Ciprobay

Ciprobay

ciprofloxacin

Manufacturer:

Bayer HealthCare Pharma

Distributor:

DKSH
Full Prescribing Info
Contents
Ciprofloxacin (tab: HCl; inj: lactate).
Description
Each 250-mg tablet contains ciprofloxacin HCl monohydrate 291 mg, corresponding to ciprofloxacin 250 mg. Each 500-mg tablet contains ciprofloxacin HCl monohydrate 582 mg, corresponding to ciprofloxacin 500 mg. Each 50-mL infusion solution contains ciprofloxacin lactate 127.2 mg, corresponding to ciprofloxacin 100 mg. Each 100-mL infusion solution contains ciprofloxacin lactate 254.4 mg, corresponding to ciprofloxacin 200 mg. Each 200-mL infusion solution contains ciprofloxacin lactate 508.8 mg, corresponding to ciprofloxacin 400 mg.
Action
Antibacterial/chemotherapeutic, gyrase inhibitor (quinolones).
Pharmacokinetics: After oral administration, Ciprobay is absorbed mainly from the small intestine, reaching peak serum concentrations 60-90 min later.
Table 1 shows serum concentrations (in mg/L) after repeated administration following a 30-min short infusion and following oral administration of Ciprobay. Table 1 shows the time from end of infusion or ingestion of tablets (hr). (See Table 1.)

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In steady state, the volume of distribution of Ciprobay is 2-3 L/kg.
Since the protein-binding of Ciprobay is low (20-30%), and since the substance is present in plasma largely in a non-ionized form, almost the entire dose administered can diffuse freely into the extravascular space. In this way the concentrations in certain body fluids and tissues can clearly exceed the corresponding serum levels.
Ciprobay is excreted essentially unchanged, the bulk being eliminated by the renal route.
Renal clearance is between 3 and 5 mL/min kg, the total clearance is 8-10 mL/min kg. Ciprobay undergoes both glomerular filtration and tubular excretion. (See Table 2.)

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The concentrations in the bile are high, but only a small proportion of the administered dose (approximately 1%) is excreted by the biliary route.
The half-life of Ciprobay is between 3 and 5 hrs, both after oral and after IV administration.
Since Ciprobay is excreted not only renally but also to a considerable extent via the intestine, only severely impaired kidney function results in prolonged serum half-lives of up to 12 hrs.
Bioavailability: After oral administration, Ciprobay is absorbed rapidly and well (bioavailability approximately 70-80%).
Toxicology: Acute Toxicity: The acute toxicity of Ciprobay after oral administration can be classified as very low. Depending on the individual species, the LD50 after IV infusion is 125-290 mg/kg. (See Table 3.)

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Subacute Tolerability Studies Over 4 Weeks: Oral Administration: Doses up to and including 100 mg/kg were tolerated without damage by rats. Pseudoallergic reactions due to histamine release were observed in dogs.
Parenteral Administration: In the highest dose group in each case (rats 80 mg/kg and monkeys 30 mg/kg), ciprofloxacin-containing crystals were found in the urine sediment. There were also changes in individual renal tubules, with typical foreign body reactions due to crystal-like precipitates.
The tubular changes observed should not (as in the case of aminoglycosides) be interpreted as a primary toxic effect of Ciprobay, but as secondary inflammatory foreign-body reactions due to the precipitation of a crystalline complex in the distal renal tubule system (see also the Subchronic and Chronic Tolerability Studies).
Subchronic Tolerability Studies Over 3 Months: Oral Administration: 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).
Parenteral Administration: Although the changes in the renal tubules observed in rats were in some cases very slight, they were present in every dose group. In monkeys, they were found only in the highest dose group (18 mg/kg) and were associated with slightly reduced erythrocyte counts and haemoglobin values.
Chronic Tolerability Studies Over 6 Months: Oral Administration: Doses up to and including 500 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).
Parenteral Administration: In monkeys, slightly elevated urea and creatinine concentrations and changes in the distal renal tubules were recorded in the highest-dose group (20 mg/kg).
Studies on Reproduction Toxicology: Fertility Studies in Rats: Fertility, the intrauterine and postnatal development of the young, and the fertility of the F1 generation were not affected by Ciprobay.
Embryotoxicity Studies: These yielded no evidence of any embryotoxic or teratogenic action of Ciprobay.
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.
Special Tolerability Studies: It is known from comparative studies in animals, both with the older gyrase inhibitors (eg, nalidixic and pipemidic acid) and the more recent ones (eg, 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 crystallization observed in the animal studies occurred preferentially under pH conditions that do not apply in man.
Compared to rapid injection, a slow infusion of Ciprobay reduces the danger of crystal precipitation.
The precipitation of crystals in the 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 the animal studies should not, therefore, as is the case with the aminoglycosides, be regarded as a primary toxic action of Ciprobay 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 is also known for other gyrase inhibitors, at high concentrations Ciprobay 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) found 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 Ciprobay 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.
Mutagenicity: In view of the mechanism of action of the gyrase inhibitors, a whole series of additional mutagenicity studies, going beyond what is required, was carried out to exclude the possibility of DNA-damaging effects and of any mutagenic activity of Ciprobay. No evidence was found for any mutagenic effects of the drug.
Microbiology:
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. Ciprobay inhibits this DNA gyrase in a way that arrests the bacterial metabolism, since vital information can no longer be read from the bacterial chromosome.
Ciprobay is extraordinarily effective in vitro against virtually all gram-negative pathogens, including Pseudomonas aeruginosa. It is also effective against gram-positive pathogens eg, Staphylococci and Streptococci. Anaerobes are generally less susceptible.
Ciprobay has a rapid bactericidal action, not only in the proliferation phase but also in the resting phase.
Resistance to Ciprobay 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 Ciprobay. It is of clinical interest that plasmid-carrying bacteria are also completely sensitive to Ciprobay.
On account of its special mode of action, Ciprobay does not suffer from general parallel resistance to other important, chemically different, active substance groups eg, β-lactam antibiotics, aminoglycosides, tetracyclines, macrolide and peptide antibiotics, sulfonamides, trimethoprim or nitrofuran derivatives. In its indication area, Ciprobay remains completely effective on pathogens resistant to the previously mentioned groups of antibiotics. Parallel resistance is observed within the group of gyrase inhibitors. However, because of the high primary sensitivity to Ciprobay shown by most organisms, parallel resistance is less pronounced with this drug. Ciprobay is thus also frequently effective on pathogens that are already resistant to the less effective gyrase inhibitors.
Because of its chemical structure, Ciprobay is completely effective on β-lactamase-forming bacteria.
Ciprobay can be used in combination with another antibiotic. In vitro studies with usually sensitive pathogens, carried out using Ciprobay 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.
Indications/Uses
Infections caused by ciprofloxacin-sensitive pathogens:
Infections of the Respiratory Tract: In the treatment of outpatients with pneumonia due to Pneumococcus, Ciprobay should not be used as a first choice of drug. Ciprobay can be regarded as an advisable treatment for pneumonias caused by Klebsiella, Enterobacter, Proteus, Pseudomonas, Haemophilus, Branhamella, Legionella and Staphylococcus.
Middle ear (otitis media) and paranasal sinuses (sinusitis), especially if these are caused by gram-negative organisms including Pseudomonas or by Staphylococcus.
Eyes; kidneys and/or the efferent urinary tract; genital organs, including gonorrhea; abdominal cavity (eg, bacterial infections of the gastrointestinal tract or of the biliary tract, peritonitis); skin and soft tissue; bones and joints; sepsis.
Infections or imminent risk of infection (prophylaxis) in the patients whose immune system have been weakened (eg, patients on immunosuppressants or in a state of neutropenia).
Selective intestinal decontamination in immunosuppressed patients.
Ciprobay acts bactericidally. The following pathogens can be regarded as sensitive: Escherichia 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, Moraxella, Acinetobacter, Brucella; Staphylococcus, Listeria, Corynebacterium, Chlamydia.
The following show varying degrees of sensitivity: Neisseria, 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. Ciprobay is ineffective against Treponema pallidum.
Dosage/Direction for Use
Unless otherwise prescribed, guide doses in Table 4 are recommended: See Table 4.

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In particularly serious infections (eg, recurrent infections in patients with mucoviscidosis, pneumonias, infections of the abdominal cavity, bones and joints) caused by Pseudomonas, Staphylococcus or Streptococcus pneumoniae and in acute pneumonia due to Streptococcus pneumoniae, the daily dose has to be increased to 2 x 750 mg orally where the patient is not being treated IV.
Urinary Tract Infections caused by Chlamydia: The daily dose should be increased, if necessary, to 2 x 750 mg (oral).
CAPD Patients with Peritonitis: The recommended daily oral dose is 500 mg 4 times a day or intraperitoneal 50 mg/L dialysate 4 times a day.
Up to 500 mg (oral) can be given as a single daily dose when uncomplicated urinary tract or gastrointestinal infections are present.
Acute Gonorrhea in Women and Men and Acute Uncomplicated Cystitis in Women: Can be treated with a single dose of 250 mg (orally) or 100 mg (IV).
Elderly Patients: Should receive a dose as low as possible; this will depend on the severity of the illness and on the creatinine clearance.
If the patient is unable to take tablets, because of the severity of his illness or for other reasons, it is recommended to commence the therapy with an IV form of Ciprobay.
After IV administration, the treatment can be continued orally.
Renal and Hepatic Impairment: 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/day for oral and 800 mg/day for an IV regimen. (1.2) Where creatinine clearance is ≤30 ml/min/1.73 m2 or where the serum creatinine concentration is ≥2 mg/100 mL, the maximum daily dose should be 500 mg/day for oral and 400 mg/day for an IV regimen.
2. Impaired Renal Function + Haemodialysis: Dose as in 1.2; on dialysis days after dialysis.
3. Impaired Renal Function + CAPD: Oral: Administration of ciprofloxacin film-coated tablets as 1 x 500-mg film-coated tablet (or 2 x 250-mg film-coated tablets).
IV: Addition of ciprofloxacin infusion solution to the dialysate (intraperitoneal): Ciprofloxacin 50 mg/L dialysate administered 4 times a day every 6 hrs.
4. Impaired Liver Function: No dose adjustment is required.
5. Impaired Renal and Liver Function: Dose adjustment as in 1.1 and 1.2.
Administration: Oral: The tablets should be swallowed whole with liquid. They may be taken independently of mealtimes. (If the tablets are taken on an empty stomach, the active substance is absorbed more quickly.)
IV: IV infusion over a period of approximately 60 min.
The infusion solution can be infused either directly or after mixing with other infusion solutions.
The infusion solution is compatible with physiological saline, Ringer's solution and Ringer's lactate solution, 5% and 10% glucose solutions, 10% fructose solution, and 5% glucose solution with 0.225% NaCl or 0.45% NaCl.
Duration of Administration: The duration of treatment depends on severity of the illness and on the clinical and bacteriological course. It is essential to continue the treatment for at least 3 days after disappearance of the fever or of the clinical symptoms.
Mean Duration of Treatment: 1 day for acute uncomplicated gonorrhea and cystitis, up to 7 days for infections of the kidneys, urinary tract and abdominal cavity, over the entire period of the neutropenic phase in patients with weakened body defenses, a maximum of 2 months in osteomyelitis, and 7-14 days in all other infections.
In streptococcal infections the treatment should last at least 10 days because of the risk of late complications.
Overdosage
Emergency Measures, Symptoms and Antidotes: No special antidote is known. The usual emergency measures are recommended; only a small amount of ciprofloxacin (<10%) is removed from the body after hemodialysis or peritoneal dialysis.
Contraindications
Hypersensitivity to ciprofloxacin or other quinolone chemotherapeutics.
Not for children, adolescents, 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 not entirely improbable that the drug could cause damage to articular cartilage in the immature organism. Animal studies have produced no evidence of teratogenic effects (malformations).
Warnings
Not applicable.
Special Precautions
Restriction on Use: Ciprobay should be used with caution in the elderly and in patients with previous damage to the CNS eg, in epilepsy and/or reduced convulsion threshold, and in the event of convulsive fits in the patient's case history, reduced cerebral blood flow, changes in the brain structure or stroke. Ciprobay should only be used where the benefits of treatment exceed the risks, since these patients are endangered because of possible central nervous system side effects.
Effects on the Ability to Drive or Operate Machinery: Even when Ciprobay 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.
Side Effects
The following side effects have been observed:
Common: ≥1% to <10%; uncommon: ≥0.1% to <1%; rare: ≥0.01% to <0.1%; very rare: <0.01%.
Infections and Infestations: Candida infections are uncommon. Antibiotic-associated colitis is rare (very rarely with possible fatal outcome).
Blood and Lymphatic System Disorders: Eosinophilia is uncommon. Leukopenia, anemia, neutropenia, leukocytosis, thrombocytopenia and thrombocythemia are rare. Hemolytic anemia, agranulocytosis, pancytopenia (life-threatening), and bone marrow depression (life-threatening) are very rare.
Immune System Disorders: Allergic reaction, allergic edema/angioedema are rare. Anaphylactic reaction, anaphylactic shock (life-threatening) and serum sickness-like reactions are very rare.
Metabolism and Nutrition Disorders: Anorexia is uncommon. Hyperglycemia is rare.
Psychiatric Disorders: Psychomotor hyperactivity/agitation is uncommon. Confusion and disorientation, anxiety reaction, abnormal dreams, depression and hallucinations are rare. Psychotic reactions are very rare.
Nervous System Disorders: Headache, dizziness, sleep disorders and taste disorders are uncommon. Paraesthesia and dysaesthesia, hypoaesthesia, tremor, seizures and vertigo are rare. Migraine, disturbed coordination, smell disorders, hyperesthesia and intracranial hypertension are very rare.
Eye Disorders: Visual disturbances are rare. Visual color distortions are very rare.
Ear and Labyrinth Disorders: Tinnitus and hearing loss are rare. Hearing impairment is very rare.
Cardiac Disorders: Tachycardia is rare.
Vascular Disorders: Vasodilatation, hypotension and syncope are rare. Vasculitis is very rare.
Respiratory, Thoracic and Mediastinal Disorders: Dyspnea (including asthmatic condition) is rare.
Gastrointestinal Disorders: Nausea and diarrhea are common. Vomiting, gastrointestinal and abdominal pains, dyspepsia and flatulence are uncommon. Pancreatitis is very rare.
Hepatobiliary Disorders: Transient increase in transaminases and increased bilirubin are uncommon. Transient hepatic impairment, jaundice and hepatitis (non-infective) are rare. Liver necrosis (very rarely progressing to life-threatening hepatic failure) is very rare.
Skin and Subcutaneous Tissue Disorders: Rash, pruritus and urticaria are uncommon. Photosensitivity reactions and unspecific blistering are rare. Petechiae, erythema multiforme minor, erythema nodosum, Stevens-Johnson syndrome and toxic epidermal necrolysis are very rare.
Musculoskeletal, Connective Tissue and Bone Disorders: Arthralgia is uncommon. Myalgia, arthritis and increased muscle tone and cramping are rare. Muscular weakness, tendonitis, tendon rupture (predominantly Achilles tendon) and exacerbation of symptoms of myasthenia gravis are very rare.
Renal and Urinary Disorders: Renal impairment is uncommon. Tubulointerstitial nephritis, renal failure, hematuria and crystalluria are rare.
General Disorders and Administration Site Conditions: Injection and infusion site reactions (only IV administration) are common. Unspecific pain, feeling unwell and fever are uncommon. Edema and sweating (hyperhidrosis) are rare. Gait disturbance is very rare.
Investigations: Transient increase in blood alkaline phosphatase is uncommon. Abnormal prothrombin level and increased amylase are rare.
Drug Interactions
Oral Administration: Multivalent cation-containing drugs and mineral supplements (eg, calcium, magnesium, aluminum, iron), polymeric phosphate binders, sucralfate or antacids and highly buffered drugs reduce the uptake (absorption) of Ciprobay. Ciprobay should therefore be administered either 1-2 hrs before or at least 4 hrs after ingestion of the antacid.
Concurrent administration of Ciprobay and theophylline can cause an undesirable increase in the theophylline plasma concentration. Therefore, it is necessary to determine the serum theophylline concentrations at brief intervals during concurrent administration with theophylline.
IV Administration: On simultaneous IV administration of Ciprobay and barbiturate-containing narcotics, monitoring of cardiovascular function is indicated.
A transient rise in the concentration of serum creatinine was observed when Ciprobay and cyclosporin were administered simultaneously. Therefore, it is necessary to control the serum creatinine concentrations in these patients frequently (twice a week).
Most Important Incompatibilities: Ciprobay infusion solution, unless compatibility with other infusion solutions/drugs has been confirmed, must always be administered separately. The visual signs of incompatibility are precipitation, clouding and discoloration.
Incompatibility appears with all infusions/drugs that are physically or chemically unstable at the pH of the solutions (eg, penicillins, heparin solutions), especially on combination with solutions adjusted to an alkaline pH (pH of the Ciprobay infusion solutions: 3.9-4.5).
Storage
Since the infusion solution is photosensitive, the infusion bottles should be removed from the box only immediately before use. In daylight conditions, complete efficacy is guaranteed for a period of 3 days.
Once the bottles have been opened, the stability is limited by possibilities of microbiological contamination. The solutions themselves are not oxygen-sensitive and are therefore stable even after the containers have been opened.
MIMS Class
ATC Classification
J01MA02 - ciprofloxacin ; Belongs to the class of fluoroquinolones. Used in the systemic treatment of infections.
Presentation/Packing
Tab 250 mg x 50's. 500 mg x 30's. Inj 200 mg/100 mL x 1's. 400 mg/200 mL x 1's.
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