Tsifran SR. of the tab. of p/o No. 10

Pharmacological properties

Drug represents a combination from two known antibacterial agents — ciprofloxacin and Tinidazolum.

Pharmacodynamics

Ciprofloxacin suppresses DNK-girazu enzyme which plays an important role in the course of a segment despiralization and spiralling of a chromosome during a phase of reproduction of bacteria and prevents a chromosomal transcription of information necessary for normal metabolism of a bacterial cell that leads to oppression of ability of the activator to breed. Drug has the fast and expressed bactericidal effect on the microorganisms which are both in a reproduction phase, and in a resting phase. Has high efficiency almost to all gram-negative and gram-positive activators. Escherichia coli, Shigella spp., Salmonella spp., Citrobacter spp., Klebsiella spp., Enterobacter spp., Serratia spp., Hafnia spp., Edwardsiella spp., Proteus (both indolpositive, and indolnegative strains), Morganella spp., Providencia spp., Yersinia, Vibrio spp., Aeromonas spp., Plesiomonas Pasteurela, Haemophillus, Campylobacter spp., Pseudomonas spp are sensitive to ciprofloxacin. (including Pseudomonas aeruginosa), Legionella, Moraxella spp., Branhamella spp., Acinetobacter spp., Brucella spp., Staphylococcus spp., Listeria spp., Corinebacterium, Chlamidia and also plasmid forms of bacteria.

As data of the researches in vitro testify and also results of application of a surrogate marker, ciprofloxacin is active against Bacillus antracis.

Different sensitivity are shown by Neisseria spp., Gardnerella spp., Flavobacterium spp., Alcaligenes spp., Streptococcus agalactiae, Enterococcus faecalis, Streptococcus pyogenes, Streptococcus pneumoniae, Streptococcus viridans, Mycoplasma hominis, Mycobacterium tuberculosis, Mycobacterium fortuitum.

Anaerobic cocci (Peptococcus, Peptostreptococcus) are moderately sensitive

to ciprofloxacin, and Bacteroides — steady. Tsifran SR. is effective concerning bacteria which make β-lactamelements. Drug is active also concerning microorganisms, resistant practically to all antibiotics, sulfanamide and nitrofuran drugs. In certain cases Tsifran SR. is active concerning strains of the microorganisms resistant to other medicaments of group of ftorkhinolon. However it is necessary to consider that between various ftorkhinolona there is a cross resistance. As a rule, rezistentna to the medicament Enterococcus faecium, Ureaplasma urealiticum, Nocardia asteroides, Treponema pallidum. The resistance to ciprofloxacin develops slowly and gradually (multistage type).

Prevalence of resistant strains can change depending on the geographical region and change over time. It is desirable to use local information on sensitivity of microorganisms to ciprofloxacin, especially at treatment of heavy infections. This information allows to receive only approximate indicators of sensitivity and resistance of any given microorganisms to ciprofloxacin.

Tinidazolum is derivative 5 nitroimidazoles with the component substituted with an imidazole which is capable to work against anaerobic bacteria and protozoa. And protozoa connect the mechanism of effect of Tinidazolum on anaerobic bacteria with penetration of medicine into cells of microorganisms and damage of DNA or oppression of its synthesis.

Tinidazolum is active as to protozoa, and obligate anaerobic bacteria.

Simplest microorganisms sensitive to Tinidazolum: Trichomonas vaginalis, Entamoeba histolytica and Giardia lamblia.

Tinidazolum is active

in relation to Gardnerella vaginalis and the majority of anaerobic bacteria, including Bacteroides fragilis, Bacteroides melaninogenicus, Bacteroides spp., Clostridium spp., Eubacterium spp., Fusobacterium spp., Peptococcus spp., Peptostreptococcus spp., Veillonella spp.

Pharmacokinetics

After oral administration ciprofloxacin is quickly and well soaked up by

, mainly from a duodenum and an upper part of a small intestine.

C _max in blood plasma is reached in 60–120 min. The bioavailability is about 70-80%. Distribution volume in a condition of stable equilibrium of 2-3 l/kg. As linking of ciprofloxacin with proteins insignificant (20–30%), and substance is in blood plasma mainly in not ionized form, almost all amount of the administered medicament can freely diffuse in ekstravazalny space. In this regard concentration of ciprofloxacin in some liquids and body tissues can exceed many times over medicine level in blood plasma (in particular high concentration in bile is noted). Ciprofloxacin generally is emitted with kidneys (≈45% in not changed look, ≈11% in the form of metabolites). Through intestines the dose rest is allocated (≈20% — in not changed look, ≈5–6% — in the form of metabolites). The renal clearance is 3–5 ml/min., the general clearance — 8–10 ml/min. T _½ makes 3–5 h. Because medicine is removed in the different ways, increase in T _½ note only at a considerable renal failure (possibly increase in this indicator up to 12 h).

Tinidazolum is quickly and completely soaked up by

at intake.

In researches of the healthy volunteers accepting Tinidazolum in a dose of 2 g in the concentration in blood plasma reached peak in 40–51 mkg/ml during 2 h and decreased to 11–19 mkg/ml in 24 h

Plasma level decreased slowly; Tinidazolum was revealed in blood plasma (in concentration to 1 mkg/ml) in 72 h after intake. T _½ Tinidazolum makes 12–14 h of blood plasma

Tinidazolum actively is distributed on all body tissues and gets through GEB. It is shown in all fabrics in therapeutic effective concentration. The volume of distribution is ≈50 l. Nearly 12% of Tinidazolum in blood plasma are connected with proteins.

Tinidazolum is emitted to

with a liver and kidneys. Researches of healthy volunteers showed what within 5 days of 60-65% of the entered dose is excreted by kidneys, and 20–25% — in not changed look. About 5% of a dose are removed with a stake.

Research of patients with a renal failure (clearance of creatinine of 22 ml/min.) demonstrate that Tinidazolum pharmacokinetics at such patients significantly does not change.

ciprofloxacin Combination with Tinidazolum does not influence pharmacokinetics of these active ingredients.

Combination of ciprofloxacin and Tinidazolum strengthens antibacterial effect of medicine and considerably expands the spectrum of action on microorganisms, sensitive to it. Tsifran SR. is effective concerning aerobic-anaerobic infections and also the mixed protozoan and bacterial infections.

Indication

Therapy at the multi-infections caused by aerobic and anaerobic microorganisms, sensitive to drug: chronic sinusitis, abscess of lungs, an empyema, intraperitoneal infections, inflammatory gynecologic diseases, postoperative infections at possible existence of aerobic and anaerobic bacteria, chronic osteomyelitis, infections of leather and soft tissues, ulcers on "diabetic foot", decubituses, infections of an oral cavity (including periodontitis and a periostitis).

Treatment of diarrhea or dysentery amoebic or mixed (amoebic and bacterial) etiologies.

Use

Tsifran Sr. to accept

inside, washing down with enough water. the mode of dosing and duration of treatment the doctor individually depending on localization defines, weights of a course of pathological process and also sensitivity of infestants.

to

Adult recommends the following dosage: 1 tablet 2 times a day.

Maximum daily dose makes 2 tablets of the medicine Tsifran ST.

to Patients with clearance of creatinine of ≤30 ml/min., to elderly people and patients with low body weight are appointed by ½ average doses.

Duration of treatment depends on disease severity, a clinical current and a bacteriological profile.

Course of treatment at sharp uncomplicated infections — 1–7 days, at treatment complicated and persistent recurrent infections — 10–14 days. In the infections caused by streptococci, it is necessary to continue treatment at least 10 days in order to avoid risk of development of complications during the remote period. In the infections caused by Chlamydia, it is also necessary to continue a course of treatment not less than 10 days. In osteomyelitis the course of treatment can make up to 2 months. At patients with reduced immunity the treatment should be carried out during the entire period of a neutropenia. Reception Tsifran SR. should be continued during 2 days after disappearance of symptoms of a disease.

Contraindication

Drug is not appointed the patient with hypersensitivity to ciprofloxacin or other ftorkhinolona, Tinidazolum or other derivatives of a nitroimidazole and also to any component of medicine in the anamnesis.

Drug is contraindicated to

in the presence of organic lesions of nervous system and diseases of blood.

Simultaneous application with tizanidiny.

Side effects

Caused by ciprofloxacin. infections and invasions: seldom — candidiasis; seldom — antibiotikoassotsiirovanny colitis; very seldom — with a possible lethal outcome.

from the haematogenic and lymphatic systems: sometimes — an eosinophilia; seldom — a leukopenia, anemia, a neutropenia, a leukocytosis, thrombocytopenia, a thrombocytosis; very seldom — hemolytic anemia, the Agranulocytosis, a pancytopenia (life-threatening), oppression of marrow (life-threatening).

from the immune system: seldom — allergic reactions, an allergic/Quincke's disease; very seldom — anaphylactoid reactions, an acute anaphylaxis (life-threatening) and the reactions similar to a serum disease.

Mental disorders: seldom — psychomotor excitability / uneasiness; seldom — confusion of consciousness and a disorientation, concern, the increased drowsiness, a depression, hallucinations; very seldom — psychoses.

from nervous system: seldom — a headache, dizziness, sleep disorders, violations of taste; seldom — paresthesias, dizesteziya, hypesthesias, a tremor, spasms, vertigo; very seldom — migraine, an incoordination, violation of sense of smell, a hyperesthesia and intracranial AG; peripheral neuropathy and polyneuropathy.

from an organ of sight: seldom — disorders of vision; very seldom — violation of perception of flowers.

from sense bodys and labyrinth violations: seldom — a ring in ears, deafness; very seldom — a hearing disorder.

from a cardiovascular system: seldom — tachycardia, a vazodilatation, decrease in the ABP, a faint; very seldom — vasculites, lengthening of an interval Q–T, ventricular arrhythmia, bidirectional ventricular tachycardia.

from a respiratory system: seldom — dispnoe (including asthmatic states).

from a GIT: seldom — anorexia; sometimes — a hyperglycemia; often — nausea, diarrhea; seldom — vomiting, bitterness in a mouth, pain in epigastriums, dispeptic frustration, a meteorism; very seldom — pancreatitis.

from a gepatobiliarny system: sometimes — tranzitorny increase in level of Transaminases, a hyperbilirubinemia; seldom — an abnormal liver function, jaundice, hepatitis (non-infectious); very seldom — liver necrosis (very seldom progresses to a liver failure, life-threatening).

from skin and hypodermic cellulose: seldom — rash (petekhialny, makulezny, urtikarny, etc.), an itch, urticaria; seldom — a photosensitization, emergence of nonspecific bubbles; very seldom — petechias, a multiformny erythema, a knotty erythema, Stephens's syndrome — Johnson and a toxic epidermal necrolysis.

from a musculoskeletal system and connective tissue: sometimes — arthralgia; seldom — myalgias, arthritises, increase in a muscle tone and a spasm; very seldom — muscle weakness, a tendinitis, ruptures of sinews (mainly an akhillova), aggravation of symptoms of a myasthenia.

from an urinary system: sometimes — a renal failure; seldom — tubulointerstitsialny nephrite, a renal failure, a hamaturia, a crystalluria.

from an organism in general: sometimes — a nonspecific pain syndrome, a general malaise, weakness, fever; seldom — hypostases, the increased sweating (hyperhidrosis); very seldom — violation of gait.

Deviation of laboratory indicators: sometimes — increase in level of liver enzymes (AlAT, AsAT, SF), an abnormal liver function, increase in level of creatinine and urea in blood plasma; seldom — change of indicators of a prothrombin; very seldom — increase in levels of amylase and a lipase.

Caused by Tinidazolum. Undesirable effects noted seldom, they were lungs and passed independently.

from nervous system: ataxy, spasms (seldom), dizziness, headache, hypesthesia, paresthesia, peripheral neuropathy, touch violations, vertigo, inflows.

from digestive system: an abdominal pain, feeling of bitterness in a mouth, metal smack in a mouth, anorexia, diarrhea, a fur, a glossitis, stomatitis, nausea, vomiting.

from the system of blood and blood formation: passing leukopenia.

from skin and appendages: reactions of hypersensitivity (sometimes heavy) in the form of skin rashes (petekhialny, makulezny, urtikarny), the nagger, hyperaemia, a small tortoiseshell and a Quincke's disease.

from an urinary system: coloring of urine in dark color.

Disturbance of the general state, connected with a medicine route of administration: fervescence, increased fatigue.

Special instructions

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Patient with epilepsy with attacks of spasms in the anamnesis, with vascular diseases and organic lesions of a brain in connection with danger of development of side reactions from central nervous system tsifran St it is necessary to appoint only according to vital indications. at emergence in time or after treatment of heavy or long diarrheas it is necessary to exclude a possibility of development of pseudomembranous colitis which demands immediate medicament withdrawal and purpose of the corresponding therapy.

Infection of a genital tract. If it is suspected or it is known that infections of a genital tract are caused by microorganisms, resistant to ftorkhinolona, it is especially important to obtain information on resistance degree to ciprofloxacin and Tinidazolum and to confirm sensitivity to medicament on the basis of results of laboratory researches.

Disturbance of warm activity. The ciprofloxacin which is Tsifran SR. part is associated with lengthening of an interval of Q-T on the ECG. Patients of advanced age can be more sensitive to impact of medicine on Q–T interval. It is necessary to apply with care ciprofloxacin with the accompanying medicines which can cause prolongation of an interval of Q-T (for example antiarrhytmic medicines of the class Ia or III), and the patient with risk factors of the specified states (for example prolongation of Q-T in the anamnesis, a nekorrigirovanny hypopotassemia).

a GIT. Emergence in time and after treatment of heavy and steady diarrhea can be manifestation of a serious gastrointestinal illness (for example pseudomembranous colitis with a possible lethal outcome) which demands immediate treatment. In such cases administration of medicament it is necessary to stop and begin application of the corresponding therapy. The medicaments inhibiting a vermicular movement are contraindicated.

tranzitorny increase in activity of Transaminases, SF or tranzitorny cholestatic jaundice, especially at patients with a liver disease in the anamnesis Are possible

.

Nervous system. Patients with epilepsy and patients with dysfunctions of central nervous system in the anamnesis (for example decrease in a convulsive threshold, a spasm, decrease in blood circulation in brain vessels, organic injuries of a brain and a stroke) can use medicament only in case of prevalence of the expected advantage over possible risk. In certain cases side reactions from central nervous system note after the first administration of drug. In rare instances the depression or psychosis can progress. In such cases the administration of medicament should be stopped.

Tinidazolum as a part of Tsifran SR. sometimes caused various neurologic violations, such as dizziness, ataxy, peripheral neuropathy, and only occasionally — spasms. In case of any neurologic violations, medicine should be cancelled.

Hypersensitivity to drug. In certain cases the hypersensitivity and allergic reactions note after the first administration of drug. In isolated cases anaphylactic/anaphylactoid reactions can progress, up to shock, the life-threatening patient. In certain cases they are revealed after the first intake of ciprofloxacin. In these cases the administration of medicament should be suspended and to immediately carry out medicament treatment.

Musculoskeletal system. At any symptoms of a tendinitis (for example a painful swelling) it is necessary to stop immediately treatment by ciprofloxacin, to avoid physical activity.

Rupture of a sinew (mainly an akhillova) was noted mainly at use of medicine for elderly people or in connection with the previous treatment of GKS.

Skin. Ciprofloxacin promotes emergence of reactions of photosensitivity. The patients taking the medicament need to avoid intensive ultra-violet radiation. At emergence of reactions of photosensitivity (for example similar sunblisters) medicine should stop therapy.

P450 Cytochrome. It is known that ciprofloxacin is moderate inhibitor of enzymes 1A2 of P450 cytochrome. It is necessary to be careful at simultaneous use of ciprofloxacin and medicines which are metabolized by these enzymes, such as theophylline, methylxanthine, caffeine, duloksetin, clozapine and others therefore increase in concentration of these medicines in blood plasma can cause specific side effects. During treatment and during not less than 72 h after treatment by Tsifran SR. (because of availability of Tinidazolum) it is necessary to avoid consumption of alcoholic beverages, considering a possibility of antabusopodobny reaction (inflows, a kolikoobrazny abdominal pain, tachycardia).

during treatment changes of some laboratory indicators are possible

: emergence of a deposit in urine; temporary increase in concentration of urea, creatinine, bilirubin, hepatic Transaminases in blood plasma, in some cases — a hyperglycemia, a crystalluria or a hamaturia, change of indicators of a prothrombin. At patients with abnormal liver functions and/or kidneys it is recommended to control concentration of ciprofloxacin in blood plasma.

Should avoid a concomitant use of tablets and the milk / enriched with calcium products (for example yogurt, juice with the increased calcium content). Other products with the content of calcium do not influence ciprofloxacin absorption.

Drug is shown to

for treatment of sharp tonsillitis (tonsillar tonsillitis).

Influence on ability to steer vehicles and to work with dangerous mechanisms. The patients accepting Tsifran SR. should abstain from the activity requiring special attention and speed of psychomotor reactions and also from control of vehicles.

Use during pregnancy and feeding by a breast. Tsifran SR. the pregnant women and women nursing cannot appoint. Considering data of tests on animals, it is impossible to exclude completely the probability of injury of articulate cartilages at newborns whereas the possibility of teratogenic effects (malformation) is not confirmed. Tinidazolum gets into breast milk where it is revealed during more than 72 h after application. Women should not nurse during use of medicine and within 3 days after medicament withdrawal.

Children. Do not apply at children.

Interaction

Should be careful at simultaneous application of a tsifran of St and antiarrhytmic medicines of the class ia or iii as ciprofloxacin can strengthen prolongation of an interval of q-t.

Simultaneous use of medicines of ciprofloxacin with iron preparations, fosfatsvyazyvayushchy polymers (for example a sevelamer) sukralfaty and the antiacid means containing magnesium, aluminum, calcium and medicines with a big buffer tank (for example antiretroviral) reduces intensity of absorption of ciprofloxacin. In this regard Tsifran SR. it is necessary to appoint for 1–2 h to or in 4 h after intake of the specified medicines. The specified restriction does not belong to the class of blockers of N ₂ - receptors.

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At the combined use of ciprofloxacin and omeprazolum the insignificant decrease With _max medicine in blood plasma and reduction of AUC can be noted.

Simultaneous application of Tsifran SR. and the medicines containing theophylline can lead

to undesirable increase in concentration of theophylline in blood plasma that, in turn, can lead to development of side effects. In rare instances side effects can threaten life / to lead to a lethal outcome. If simultaneous use of these medicines cannot be avoided, it is necessary to control concentration of theophylline in blood plasma and adequately to reduce its dose.

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After the simultaneous application of Tsifran SR. and means containing caffeine or pentoksifillin (okspentifillin) it was reported about increase in concentration of these xanthines in blood plasma.

Combined application of hinolon in very high doses (giraza inhibitors) and some NPVP (excepting acetylsalicylic acid) can provoke spasms.

At simultaneous application of Tsifran SR. and cyclosporine in some cases noted increase in concentration of creatinine in blood plasma therefore regular control of this indicator is necessary (2 times a week).

At simultaneous application of Tsifran SR. and antagonist of vitamin K the anticoagulating effect of ciprofloxacin can amplify. The risk can vary depending on an infection, age, the general condition of the patient therefore it is difficult to estimate exact influence of ciprofloxacin on increase in value of the international normalized relation (INR). It is necessary to carry out regular control of MNO to time and right after the combined application of Tsifran SR. and the antagonist of vitamin K (for example warfarin, an atsenokumarol, a fenprokumon or a fluindion).

Owing to interaction of ciprofloxacin and glibenclamide the increase in expressiveness of action of the last is possible

that is shown by a hypoglycemia.

Combined application of Tsifran SR. and a probenetsid is followed by increase in concentration of ciprofloxacin in blood plasma.

At simultaneous application with ciprofloxacin the delay of tubular transport (kidney metabolism) of a methotrexate is possible

that can be followed by increase in concentration of a methotrexate in blood plasma. At the same time the probability of emergence of the by-effects caused by a methotrexate can increase. In this regard the patients receiving combination therapy by a methotrexate and ciprofloxacin need to be observed carefully.

Metoclopramidum accelerates ciprofloxacin absorption therefore the period of achievement of the C _max ciprofloxacin in blood plasma is reduced (it does not affect bioavailability of the last).

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as a result of clinical trial with participation of healthy volunteers at simultaneous use of ciprofloxacin and a tizanidin revealed increase in concentration of a tizanidin in blood plasma (the C _max — by 7 times, range — at 4-21 time; increase in AUC — by 10 times, range — 6–24 times). Hypotensive and sedative by-effects are connected with increase in concentration of a tizanidin in blood plasma. Thus, simultaneous use of ciprofloxacin and tizanidin contraindicated.

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during clinical trials it is revealed that simultaneous application of a duloksetin and powerful inhibitors of CYP isoenzyme 1A2 (such as fluvoksamin) can lead to increase in AUC and S _max a duloksetin. Despite the absence of clinical data on interaction with ciprofloxacin, it is possible to provide a possibility of interaction at simultaneous use of ciprofloxacin and a duloksetin.

Ciprofloxacin can be applied in combinations with azlotsilliny and tseftazidiny at the infections caused by Pseudomonas; with mezlotsilliny, azlotsilliny and other effective β-laktamny antibiotics — at streptococcal infections; with izoksazolpenitsillina, Vancomycinum — at staphylococcal infections, with metronidazole, clindamycin — at mephitic gangrenes.

Uricosuric medicines (Allopyrinolum) promote delay of elimination of ciprofloxacin for 50% and to increase in its concentration in blood plasma.

Simultaneous application of a ropinirol with the ciprofloxacin moderated by inhibitor of CYP isoenzyme 1A2 leads

to increase in AUC and S _max a ropinirola for 60 and 84% respectively.

Monitoring of side effects of a ropinirol and the corresponding dose adjustment is recommended to be carried out in time and right after simultaneous introduction with ciprofloxacin.

Simultaneous use of the medicines containing lidocaine and ciprofloxacin of a hydrochloride, moderate inhibitor of CYP isoenzyme 1A2, reduces clearance of the lidocaine entered in/in by 22%. Though treatment with lidocaine was well transferred, after simultaneous application with ciprofloxacin a certain interaction can be noted that can be followed by side reactions.

After simultaneous application of 250 mg of ciprofloxacin with clozapine within 7 days of concentration in blood plasma of clozapine and N-desmetilklozapina is increased by 29 and 31% respectively. Clinical supervision and the corresponding dose adjustment of clozapine is recommended to be carried out in time and right after the combined introduction with ciprofloxacin (see. Special INSTRUCTIONS).

showed to

Research with participation of healthy volunteers increase With _max and AUC sildenafit approximately twice after intake 50 mg along with 500 mg of ciprofloxacin. Therefore it is necessary to appoint with care simultaneous use of ciprofloxacin with sildenafily, carefully estimating risk and advantage.

Simultaneous alcohol intake and Tsifran SR. application (because of availability of Tinidazolum) can cause antabusopodobny reaction therefore it needs to be excluded.

Anticoagulants: medicines of similar chemical structure can enhance effect of oral anticoagulants. It is necessary to control constantly indicators of a prothrombin time and to consider a possibility of dose adjustment of anticoagulant.

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Overdose

Owing to overdose at oral administration of ciprofloxacin in certain cases noted reversible toxic action on a parenchyma of kidneys. therefore in case of overdose, except holding ordinary actions (gastric lavage, application of the means causing vomiting, introduction of a large amount of liquid, creation of acid reaction of urine), it is also recommended to control a condition of function of kidneys and to accept the antacids containing magnesium and calcium which reduce ciprofloxacin absorption. by means of a hemodialysis only a small amount of ciprofloxacin (10%) is removed.

Specific antidote is unknown to

.

to

It was reported about frivolous cases of overdose at the patients receiving Tinidazolum, but they do not give a full picture about overdose symptoms.

is not present

Specific antidote for treatment of overdose of Tinidazolum. Treatment has to be symptomatic and supporting. Useful can be a gastric lavage. Tinidazolum is easily removed by a hemodialysis.

Storage conditions

In the dry place at a temperature not above 25 °C.