Download 1 INSTRUCTION FOR MEDICAL APPLICATION OF THE

1
INSTRUCTION
FOR MEDICAL APPLICATION OF THE PREPARATION OF
CIPROFLOXACIN
Trade name of the preparation: Ciprofloxacin
International nonproprietary name: Ciprofloxacin
Dosage form: tablets covered with film coating
Content of 1 tablet:
Core:
Active substance: ciprofloxacin hydrochloride monohydrate – 295 mg./590 mg/885 mg (in equivalent
ciprofloxacin - 250 mg/500 mg/750 mg respectively);
Accessory substances: maize starch – 3.6 mg/7.2 mg/10.8 mg, pre gelatinized starch (starch 1500) –
10.0 mg/20.0 mg/30.0 mg, crospovidone (kollidon CL-M, kollidon CL) – 7.7 mg/15.4 mg/23.1 mg
monohydrate lactose (milk sugar, tablettose) – 13.3 mg/26.6 mg/39.9 mg microcrystalline cellulose –
39.2 mg/78.4 mg/117.6 mg, talcum powder – 7.4 mg/14.8 mg/22.2 mg, magnesium stearate – 3.8 mg/7.6
mg/11.4 mg.
Coating
Hypromellose (hydroxypropylmethyl cellulose, oxypropylmethyl cellulose, methocel) -3.4 mg/6.8
mg/10.2 mg, macrogol-4000 polyethylene oxide 4000, polyethyleneglycol 4000) -1.3 mg/2.6 mg/3.9
mg, propylene glycol – 1.6 mg/ 3.2 mg/4.8 mg, talcum powder – 0.5 mg/1.0 mg/1.5 mg, copovidone
(kollidon VA 64, kollidon VA-64) - 1.6 mg/3.2 mg/4.8 mg, titania (titanium dioxide) – 1.6 mg/3.2
mg/4.8 mg.
Description: tablets of white or almost white color, convexo-convexe, covered with film
coating, one layer of white color is seen on the cross section. The tablets of 250 mg each of round
shape, tablets of 500 mg and 750 mg are of oval shape.
Pharmacotherapeutic group: antimicrobial agent - fluoroquinolone
ATC-code [J01MA02]
Pharmacologic properties
Pharmacodynamics
Antimicrobial agent of wide range of action, derivative of quinolones, suppresses bacterial DNAgyrase (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
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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).
Active in regard to Bacillus anthracis in vitro.
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). The following are
resistant to the preparation: Bacteroides fragilis, Pseudomonas cepacia, Pseudomonas maltophilia,
Ureaplasma urealyticum, Clostridium difficile, Nocardia asteroides. It is not effective in regard to
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
At oral administration it quickly and sufficiently completely soaks out of gastrointestinal tract (G.
I.T.) (predominantly in dodecadactylon and empty intestine). Food intake slows down absorbing but
does not change maximum concentration (Cmax) and bioavailability. Bioavailability is 50-85 %,
distribution volume is 2-3.5 l/kg, connection with plasma protein is 20-40 %. Time of achievement of
maximum concentration (TCmax) at oral administration is 60-90 minutes, Сmax linear depends on value
of the accepted dosage and amounts at dosages 250, 500, 750 and 1000 mg respectively 1, 2, 2.4, 4.3
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and 5.4 microgram/ milliliter. In 12 hours after per os administration 250, 500 and 750 milligrams the
concentration of the preparation in the blood plasm goes down to 0.1, 0.2 and 0.4 micrograms/milliliter
respectively.
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 blod 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, formilciprofloxacin).
Half-life period (T1/2) is about 4 hours, in case of a chronic kidney disease 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 (40-50 %) and in the form of metabolites (15 %), the rest portion through gastrointestinal tract. In
small amounts it is discharged with human milk.
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); 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);
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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 introduction of infection of Bacillus anthracis), lactose
intolerance, lactase insufficiency, glucose–galactose malabsorption syndrome.
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.
Application in time of pregnancy and in the period breast feeding
The preparation is contraindicated at pregnancy and in lactation period.
Mode of administration and dosages
Per os. The tablets should be swallowed all of a piece with small quantity of liquid after meal. In
case of administration of the tablets on an empty stomach the active substance is soaked quicker.
In infections of the lower respiratory passages of easy and middle stages one should take 500
milligrams 2 times per day, at severe run one should take 750 мг milligrams 2 times per day. Course of
treatment is 7-14 days.
In acute sinuitis take by 500 milligrams 2 times per day. Course of treatment is 10 days.
In infections of skin and soft tissues of easy and middle stage one should take 500 milligrams 2
times per day, at severe run one should take 750 мг milligrams 2 times per day. Course of treatment is
7-14 days.
In infections of bones and movable joints one should take 500 milligrams 2 times per day, at severe
run one should take 750 milligrams 2 times per day. Course of treatment is 4-6 weeks.
In urinary tract infections one should take by 250-500 milligrams 2 times per day. Course of
treatment is 7-14 days, in uncomplicated cystitis in women is 3 days.
In chronical bacterial prostatitis one should take by 500 milligrams 2 times per day, course of
treatment is 28 days.
In uncomplicated gonorrhea one should t 250-500 milligrams one time.
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In infective diarrhea one should take by 500 milligrams 2 times per day. Course of treatment is 57 days.
In typhoid fever one should take by 500 milligrams 2 times per day. Course of treatment is 10
days.
In complicated intra-abdominal infection one should take by 500 milligrams every 12 hours, the
course of treatment is 7-14 days.
For prophylaxis and treatment of pulmonary anthrax one should take by 500 milligrams 2 times
per day within 60 days.
Chronic kidney disease: in creatine kinase more than 50 milliliter/minute there is no need for
the dosage correction; in creatine kinase 30-50 milliliter/minute - 250-500 milligrams every 12 hours;
in creatine kinase 5-29 milliliter/minute - 250-500 milligrams every 18 hours. If the patient is under way
with haemodialysis or peritoneal dialysis then the one should take 250-500 milligram per day, but one
should take the preparation after the run of haemodialysis
In pediatrics:
in treatment of complications cause by Pseudomonas aeruginosa, in children with mucoviscidosis of
lungs from 5 to 17 years the dosage is 20 milligrams per kilogram twice per day (maximal dosage is 1.5
gram). The course of treatment is 10-14 days;
in pulmonary anthrax (prophylaxis and treatment) -15 milligrams per kilogram twice per day.
Maximum single dose is 500 milligrams, maximum daily dose is 1gram. General duration of the
ciprofloxacin administration is 60 days.
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.
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,
thrombosis of encephalic arterias.
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.
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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, raise photosensitivity, superinfection (candidiasis, pseudomembranous
colitis), flush, excessive sweating.
If any of the adverse events indicated in the instruction tend to aggravate or you have notices any
other adverse events not indicated in the instruction, please inform the doctor about them.
Overdosage
Treatment: specific antidote is unknown. Gastric lavage and other measures of rescue emergency
care, 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 means of indirect action.
Oral administration in combination with iron-containing medicinal preparations, sucralfate and
antiacid medicinal preparations containing ions of magnesium, calcium and aluminium, results in
decrease of absorption of ciprofloxacin, for this reason it should be ordered 1-2 hours before or 4 hours
after administration of the above mentioned medicinal preparations.
Nonsteroidal anti-inflammatory preparations (excluding acetosalicylic acid) enhance risk of
convulsion development.
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Didanozin decreases absorption of ciprofloxacin on account of formation with it complexes with ions of
aluminium and magnesium contained in didanozin.
Metoclopramide accelerates absorption, resulting in decrease of time necessary for its
achievement of Cmax.
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.
Special instructions
Ciprofloxacin is not a drug of choice in case of suspected or determinated pneumonia caused by
Streptococcus pneumoniae.
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.
In patients with epilepsy, convulsive attack in anamnesis, vascular diseases and organic lesions
of cerebrum, in connection with threat of development of the adverse reactions on the part of the
central nervous system the ciprofloxacin should be ordered only for "intravital" indications.
In emergence at the time of or after treatment of severe and long-lasting diarrhea exclude the
diacrisis of pseudomembranous colitis, which requires immediate cancellation of the preparation and
prescription of the corresponding treatment.
In case of occurance of pains in tendons or first signs tendovaginitis the treatment should be
ceased (specific cases of inflammation and even tendon tear at the time of treatment by fluoroquinolones
are reported).
The influence on capability to drive transport vehicles, operation of machines and mechanisms
At the time of treatment one should keep from driving transport vehicles and operation of
machines and mechanisms that require elevated concentrations of attention and quickness of
psychomotor actions.
On application of ciprofloxacin it is necessary to avoid direct sun rays and intensive ultra-violet
radiation. in case of emergence of photoelectric sensitivity (occurrence of burn like skin reactions)
administration of the preparation should be ceased.
Product form
Tablets covered with film coating, 250 milligrams, 500 milligrams, 750 milligrams.
10 tablets by 250 milligrams; 5 tablets by 500 milligrams, 750 milligrams in contour cellular
packagings.
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10, 20 tablets by 250 milligrams; 5, 10, 20 tablets by 500 milligrams and 750 milligrams in
polymeric jars.
Put each jar, 1, 2 contour cellular packagings with 10 tablets by 250 milligrams, 1, 2, 4 contour
cellular packagings with 5 tablets by 500 milligrams and 750 milligrams with application
instructions into cardboard packages.
Storage conditions
It should be stored in a dry place protected from the light, at temperature not exceeding 25°C.
Keep out of reach of children.
Period of validity
5 years. Do not use after expiry date.
Delivery condition
Prescription medicine
Holder of the registration certificate/manufacturer/organization accepting reclamations
Open Joint Stock "Kurgan Joint Stock Company of Medical Preparations and Articles "Sintez"
(Sintez JSC)
No. 7, Prospect Konstitutsii, city of Kurgan, Russian Federation, 640008
Tel/fax (3522) 48-16-89
e-mail: [email protected]
Web site of the manufacturing company: http://www.kurgansintez.ru