6
instruction
for Medical Application
of the Preparation of Ciprofloxacin
Trade name of the preparation: Ciprofloxacin
International nonproprietary name: Ciprofloxacin
Dosage form: solution for infusions
Content for 1 ml:
Active substance: ciprofloxacin hydrochloride monohydrate (in equivalent ciprofloxacin) – 2 mg;
Accessory substance: sodium chloride, edetate disodium, hydroxy propionic acid, water for injections.
Description: transparent slightly yellowish or slightly greenish liquid.
Pharmacotherapeutic group: antimicrobial agent, fluoroquinolone
ATC-code: [J01MA02]
Pharmacological action
Antimicrobial agent of wide range of action, derivative of quinolones, 2suppresses bacterial DNA-gyrase (standard sizes II and IV, responsible for the process of supercoiling by chromosomal DNA round nuclear RNA, that is necessary for reading of genetical information), disturbs synthetic process of DNA, growth and fission of bacteria; promotes frank morphological changes (including cell walls and membranes) and quick death of the bacterial cell.
It acts bacillicidal against gram-negative organisms in the period of rest and fission (as it influences not only against DNA-gyrase, but also smarts lysis of a cell wall) and it acts bacillicidal against gram-positive microorganisms only in the period fission.
The low toxicity for cells of the macroorganism is accounted for absence of DNA-gyrase in them. Against the background of administration of ciprofloxacin the parallel development of tolerance to other antibiotics not belonging to the group of dissociable inhibitors of gyrase does not take place, that makes it high-efficiency with regard to bacteria, which are resistant, for instance to aminoglycosides, penicillins, cephalosporins, tetracyclines and many other antibiotics.
The following gram-negative aerobic bacteria is sensitive to ciprofloxacin (Escherichia coli, Salmonella spp., Shigella spp., Citrobacter spp., Klebsiella spp,, Enterobacter spp., Proteus mirabiKs, Proteus vulgaris, Serratia marcescens, Hamia alvei, Edwardsiella tarda, Providencia spp., Morganella morganii, Vibrio spp., Yersinia spp.), other gram-negative bacteria (Haemophilus spp., Pseudomonas aeruginosa, Moraxella catarrhalis, Aeromonas spp., Pasteurella multocida, Plesiomonas shigelloides, Campylobacter jejuni, Neisseria spp.), some intracellular causal organisms: Legionella pneumophila, Brucella spp., Listeria monocytogenes, Mycobacterium tuberculosis, Mycobacterium kansasii;
gram-positive aerobic bacteria: Staphylococcus spp. (Staphylococcus aureus, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus saprophyticus), Streptococcus spp. (Streptococcus pyogenes, Streptococcus agalactiae).
The majority of staphylococci, resistant to methicillin are also resistant to ciprofloxacin. Sensibility of Streptococcus pneumoniae, Enterococcus faecalis, Mycobacterium avium (situated intracellular) is moderate (for their suppression high concentrations are required).
Bacillus anthracis is also sensitive to ciprofloxacin. Bacteroides fragilis, Pseudomonas cepacia, Pseudomonas maltophilia, Ureapiasma urealyticum, Clostridium difficile, Nocardia asteroids are resistant to the preparation. It is not effective against Treponema pallidum.
The resistance develops extremely slowly, because, on the one side, after action of ciprofloxacin practically no persistent microorganisms remain, and on the other side there are no enzymes in bacterial cells to inactivate it.
Pharmacokinetics
After intravenous infusion of 200 milligrams or 400 milligrams the time necessary for achievement of maximum concentration (TC max) is 60 minutes, the maximum concentration (Сmax) is 2.1 and 4.6 µg/ml respectively, connection with plasma proteins is - 20-40 %.
Ciprofloxacin well apportions in body tissues (excluding high-fat tissues for example nervous tissue). The concentration in tissues is 2-12-fold higher than in blood plasm. Therapeutic concentration are achieved in saliva, tonsils, liver, gall bladder, bile, intestinal canal, organs of abdominal cavity and small pelvis (endometrium, Fallopian tubes and female gonad, metra), seminal fluid, tissue prostate gland, kidney and urinoexcretory organs, pulmonary tissue, bronchial discharge, bony tissue, muscles, synovial fluid and articular cartilage, peritoneal liquid, skin. It penetrates into cerebrospinal fluid with small amounts, where its concentration in the absence of brain-tunic inflammation amounts 6-10 % from such in blood serum, and at inflamed brain-tunic is 14-37 %. The ciprofloxacin also well penetrates into eye liquid, bronchial discharge, pleural membrane, abdominal membrane, lymphatic fluid, through placenta. The concentration of ciprofloxacin in neutrophils of blood is 2-7-fold higher than that in the blood serum.
Its activity somewhat declines at pH values less than 6.
It metabolizes in the liver (15-30 %) with formation of low-active metabolites (diethyl ciprofloxacin, sulphociprofloxacin, oxociprofloxacin, formil ciprofloxacin).
Half-life period (T1/2) is about 5-6 hours in intravenous injection, in case of a chronic kidney disease it is up to 12 hours. It is discharged for the most part by kidneys by the way of canalicular filtration and canalicular secretion in unaltered form (50-70 %) and in the form of metabolites (10 %), the rest portion through gastrointestinal tract. In small amounts it is discharged with human milk.
After intravenous injection the concentration in urine within first 2 hours after administration almost is 100 times larger than that in the blood serum, that surpasses by far the minimal inhibitory concentration for majority of infectious germs of the urinary tracts.
Renal clearance is 3-5 milliliter/minute/kilogramme; systemic clearance is 8-10 milliliter/minute/kilogramme. In case of chronic kidney disease (creatine clearance (CC) is higher than 20 milliliter/minute) the percentage of the preparation egested through kidneys declines, but the cumulation in the organism does not take place on account of compensatory increase of metabolism of the preparation and excretion through the gastrointestinal tract.
Indications to applications.
Bacterial infections caused by sensitive microorganisms:
diseases of the lower respiratory passages (sharp and chronic bronchitis (in the stage of aggravation), pneumonia, multiple bronchiectasis, infectious complications of mucoviscidosis); infections of ear, nose, throat-organs (acute sinuitis);
infections of kidneys and urinary tracts (cystitis, pyelonephritis);
complicated intra-abdominal infections (in combination with metronidazole) including peritonitis;
chronical bacterial prostatitis;
uncomplicated gonorrhea;
typhoid fever, campilobacteriosis, shigellosis, turista;
infections of skin and soft tissues (infected ulcers, wounds, burns, apostasis, phlegmon);
bones and movable joint (osteomyelitis, septic arthritis);
infections against the background of immunodeficiency (appearing at treatment by immunodepressive medicinal preparations or in patients with neutropenia); prophylaxis and treatment of pulmonary anthrax (infection of Bacillus anthracis.
Children. therapy complications, caused by Pseudomonas aeruginosa in children with mucoviscidosis of lungs from 5 to 17 years; prophylaxis and treatment of pneumonic form of anthrax (introduction of infection of Bacillus anthracis).
Contra indications
Hyperresponsiveness, simultaneous administration with tizanidine (risk of frank decrease of arterial tension, sleepiness), age under 18 years (except medical maintenance of complications caused by Pseudomonas aeruginosa in children with mucoviscidosis of lungs from 5 to 17 years; prophylaxis and treatment of pneumonic form of anthrax), pregnancy, lactation period.
With care
Frank cerebral atherosclerosis, abnormality of cerebral circulation, mental illnesses, epilepsy, frank nephritic and/or hepatic insufficiency, elderly age, damage tendon at previously conducted medical maintenance by fluoroquinolones.
Mode of administration and dosages
Intravenous infusion: the duration of infusion is 30 minutes in dosage of 200 milligrams and 60 minutes in dosage of 400 milligrams. The infusion solutions ready-to-use can be mixed with 0.9 % of solution of sodium chloride, Ringer's solution and Ringer- lactate, 5% and 10 % solution of dextroglucose, 10% solution of fructose, as well as solution containing 5 % solution of dextroglucose with 0.225 % or 0.45 % solution of sodium chloride.
In infections of lower respiratory passages: 200-400 milligrams 2 times per day.
In urinary tract infections: acute uncomplicated - 100 milligrams 2 times per day;
cystitis in women (till menopause) – single dosage of 100 milligrams; complicated - 200 milligrams 2 time per day.
In uncomplicated gonorrhea – single dosage of 100 milligrams, in extragenital - 100 milligrams 2 times per day.
Infectious diarrhea - 200 milligrams 2 times, course of treatment - 5-7 days.
Special severe infections (streptococcal pneumonia, infectious complication mucoviscidosis, infection bones and movable joint, septicemia, peritonitis), especially caused by Pseudomonas, Staphylococcus - 400 milligrams 3 times per day.
Pulmonary anthrax (treatment and preventive measures): 400 milligrams 2 times per day.
For infection prophylaxis in surgical intervention - 200-400 milligrams 0.5-1 hour before the operation; in case of the operation duration of more than 4 hours it should be injected repeatedly in the same dosage.
In other infections (depending on severity of the run) - 200-400 milligrams 2 times per day.
The patients of elderly age should be prescribed with lower dosages depending on the infection severity and CK factor.
In pediatrics:
in treatment of the complications induced by Pseadomonas aeruginosa in children with mucoviscidosis of the lungs from 5 till 17 years - 10 milligran/kg 3 times per day (maximum dosage is 1200 milligrams).
Duration of the treatment -10-14 days.
In pulmonary anthrax (prophylaxis and treatment) the dosage is 10 milligrams/kilogramme twice per day. Maximum single dose is 400 milligrams, daily - 800 milligrams. Total duration of administration of ciprofloxacin is 60 days.
Chronic kidney disease : at the speed of glomerular filtration (CK 31-60 milliliters/minute/1.73 cub. Meter or serum concentration of creatinine from1.4 to 1.9 milligrams/100 milliliters) maximum daily dose is 800 milligrams. At the speed of glomerular filtration (CK lower than 30 milliliter/ minute/1.73 cub. meter or serum concentration of creatinine higher than 2 mg/100 ml) and in case of running haemodialysis the maximum daily dose is 400 mg; in haemodialysis ciprofloxacin should be brought after session of haemodialysis.
In peritoneal dyalysis the infusion solution should be added to dyalysis (intraperitoneal) in dose of 50 mg per 1 liter of dialysate 4 times per day (every 6 hours).
An average course of treatment is 1 day in acute uncomplicated gonorrhea and cystitis; up to 7 days in infection of kidneys, urinary tracts and abdominal cavity; during the whole period of neutropenic phase in patients with weaken body defenses, but at most 2 months in osteomyelitis and 7-14 days in all other infections. In streptococcosis infections in connection with danger of late complications the treatment should continue at least 10 days. In patients with immunodeficiency the treatment should be conducted during the whole period of neutropenia. The treatment should be continued not less than 3 more days after normalization of the body temperature or disappearance of clinical symptoms.
After intravenous application it is possible to continue the treatment orally.
Side effects
On the part of digestive system: nausea, diarrhea, vomit, stomach-ache, meteorism, anorexia, cholestatic jaundice (especially in patients with previous diseases of liver), hepatitis, hepatonecrosis.
On the part of nervous system: paraequilibrium, headache, increased fatigability, uneasiness, tremor, insomnia, nightmare, peripheral paralgesia (anomaly of sense of pain perception), rise of intracranial pressure, confused mental state, depression, hallucinations, as well as other manifestation of psychotic reactions (occasionally progressing to the conditions wherein patient can inflict harm to himself), browache, faintness, thrombosis of encephalic arteries.
On the part of sense organs: abnormality of taste and smell, impairment of vision (diplopia, change of color perception), buzzing in ears, decrease of sense of hearing.
On the part of cardiovascular system: tachycardia, rhythm disturbance, decrease of arterial tension.
On the part of hematopoietic system: leukopenia, granulocytopenia, anaemia, thrombocytopenia, leucocytosis, thrombocytosis, hemolytic anemia.
On the part of laboratory factors: hypoprothrombinemia, increment in activity of "hepatic" transaminases and alkaline phosphatase, hypercreatininemia, hyperbilirubinemia, hyperglycemia.
On the part of locomotor apparatus: arthralgia, arthritis, tendovaginitis, tendon tear, myalgia.
On the part of urinary system: hematocyturia, crystalluria (in the first instance in case of alkalinuria and hypouresis), glomerulonephritis, dysuria, polyuria, uroschesis, albuminuria, urethral hemorrhage, hematocyturia, decrease of nitrogen secretory function of kidneys, interstitial nephritis.
Hypersensitivity reaction: skin itching, urticaria fever, blistering accompanied with bleeding and appearance of small knots forming scabs, drug fever, petechiae on skin, face or throat hydrops, labored breathing, eosinophilia, vasculitis, erythema nodosum, multi-shape exudative erythema (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome).
Others: asthenia, superinfections (candidiasis, pseudomembranous colitis), flush, excessive photosensitivity.
Overdosage
Treatment: specific antidote is unknown. Strict control of the patient’s condition, provision of sufficient liquid intake. With the help of hemo - or peritoneal dialysis can be egested only some few (less than 10%) amount of the preparation.
Interaction with other medicinal preparations
In consequence of lowering of microsomal oxidation process activity in hepatocytes the ciprofloxacin enhances concentration and extends T1/2 of theophyllin (and other xanthine, for example caffeine), peroral hypoglycemic medicinal preparations, anticoagulant means of indirect action, contributes to decrease of prothrombin consumption index.
In combination with other antimicrobial medicinal preparations (beta-lactam antibiotics, amino glycosides, clindamycin, metronidazole) synergism is usually observed; it can be successfully used in combination with azlocillin and ceftazidime in case of infections caused by Pseudoraonas spp.; with mezlocillin, azlocillin and other beta-lactam antibiotics in case of streptococcal infections; with isoxazolil penicillins and vancomycin in case of staphylococcal infections; with metronidazole and clindamycin in case of anaerobic infections.
It strengthens nephrotoxic action of cyclosporine, increase of serosity creatinine is registered, in such patients that factor is necessary to be controlled bi-weekly.
In case of simultaneous reception it strengthens action of anticoagulant agents of indirect action.
Nonsteroidal anti-inflammatory preparations (excluding acetosalicylic acid) enhance risk of convulsion development.
Simultaneous application of uricosuric medicinal preparations results in deceleration of excretion (up to 50%) and rise of plasma concentration of ciprofloxacin.
It enhances Cmax 7-fold (from 4 to 21-fold) and the area under curve “concentration-time” (AUC) 10-fold (from 6 to 24-fold) of tizanidine, that enhances risk of frank decrease of arterial tension and drowsiness.
The infusion solution is pharmaceutically incompatible with all of infusion solutions and medicinal preparations, which physical-chemically unstable in acid environment (pH of infusion solution ciprofloxacin – 3.9 – 4.5). The solution for intravenous injection must not be intermixed with solutions having pH more than 7.
Special instructions
Ciprofloxacin is not a drug of choice in case of suspected or determinated pneumonia caused by Streptococcus pneumoniae.
In simultaneous intravenous injection of ciprofloxacin and medicinal preparations for general anesthesia of the of group of barbiturates permanent monitoring of the number of cardiac beats, arterial tension, electrocardiogram should be carried out.
In order to avoid development of crystalluria it is impermissible to exceed the recommend daily dose, it is also necessary to have sufficient liquid intake and maintenance of acid reaction of the urina.