of 20 mg/kg orally twice daily (maximum daily dose 1500 mg).
For the indication of inhalation anthrax (post exposure), the risk-benefit assessment indicates that treatment of paediatric patients with ciprofloxacin is appropriate. For paediatric patients, the recommended oral dose is 15 mg/kg twice daily (not to exceed a maximum does of 500 mg per dose, 1000 mg per day). Drug administration should begin as soon as possible after suspected or confirmed exposure.
Method of Administration
The tablets are swallowed whole with a small amount of fluid. They can be taken independent of mealtimes. (If the tablets are taken on an empty stomach, the active substance is absorbed more rapidly). Tablets should not be taken concurrently with dairy products or with mineral fortified drinks alone (eg. milk, yoghurt, calcium fortified orange juice). However, dietary calcium as part of a meal does not significantly affect ciprofloxacin absorption.
If the patient is unable to take tablets because of the severity of the illness or for other reasons, it is recommended to commence the therapy with an intravenous form of ciprofloxacin. After intravenous administration the treatment may be continued orally.
Duration of Treatment
The duration of treatment depends on the severity of the illness and on the clinical and bacteriological course. It is essential to continue therapy for at least 3 days after disappearance of the fever or of the clinical symptoms.
Mean duration of treatment:
1 day for acute uncomplicated gonorrhoea and cystitis;
up to 7 days for infections of the kidneys, urinary tract, and abdominal cavity;
a maximum of 2 months in osteomyelitis;
60 days in inhalational anthrax (post-exposure) and
7-14 days in all other infections.
In streptococcal infections the treatment must last at least 10 days because of the risk of late complications.
Infections caused by Chlamydia should also be treated for a minimum of 10 days.
For acute pulmonary exacerbation of cystic fibrosis associated with P. aeruginosa infection in paediatric patients (aged 5-17 years), the duration of treatment is 10-14 days. For inhalational anthrax (post-exposure), the duration of treatment is 60 days.
Renal & Hepatic Impairment
Adults
| 1. | Impaired renal function |
|---|---|
| 1.1 | Where creatinine clearance is between 31 and 60 ml/min/1.73 m² or where the serum creatinine concentration is between 1.4 and 1.9 mg/100 ml the maximum daily dose should be 1000 mg per day for oral administration. |
| 1.2 | Where creatinine clearance is equal or is less than 30 ml/min/1.73 m² or where the serum creatinine concentration is equal or higher than 2.0 mg/100 ml the maximum daily dose should be 500 mg per day for oral administration. |
| 2. | Impaired renal function + haemodialysis: dose as in 1.2; on dialysis days after dialysis. |
| 3. | Impaired renal function + CAPD: Administration of ciprofloxacin film coated tablets (oral) as 1 x 500 mg film coated tablet (or 2 x 250 mg film coated tablets). |
| 4. | Impaired liver function No dose adjustment is required. |
| 5 | Impaired renal and liver function Dose adjustment as in 1.1 and 1.2 |
Children
Dosing in children with impaired renal and or hepatic function has not been studied.
Contraindications
Ciprofloxacin must not be used in cases of hypersensitivity to ciprofloxacin or other quinolone chemotherapeutics.
Ciprofloxacin must not be prescribed for pregnant women or nursing mothers as there is no experience regarding safety in these patient groups and since, on the basis of animal studies, it is possible that the drug could cause damage to articular cartilage in the foetus or infant. Animal studies have not shown any evidence of teratogenic effects. When considering treatment for inhalational anthrax (post-exposure), the risks and benefits of ciprofloxacin and alternative antibiotic therapies must be carefully considered, and explained to the patient.
Warnings and Precautions
May cause tendinitis, hypoglycaemia.
Paediatric Use
As with drugs in its class, ciprofloxacin has been shown to cause arthropathy in weight-bearing joints of immature animals. The analysis of available safety data from ciprofloxacin use in patients less than 18 years of age, the majority of whom had cystic fibrosis, did not disclose any evidence of drug related cartilage or articular damage. For the indication of inhalational anthrax (post-exposure), the risk-benefit assessment indicates that administration of ciprofloxacin to paediatric patients is appropriate. For information regarding paediatric dosing in inhalational anthrax (post-exposure), see Dosage and Administration. The use of ciprofloxacin for indications other than the treatment of acute pulmonary exacerbation of cystic fibrosis caused by P. aeruginosa infection, and inhalational anthrax (post-exposure), is not recommended.
Gastrointestinal System
In the event of severe and persistent diarrhoea during or after treatment a doctor must be consulted, since this symptom can hide a serious intestinal disease (life threatening pseudomembranous colitis with possible fatal outcome), requiring immediate treatment. In such cases Ciprofloxacin must be discontinued and appropriate therapy initiated (e. g. vancomycin, orally, 4 x 250 mg/day). Drugs that inhibit peristalsis are contraindicated.
There can be a temporary increase in transaminases, alkaline phosphatase or cholestatic jaundice, especially in patients with previous liver damage.
Nervous System
In epileptics and in patients who have suffered from previous CNS-disorders (e.g. lowered convulsion threshold, previous history of convulsion, reduced cerebral blood flow, altered brain structure or stroke), ciprofloxacin should only be used where the benefits of treatment exceed the risks, since these patients are at risk because of possible CNS side effects.
In some instances CNS reactions have occurred after the first administration of Ciprofloxacin. In rare cases depression or psychosis can progress to self endangering behaviour. In these cases Ciprofloxacin must be discontinued and the doctor should be informed immediately.
Hypersensitivity
In some instances, hypersensitivity and allergic reactions may occur after the first administration. The doctor should be informed immediately.
Anaphylactic/anaphylactoid reactions in very rare instances can progress to a life threatening shock, in some instances after the first administration. In these cases Ciprofloxacin has to be discontinued, medical treatment (e.g. treatment for shock) is required.
Musculo-Skeletal System
At any sign of tendinitis (e. g. painful swelling) the administration of Ciprofloxacin should be discontinued, physical exercises be avoided, and a physician consulted.
- Cifran may cause tendonitis or tendon rupture.
- The risk of tendonitis or tendon rupture is increased in patients: over the age of 60 years; on concomitant systemic steroid therapy; or who have received a kidney, heart or lung transplant.
- Cifran should not be used in patients with a history of fluoroquinolone associated tendonopathy.
- Tendonitis and tendon rupture risk is present during use and for 6 months following use of fluoroquinolones such as Cifran.
- Prescribers should advise patients that at the first sign of tendon pain, inflammation or tendon rupture, to stop taking Cifran, avoid exercise or use of the affected area and immediately contact their doctor.
Skin and Appendages
Ciprofloxacin has been shown to produce photosensitivity reactions. Patients taking Ciprofloxacin should avoid direct exposure to excessive sunlight or UV-light. Therapy should be discontinued if photosensitisation (i. e. sunburn-like skin reactions) occur.
Hypoglycaemia
Hypoglycaemia has been noted with enoxacin and lomefloxacin but it is not known whether it occurs with ciprofloxacin.
Interactions
The simultaneous administration of ciprofloxacin (oral) and iron, sucralfate or antacids and highly buffered drugs (e.g. antiretrovirals), containing magnesium, aluminium, or calcium reduce the absorption of ciprofloxacin. Consequently, ciprofloxacin should be administered either 1-2 hours before, or at least 4 hours after these preparations. This restriction does not apply to antacids belonging to the class of H2 receptor blockers.
The concurrent administration of dairy products or mineral fortified drinks alone (eg. Milk, yoghurt, calcium fortified orange juice) and ciprofloxacin should be avoided because absorption of ciprofloxacin may be reduced. Dietary calcium as part of a meal, however, does not significantly affect absorption.
Concurrent administration of ciprofloxacin and theophylline can cause an undesirable increase in the serum theophylline concentration. This can lead to theophylline-induced side effects; in very rare cases these side effects can be life threatening or fatal. If concurrent use of the two products is unavoidable, the serum theophylline concentration should therefore be checked and the theophylline dose appropriately reduced.
Animal studies have shown that the combination of very high doses of quinolones (gyrase inhibitors) and certain non-steroidal anti-inflammatory agents (but not acetylsalicylic acid) can provoke convulsions.
A transient rise in the concentration of serum creatinine was observed when ciprofloxacin and cyclosporin were administered simultaneously. Therefore, it is necessary to monitor the serum creatinine concentrations in these patients frequently (twice a week).
The simultaneous administration of ciprofloxacin and warfarin may intensify the action of warfarin.
In particular cases, concurrent administration of ciprofloxacin and glibenclamide can intensify the action of glibenclamide (hypoglycaemia)
Probenecid interferes with renal secretion of ciprofloxacin. Co-administration of probenecid and ciprofloxacin increases the ciprofloxacin serum concentrations.
Renal tubular transport of methotrexate may be inhibited by concomitant administration of ciprofloxacin potentially leading to increased plasma levels of methotrexate. This might increase the risk of methotrexate associated toxic reactions. Therefore, patients under methotrexate therapy should be carefully monitored when concomitant ciprofloxacin therapy is indicated.
Metoclopramide accelerates the absorption of ciprofloxacin (oral) resulting in a shorter time to reach maximum plasma concentrations. No effect was seen on the bioavailability of ciprofloxacin.
Effect on Ability to Drive and Use Machines:
Even when the drug is taken exactly as prescribed, it can affect the speed of reaction to such an extent that the ability to drive or to operate machinery is impaired. This applies particularly in combination with alcohol.
Pregnancy and Lactation:
Ciprofloxacin must not be prescribed for pregnant women, or nursing mothers, since there is no experience on the drug's safety in these patient groups and since, on the basis of animal studies, it is possible that the drug could cause damage to articular cartilage in the foetus or infant. Animal studies have not shown any evidence of teratogenic effects (malformations).
Adverse Effects
The most common Adverse Reactions based on all clinical studies with ciprofloxacin (oral) sorted by CIOMS III categories of frequency and COSTART (5th Edition, 1995) body system and terms (n = 41151 patients, status: 20.11.1997).
| Body System | Adverse Drug Reactions |
|---|---|
| Incidence of frequency ≥1% < 10% | |
| Digestive system | nausea, diarrhoea |
| Skin and appendages | rash |
| Incidence of frequency ≥ 0.1% < 1% | |
| Body as a whole | abdominal pain, moniliasis, asthenia (general feeling of weakness, tiredness) |
| Cardiovascular system | (thrombo)-phlebitis |
| Digestive system | SGOT increased, SGPT increased, vomiting, dyspepsia, abnormal liver function test, alkaline phosphatase increased, anorexia, flatulence, bilirubinemia |
| Haemic and lymphatic system | eosinophilia, leucopenia |
| Injection site | injection site reaction |
| Metabolic and nutritional disorder | creatinine increased, BUN (urea) increased |
| Musculo Skeletal system | arthralgia (joint pain) |
| Nervous system | headache, dizziness, insomnia, agitation, confusion |
| Skin and appendages | pruritus, maculopapular rash, urticaria |
| Special senses | taste perversion |
| Incidence of frequency ≥ 0.01% < 0.1% | |
| Body as a whole | Pain, pain in extremities, back pain, chest pain |
| Cardiovascular system | tachycardia, migraine, syncope (fainting vasodilatation (hot flushes), hypotension |
| Digestive system | moniliasis (oral), jaundice, cholestatic jaundice, pseudomembranous colitis |
| Haemic and lymphatic system | anaemia, leucopenia (granulocytopenia), leucocytosis, altered prothrombin values, thrombocytopenia, thrombocytemia (thrombocytosis) |
| Hypersensitivity | allergic reaction, drug fever, anaphylactoid (anaphylactic) reaction |
| Metabolic disorders | edema (peripheral, vascular, face), hyperglycemia |
| Musculo-Skeletal system | myalgia (muscular pain), joint disorder (joint swelling) |
| Nervous system | hallucination, sweating, paresthesia (peripheral paralgesia), anxiety, abnormal dreams (nightmares), depression, tremor (trembling), convulsion, hyperaesthesia |
| Respiratory system | dyspnea, larynx edema |
| Skin and appendages | photosensitivity reaction |
| Special senses | tinnitus, transitory deafness (especially at high frequencies), abnormal vision (visual disturbances), diplopia, chromatopsia, taste loss (impaired taste) |
| Urogenital system | acute kidney failure, kidney function abnormal, vaginal moniliasis haematuria, crystalluria, nephritis interstitial |
| Incidence of frequency < 0.01% | |
| Cardiovascular system | vasculitis (petechiae, haemorrhagic bullae, papules, crust formation) |
| Digestive system | moniliasis (gastrointestinal), hepatitis |
| Haemic and lymphatic system | haemolytic anaemia |
| Hypersensitivity | shock (anaphylactic; life threatening), pruritic rash |
| Musculo-skeletal system | myasthenia |
| Nervous system | grand mal convulsion, abnormal (unsteady) gait |
| Skin and appendages | petechiae, erythema multiforme (minor), erythema nodosum, fixed eruption |
The most common Adverse Reactions based on spontaneous reports sorted by CIOMS
III categories of frequency and COSTART (5th Edition, 1995) body system and
terms calculated on patient exposure (n = 7790 reported cases, status
30.09.1997).
| Incidence of frequency < 0.01% | |
|---|---|
| Digestive system | liver necrosis (very rarely progressing to life-threatening hepatic failure), life threatening pseudomembranous colitis with possible fatal outcome |
| Haemic and lymphatic system | petechiae (punctuate skin haemorrhages) pancytopenia (life-threatening), bone marrow, depression (life-threatening), agranulocytosis |
| Musculo-Skeletal system | Tendinitis (predominantly achillotendinitis); partial or complete
tendon rupture (predominantly achilles tendon) Exacerbation of symptoms of myasthenia gravis. |
| Nervous system | psychosis, intracranial hypertension, ataxia, hyperaesthesia, hypertonia, twitching |
| Skin and appendages | Stevens-Johnson-Syndrome, epidermal necrolysis (Lyell-Syndrome) |
| Hypersensitivity | Serum sickness like reaction |
| Special senses | parosmia (impaired smell) anosmia (usually reversible on discontinuation) |
Overdosage
In the event of acute, excessive oral overdosage, reversible renal toxicity has been reported in some cases. Therefore, apart from routine emergency measures, it is recommended to monitor renal function and to administer Mg- or Ca-containing antacids which reduce the absorption of ciprofloxacin.
Only a small amount of ciprofloxacin (< 10 %) is removed from the body after haemodialysis or peritoneal dialysis.
Preclinical Safety Data
Acute toxicity:
The acute toxicity of ciprofloxacin after oral administration can be classified as very low.
Subacute Toxicity:
Subacute tolerability studies over 4 weeks.
Doses up to and including 100 mg/kg were tolerated without damage by rats. Pseudoallergic reactions due to histamine release were observed in dogs.
Subchronic Toxicity:
Subchronic tolerability studies over 3 months.
All doses up to and including 500 mg/kg were tolerated without damage by rats. In monkeys, crystalluria and changes in the renal tubules were observed in the highest-dose group (135 mg/kg).
Chronic Toxicity
Chronic tolerability studies over 6 months.
Doses up to and including 500 mg/kg and 30 mg/kg were tolerated without damage by rats and monkeys, respectively. Changes in the distal renal tubules were again observed in some monkeys in the highest-dose group (90 mg/kg).
Carcinogenicity
In carcinogenicity studies in mice (21 months) and rats (24 months) with doses up to approx. 1000 mg/kg bw/day in mice and 125 mg/kg bw/day in rats (increased to 250 mg/kg bw/day after 22 weeks), there was no evidence of carcinogenic potential at any dose level.
Reproduction Toxicology
Fertility studies in rats
Fertility, the intrauterine and postnatal development of the young, and the fertility of F1 generation were not affected by ciprofloxacin.
Embryotoxicity studies
These yielded no evidence of any embryotoxic or teratogenic action of ciprofloxacin.
Perinatal and postnatal development in rats
No effects on the perinatal or postnatal development of the animals were detected. At the end of the rearing period histological investigations did not bring to light any sign of articular damage in the young.
Mutagenicity
Eight in vitro mutagenicity tests have been conducted with ciprofloxacin.
Test results are listed below:
Salmonella: Microsome Test (Negative)
E. coli: DNA Repair Assay (Negative),
Mouse Lymphoma Cell Forward Mutation Assay (Positive)
Chinese Hamster V79 Cell HGPRT Test (Negative),
Syrian Hamster Embryo Cell Transformation Assay (Negative)
Saccharomyces cerev.: Point Mutation Assay (Negative), Mitotic Crossover and Gene Conversion Assay (Negative)
Rat Hepatocyte Primary Culture DNA Repair Assay (UDS) (Positive)
Thus, two of the eight tests were positive, but results of the following four in vivo test systems gave negative results:
Rat Hepatocyte DNA Repair Assay
Micronucleus Test (Mice)
Dominant Lethal Test (Mice)
Chinese Hamster Bone Marrow
Although two of the eight in vitro assays (i.e. the Mouse Lymphoma Cell Forward Mutation Assay and the Rat Hepatocyte Primary Culture DNA Repair Assay (UDS)) were positive, all of the in vivo test systems covering all relevant endpoints gave negative results.
In summary, ciprofloxacin poses no significant mutagenic potential. This assessment is confirmed by the negative outcome of the long-term carcinogenicity studies in mice and rats.
Special Tolerability Studies
It is known from comparative studies in animals, both with the older gyrase inhibitors (e.g. nalidixic and pipemidic acid) and the more recent ones (e.g. norfloxacin and ofloxacin), that this substance class produces a characteristic damage pattern. Kidney damage, cartilage damage in weight-bearing joints of immature animals, and eye damage may be encountered.
Renal tolerability
The crystallisation observed in the animal studies occurred preferentially under pH conditions that do not apply in humans.
The precipitation of crystals in renal tubules does not immediately and automatically lead to kidney damage. In the animal studies damage occurred only after high doses, with correspondingly high levels of crystalluria. For example, although they always caused crystalluria, even high doses were tolerated over 6 months without damage and without foreign-body reactions occurring in individual distal renal tubules.
Damage to the kidneys without the presence of crystalluria has not been observed. The renal damage observed in animal studies must not, therefore, as is the case e.g. with the aminoglycosides, be regarded as a primary toxic action of ciprofloxacin on the kidney tissue, but as typical secondary inflammatory foreign-body reactions due to the precipitation of a crystalline complex of ciprofloxacin, magnesium, and protein.
Articular tolerability studies
As with other gyrase inhibitors, ciprofloxacin causes damage to the large, weight-bearing joints in immature animals.
The extent of 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.
Studies aimed at excluding cataractogenic effects
On the basis of the investigations it may be stated from a toxicological point of view that ciprofloxacin treatment does not involve any risk of cataract induction, particularly because in parenteral administration maximal bioavailability can be assumed and the duration of administration was 6 months.
Retina tolerability studies
Ciprofloxacin binds to the melanin containing structures including the retina. Potential effects of ciprofloxacin on the retina were assessed in various pigmented animal species. Ciprofloxacin treatment had no effect on the morphological structures of the retina and on electroretinographic findings.
Pharmaceutical Precautions
Store below 25°C. Shelf-life is 3 years.
Medicine Classification:
Prescription Medicine
Package Quantities
Ciprofloxacin 250 mg, 500 mg and 750 mg tablets packed in PVC/PVDC/Al foil blisters containing 10 and 30 tablets.
Further Information
Ciprofloxacin 250 mg, 500 mg and 750 mg tablets contain microcrystalline cellulose, maize starch, magnesium stearate, colloidal anhydrous silica, talc and Opadry OY-S-58910 White which contains hypromellose, macrogol 400, titanium dioxide and talc.
Name and Address
Douglas Pharmaceuticals Ltd
PO Box 45 027
Auckland 0651
Ph: (09) 835-0660
Fax: (09) 835-0665
Date of Preparation
July 2008