Klaritromitsin

General characteristics. Structure:

Active ingredient: 250 mg or 500 mg of a klaritromitsin in 1 tablet.

Excipients: starch prezhelatinizirovanny, cellulose microcrystallic, croscarmellose sodium, povidon-K30, silicon dioxide colloid, magnesium stearate.

Cover: Опадрай the II white (polyvinyl alcohol, titanium dioxide, macrogoal, talc)

Pharmacological properties:

Pharmacodynamics. Semi-synthetic bacteriostatic makrolidny antibiotic of a broad spectrum of activity. Breaks synthesis of protein of microorganisms (communicates with 50S in subunit of ribosomes of a microbic cell). Works on out of - and intracellularly located activators. Activity of a klaritromitsin concerning the majority of strains of the following microorganisms is proved as in vitro, and in clinical practice:

- aerobic gram-positive microorganisms: Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Listeria monocytogenes;

- aerobic gram-negative microorganisms: Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, Neisseria gonorrhoeae, Legionella pneumophila;

- other microorganisms: Mycoplasma pneumoniae, Chlamydia pneumoniae;

- mycobacteria: Mycobacterium leprae, Mycobacterium chelonae, Mycobacterium kansasii, Mycobacterium fortuitum; Mycobacterium avium complex (MAC) - the complex including: Mycobacterium avium and Mycobacterium inlracellulare; Helicobacter pylori.

Beta лактамазы do not influence activity of a klaritromitsin.

Enterobacteriaceae and Pseudomonas spp., also as well as others, the gram-negative bacteria which are not fermenting lactose, are not sensitive to a klaritromitsin.

Activity of a klaritromitsin of in vitro:

- aerobic gram-positive microorganisms: Streptococcus agalactiae, Streptococci group of C, F, G, Streptococci of the viridans group;

- aerobic gram-negative microorganisms: Bordetella pertussis, Pasteurella multocida;

- anaerobic gram-positive microorganisms: Clostridium perfringens, Peptococcus niger, Propionibacterium acnes;

- anaerobic gram-negative microorganisms: Bacteroides melaninogenicus;

- spirochetes: Borrelia burgdorferi, Treponema pallidum;

- campylobacters: Campylobacter jejuni.

The main metabolite of a klaritromitsin in a human body is microbiological active metabolite 14-gidroksiklaritromitsin (14(R) - кларитромицин). Microbiological activity of a metabolite same as at initial substance, or is 1-2 times weaker concerning the majority of microorganisms. The exception makes N. of influenzae concerning which efficiency of a metabolite is twice higher. Initial substance and its main metabolite render either the additive, or synergy effect concerning N. to influenzae in the conditions of in vitro and in vivo depending on a strain of bacteria.

The majority of strains of the stafilokokk steady against Methicillinum and Oxacillinum, rezistentna to a klaritromitsin.

Development of cross resistance to a klaritromitsin and other antibiotics of group of macroleads, and also lincomycin and clindamycin is possible.

Pharmacokinetics. Absorption - bystry. Meal just before administration of drug increased bioavailability of drug on average by 25%. Bioavailability makes about 50%. Communication with proteins of plasma - 65-75%. After a single dose 2 peaks of the maximum equilibrium concentration in a blood plasma (Cmax) are registered. The second peak is caused by ability of drug to collect in a gall bladder with the subsequent gradual or bystry receipt in intestines and absorption. Time of achievement of Cmax (TCmax) - 2-3 h.

After intake of 20-30% of the accepted dose of a klaritromitsin quickly it is hydroxylated in a liver by isoenzymes of CYP3A4, CYP3A5 and CYP3A7 cytochrome with formation of the main metabolite - 14(R) - the klaritromitsin having the expressed antimicrobic activity concerning Haemophilus influenzae. Is inhibitor of isoenzymes CYP3A4, CYP3A5 and CYP3A7.

At regular reception on 250 mg/days equilibrium concentration (Css) of not changed drug and its main metabolite - 1,0 and 0,6 mkg/ml respectively; an elimination half-life (T1/2) - 3-4 and 5-6 h respectively. At increase in a dose up to 500 mg/days of Css of not changed drug and its metabolite in plasma - 2,7-2,9 and 0,83-0,88 mkg/ml respectively; T1/2 - 4,8-5,0 and 6,9-8,7 h respectively.

Klaritromitsin and his metabolite are well distributed in fabrics and liquids of an organism. Fabric concentration usually are several times higher than serumal.

It is removed by kidneys and intestines (20-30% - in not changed form, the rest - in the form of metabolites). At a single dose of 250 mg and 1200 mg kidneys remove 37,9 and 46%, by intestines - 40,2 and 29,1% respectively.

At use of a klaritromitsin in a dose of 250 mg each 12 h about 20% of a dose it is removed by kidneys in not changed look. At use of a klaritromitsin in a dose of 500 mg each 12 h about 30% of a dose it is removed by kidneys in not changed look. The renal clearance of a klaritromitsin significantly does not depend on a dose and approaches a normal glomerular filtration rate. The main metabolite found in urine is 14(R) - кларитромицин which share makes 10-15% of a dose (250 mg or 500 mg each 12 h).

At the patients with an impaired renal function receiving drug inside in a dose of 500 mg repeatedly, T1/2, Cmax, the minimum equilibrium concentration in a blood plasma (Cmin) and the area under a pharmacokinetic curve "concentration - time" were higher (AUC) of a klaritromitsin and a metabolite, than at healthy people. Deviations of these parameters correlated with degree of a renal failure: at more expressed renal failure of distinction were more considerable.

At the adult patients with HIV infection receiving drug in usual doses, Css of a klaritromitsin and its metabolite were similar to those at healthy people. However at use of a klaritromitsin in higher doses which can be required at treatment of mikobakterialny infections concentration of an antibiotic can exceed usual considerably.

Indications to use:

The infectious and inflammatory diseases caused by microorganisms, sensitive to a klaritromitsin:

- lower respiratory tract infections (including exacerbation of chronic bronchitis, community-acquired pneumonia);

- upper respiratory tract infection and ENT organs (including pharyngitis, tonsillitis, acute sinusitis, acute average otitis);

- uncomplicated infections of skin and soft tissues (including folliculitis, inflammation of hypodermic cellulose, ugly face);

- the disseminated or localized mikobakterialny infections caused by Mycobacterium avium and Mycobacterium intracellulare. The localized infections caused by Mycobacterium chelonae, Mycobacterium fortuitum and Mycobacterium kansasii;

- eradikation of Helicobacter pylori and decrease in frequency of a recurrence of an ulcer of a duodenum;

- prevention of spread of the infection caused by the Mycobacterium avium (MAC) complex HIV-positive patients with the maintenance of lymphocytes have CD4 (T-helper lymphocytes) of no more than 100 in 1 mm3;

- dontogenous infections.

Route of administration and doses:

Pill is taken inside, irrespective of meal. Usually to adults and children 12 years are more senior appoint 250 mg of a klaritromitsin 2 times a day. In more hard cases the dose is increased to 500 mg by 2 times a day.

Usually duration of treatment makes from 5 to 14 days. The exception is made by community-acquired pneumonia and sinusitis which demand treatment from 6 to 14 days.

For the purpose of Helicobacter pylori eradikation in a combination with other medicines. The combined treatment by three drugs. Klaritromitsin - 500 mg, лансопразол - 30 mg and amoxicillin - 1000 mg, all medicines on 2 times a day, within 10 days; кларитромицин - 500 mg, омепразол - 20 mg and amoxicillin - 1000 mg, all medicines on 2 times a day, within 7-10 days;

The combined treatment by two drugs. Klaritromitsin - 500 mg 3 times a day, омепразол 40 mg/days, within 14 days, with purpose of an omeprazol during the next 14 days in a dose of 20-40 mg/days.

Klaritromitsin on 500 mg 3 times a day + лансопразол 60 mg/days within 14 days.

For full healing of an ulcer additional decrease in acidity of a gastric juice can be required.

At dontogenous infections the dose of a klaritromitsin makes 250 mg 2 times a day within 5 days.

Doses for treatment of mikobakterialny infections, except tuberculosis: at mikobakterialny infections the dose of a klaritromitsin of 500 mg 2 times a day is recommended. Treatment of the disseminated MAC of infections at patients about AIDS should be continued until there is a clinical and microbiological performance. Klaritromitsin it is necessary to apply in a combination with other germicides, active to these activators. Duration of treatment of other not tuberculosis mikobakterialny tuberculosis infections is established by the doctor.

For prevention of the infections caused by MAC: the recommended dose of a klaritromitsin for adults - 500 mg 2 times a day.

Patients with a renal failure. To patients with clearance of creatinine less than 30 ml/min. appoint a half of a usual dose of a klaritromitsin, i.e. 250 mg once a day or, at heavier infections, on 250 mg 2 times a day. Treatment of such patients is continued by no more than 14 days.

Features of use:

Pregnancy and lactation. Use of drug at pregnancy (especially in the I trimester) is possible only in case there is no alternative therapy, and the estimated advantage for mother surpasses potential risk for a fruit.

Klaritromitsin is allocated with breast milk therefore in need of use of drug in the period of a lactation breastfeeding should be stopped.

At use of a klaritromitsin it was reported about hepatic dysfunction (increase in concentration of liver enzymes in blood, hepatocellular and/or cholestatic hepatitis with jaundice or without).

Hepatic dysfunction can be heavy, but usually is reversible. There are cases of a liver failure with a lethal outcome mainly connected with existence of serious associated diseases and/or with simultaneous use of other medicines. At emergence of signs and symptoms of hepatitis, such as anorexia, jaundice, urine darkening, itch, morbidity of a stomach at a palpation, it is necessary to stop immediately therapy klaritromitsiny.

In the presence of chronic diseases of a liver it is necessary to carry out regular control of activity of enzymes in blood serum.

In case of combined use with warfarin or other indirect anticoagulants it is necessary to control a prothrombin time and MNO.

At development of consecutive infection adequate therapy has to be appointed.

At prolonged use of drug development of superinfection is possible.

Aggravation of symptoms of a myasthenia of gravis is possible.

At emergence in time or after treatment of heavy and long diarrhea it is necessary to exclude the diagnosis of pseudomembranous colitis which demands immediate drug withdrawal and purpose of the corresponding treatment.

With care to use drug to patients with predisposition to lengthening of an interval of QT. At these states it is regularly necessary to carry out control of the electrocardiogram regarding increase in an interval of QT.

In case of acute reactions of hypersensitivity, such as anaphylactic reaction, Stephens-Johnson's syndrome, a toxic epidermal necrolysis, anaphylactic reactions, medicinal rash with an eosinophilia and system symptomatology, Shenleyna-Genokh's purpura, it is necessary to stop at once reception of a klaritromitsin and to begin the corresponding therapy.

Considering the growing resistance of Streptococcus pneumoniae to macroleads, it is important to hold testing of sensitivity at purpose of a klaritromitsin.

Development of cross resistance to a klaritromitsin and other antibiotics of group of macroleads is possible.

Influence on ability to manage vehicles and mechanisms. During treatment it is necessary to be careful at control of vehicles and occupation other potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions. It is necessary to take potentiality of development of such side effects into account as dizziness, вертиго, confusion of consciousness and a disorientation. At emergence of the described undesirable phenomena it is necessary to refrain from performance of the specified types of activity.

Side effects:

Classification of side reactions by development frequency (the number of the patients registered cases/quantity): very often (> 1/10), it is frequent (> 1/100, <1/10), infrequently (> 1/1000, <1/100), it is unknown (side effects from experience of post-marketing use; frequency cannot be estimated on the basis of the available data).

Allergic reactions. Often: rash. Infrequently: anaphylactoid reaktsiya1, hypersensitivity, dermatitis bulleznyy1, itch, urticaria, makulopapulezny syp3. It is unknown: anaphylactic reaction, Stephens-Johnson's syndrome, a toxic epidermal necrolysis, medicinal rash with an eosinophilia and system symptomatology (DRESS - a syndrome).

From a nervous system. Often: headache, sleeplessness. Infrequently: loss soznaniya1, diskineziya1, dizziness, the drowsiness, a tremor, concern increased vozbudimost3, krik3. It is unknown: spasms, psychotic frustration, confusion of consciousness, depersonalization, depression, disorientation, hallucinations, disturbances of dreams ("dreadful" dreams), paresthesia, mania.

From integuments. Often: intensive sweating. It is unknown: acne, Shenleyna-Genokh's purpura, hemorrhage.

From an urinary system. It is unknown: renal failure, intersticial nephrite.

From a metabolism and food. Infrequently: anorexia, deterioration in appetite. It is unknown: hypoglycemia.

From a musculoskeletal system. Infrequently: muscular spazm3, musculoskeletal skovannost1, mialgiya2. It is unknown: rabdomioliz2, myopathy, strengthening of symptoms of a myasthenia of gravis.

From the alimentary system. Often: diarrhea, vomiting, dyspepsia, nausea, pain in a stomach. Infrequently: ezofagit1, gastroesophageal reflux bolezn2, gastritis, proktalgiya2, stomatitis, a glossitis, swelling zhivota4, a lock, dryness in a mouth, an eructation, a meteorism, holestaz4, hepatitis including cholestatic or gepatotsellyulyarnyy4. It is unknown: acute pancreatitis, discoloration of language and teeth, liver failure, jaundice.

From respiratory system. Infrequently: astma1, nasal krovotecheniye2, thromboembolism pulmonary arterii1.

From sense bodys. Often: dysgeusia, food faddism. Infrequently: вертиго, a hearing disorder, a ring in ears. It is unknown: deafness, ageusia (loss of flavoring feelings), parosmiya, anosmia.

From cardiovascular system. Often: vazodilatatsiya1. Infrequently: a stop serdtsa1, ciliary aritmiya1, lengthening of an interval of QT on the electrocardiogram, ekstrasistoliya1, an atrial flutter. It is unknown: ventricular tachycardia, including pirouette type.

Laboratory indicators. Often: a deviation in hepatic test. Infrequently: increase in concentration kreatinina1, increase in concentration mocheviny1, change of the relation albumine - globulin1, a leukopenia, neytropeniya4, eozinofiliya4, trombotsitemiya3, increase in concentration in blood: alaninaminotranspherases (ALT), aspartate aminotransferases (ACT), gammaglutamiltransferaza (GGTP)4, alkaline fosfatazy4, lactate dehydrogenases (LDG)4. It is unknown: an agranulocytosis, thrombocytopenia, increase in value of the international normalized relation (INR), lengthening of a prothrombin time, urine discoloration, increase in concentration of bilirubin in blood.

General frustration. Infrequently: nedomoganiye4, gipertermiya3, an adynamy, pain in chest kletke4, oznob4, utomlyaemost4.

Infectious and parasitic diseases. Infrequently: tsellyulit3, candidiasis, gastroenterit2, secondary infektsii3 (including vaginal). It is unknown: pseudomembranous colitis, ugly face, erythrasma.

Patients with the suppressed immunity. At the patients with AIDS and other immunodeficiencies receiving кларитромицин in higher doses for a long time for treatment of mikobakterialny infections it is often difficult to distinguish undesirable effects of drug of symptoms of HIV infection or an associated disease.

The most frequent undesirable phenomena at the patients accepting a daily dose of a klaritromitsin, equal 1000 mg were: nausea, vomiting, a food faddism, pain in a stomach, diarrhea, rash, a meteorism, a headache, a lock, a hearing disorder, increase in concentration of ACT and ALT in blood. Also cases of the undesirable phenomena with a low frequency of emergence, such as asthma, sleeplessness and dryness in a mouth were noted.

At patients with the suppressed immunity carried out assessment of laboratory indicators, analyzing their considerable aberrations (sharp increase or decrease). On the basis of this criterion at 2-3% of the patients receiving кларитромицин in a dose of 1000 mg daily substantial increase of concentration of ACT and ALT in blood, and also decrease in number of leukocytes and thrombocytes was registered. At a small number of patients increase in concentration of residual nitrogen of urea was also registered.

* In some messages on a rabdomioliza кларитромицин was accepted together with other medicines with which reception, as we know, development of a rabdomioliz is connected (statines, fibrata, colchicine or Allopyrinolum).

1 Messages on these side reactions were received only at use of a klaritromitsin, lyophilisate for preparation of solution for infusions.

2 Messages on these side reactions were received only at use of a klaritromitsin, tablet of the prolonged action, film coated.

3 Messages on these side reactions were received only at use of a klaritromitsin, powder for preparation of suspension for intake.

4 Messages on these side reactions were received only at use of a klaritromitsin, tablet, film coated.

Interaction with other medicines:

Use of the following drugs together with кларитромицин ohm contraindicated in connection with a possibility of development of serious side effects

Tsizaprid, Pimozidum, терфенадин and астемизол. At joint reception of a klaritromitsin with tsizapridom/pimozidom/terfenadinom/astemizoly it was reported about increase in concentration of the last in a blood plasma that can lead to increase in an interval of QT and emergence of cardiac arrhythmias, including ventricular tachycardia, fibrillation of ventricles and ventricular tachycardia like "pirouette" (see the section "Contraindications"),

Ergot alkaloids. Post-market researches show that at combined use of a klaritromitsin with ergotamine or dihydroergotamine the following effects connected with acute poisoning with drugs of group of ergotamines are possible: a vascular spasm, ischemia of extremities and other fabrics, including the central nervous system. Simultaneous use of a klaritromitsin and alkaloids of an ergot contraindicated (see the section "Contraindications"),

Influence of other medicines on кларитромицин. The drugs which are CYP3A4 isoenzyme inductors (for example, the rifampicin, Phenytoinum, carbamazepine, phenobarbital, a St. John's Wort which is made a hole), can induce metabolism of a klaritromitsin. It can result in subtherapeutic concentration of a klaritromitsin that leads to decrease in its efficiency. Besides, it is necessary to watch concentration of the inductor of an isoenzyme of SUR3A4 in a blood plasma which can raise because of CYP3A4 isoenzyme inhibition klaritromitsiny. At combined use of a rifabutin and klaritromitsin increase in plasma concentration of a rifabutin and decrease in plasma concentration of a klaritromitsin with the increased risk of development of a uveitis was observed.

The following drugs have the proved or alleged influence on concentration of a klaritromitsin in a blood plasma; in case of their combined use with klaritromitsiny correction of doses or transition to alternative treatment can be required.

Efavirenz, not Virapinum, rifampicin, рифабутин and rifapentine. Strong inductors of system of P450 cytochrome, such as эфавиренз, not Virapinum, rifampicin, рифабутин and rifapentine can accelerate metabolism of a klaritromitsin and, thus, lower concentration of a klaritromitsin in plasma and weaken therapeutic effect, and at the same time increase concentration 14(R) - a klaritromitsina - the metabolite which is also microbiological active. As microbiological activity of a klaritromitsin and 14(R) - a klaritromitsina differs concerning various bacteria, the therapeutic effect can decrease at combined use of a klaritromitsin and inductors of isoenzymes of P450 cytochrome.

Etravirin. Concentration of a klaritromitsin decreases when using an etravirin, but concentration of an active metabolite 14(K) - a klaritromitsina increases. As 14(11) - the klaritromitsina has low activity in relation to infections of Mycobacterium avium complex (MAC), the general activity concerning these activators therefore for treatment of MAC it is necessary to consider alternative treatment can change.

Flukonazol. Joint reception of a flukonazol in a dose of 200 mg daily and a klaritromitsina in a dose of 500 mg twice a day at 21 healthy volunteers led to increase in average Cmin and AUC value by 33% and 18%, respectively. At the same time joint reception considerably did not influence average equilibrium concentration of an active metabolite 14(R) - a klaritromitsina. Dose adjustment of a klaritromitsin in case of the accompanying reception of a flukonazol is not required.

Ritonavir. The pharmacokinetic research showed that joint reception of a ritonavir in a dose of 200 mg each eight hours and a klaritromitsin in a dose of 500 mg each 12 hours led to noticeable suppression of metabolism of a klaritromitsin. At joint reception of a ritonavir of Cmax of a klaritromitsin increased by 31%, Cmin increased by 182% and AUC increased by 77%. Full suppression obrazovaniya14 (R) - a klaritromitsina was noted. Thanks to the broad therapeutic range of a klaritromitsin reduction of its dose with normal renal function is not required from patients. At patients with a renal failure it is reasonable to consider the following options of dose adjustment: at KK of 30-60 ml/min. the dose of a klaritromitsin has to be reduced by 50%; at KK less than 30 ml/min. the dose of a klaritromitsin has to be reduced by 75%, using for this purpose the corresponding dosage form of a klaritromitsin. Ritonavir it is not necessary to apply jointly with klaritromitsiny in the doses exceeding 1 g/day.

Peroral hypoglycemic means / insulin. At combined use of a klaritromitsin and peroral hypoglycemic means and/or insulin the expressed hypoglycemia can be observed. Against the background of the concomitant use of a klaritromitsin and some drugs reducing concentration of glucose such as натеглинид, пиоглитазон, репаглинид and росиглитазон, CYP3A isoenzyme inhibition klaritromitsiny can take place, the hypoglycemia can become result of what. Careful control of concentration of glucose is recommended.

Action of a klaritromitsin on other medicines. Antiarrhytmic means (quinidine and Disopyramidum). Developing of ventricular tachycardia like "pirouette" at combined use of a klaritromitsin and quinidine or Disopyramidum is possible. At a concomitant use of a klaritromitsin with these drugs it is regularly necessary to carry out control of the electrocardiogram regarding increase in an interval of QT, and also it is necessary to control plasma concentration of these drugs.

The interactions caused by CYP3A isoenzyme. Joint reception of a klaritromitsin which, as we know, inhibits CYP3A isoenzyme and drugs, initially metabolized CYP3A isoenzyme, can be associated with mutual increase in their concentration that can strengthen, or prolong both therapeutic, and side effects. Klaritromitsin the patients receiving the drugs which are CYP3A isoenzyme substrates, especially should apply with care if these drugs have narrow therapeutic range (for example, carbamazepine), and/or are intensively metabolized by this enzyme. In case of need dose adjustment of the drug accepted together with klaritromitsiny has to be carried out. Also, whenever possible, monitoring of plasma concentration of the drugs which are initially metabolized CYP3A has to be carried out.

Metabolism of the following drugs / classes is carried out by the same isoenzyme of CYP3A, as metabolism of a klaritromitsin, for example, to alprazola, carbamazepine, цилостазол, cyclosporine, Disopyramidum, Methylprednisolonum, midazolam, омепразол, indirect anticoagulants (for example, warfarin), quinidine, рифабутин, sildenafit, такролимус, to triazoles and vinblastine. Also to agonists of an isoenzyme of CYP3A the following drugs contraindicated belong to combined use with klaritromitsiny: астемизол, цизаприд, Pimozidum, терфенадин, ловастатин, симвастатин and ergot alkaloids (see the section "Contraindications"). Phenytoinum, theophylline and valproic acid belong to the drugs interacting in this way through other isoenzymes within system of P450 cytochrome.

Inhibitors of GMG-KOA-reduktazy (statines). Joint reception of a klaritromitsin with lovastatiny or simvastatiny is contraindicated (see the section "Contraindications") because these statines are substantially metabolized by CYP3A4 isoenzyme, and combined use with klaritromitsiny increases their plasma concentration that leads to increase in risk of development of a myopathy, including рабдомиолиз. It was reported about cases of a rabdomioliz at the patients accepting кларитромицин together with these drugs. In case of need uses of a klaritromitsin, it is necessary to stop reception of a lovastatin or simvastatin for the period of therapy.

Klaritromitsin it is necessary to apply with care at a combination therapy with statines. In case of need joint reception, it is recommended to accept the smallest dose of statine. It is necessary to apply the statines which are not depending on metabolism of an isoenzyme of CYP3A (for example, флувастатин).

Indirect anticoagulants. At joint reception of warfarin and a klaritromitsin bleeding, the expressed increase in MNO and prothrombin time is possible. In case of combined use with warfarin or other indirect anticoagulants it is necessary to control MNO and a prothrombin time.

Omeprazol. Klaritromitsin (on 500 mg each 8 hours) was investigated at healthy adult volunteers in a combination with omeprazoly (on 40 mg daily). At combined use of a klaritromitsin and omeprazol equilibrium plasma concentration of an omeprazol were increased (Cmax, AUC0-24 and T1/2 increased by 30%, 89% and 34% respectively). Average PH value of a stomach within 24 hours made 5,2 at reception of an omeprazol separately and 5,7 at reception of an omeprazol together with klaritromitsiny.

Sildenafil, tadalafit and vardenafit. Each of these inhibitors of phosphodiesterase is metabolized, at least, partially with participation of an isoenzyme of CYP3A. At the same time the isoenzyme of CYP3A can be inhibited in the presence of a klaritromitsin. Combined use of a klaritromitsin with sildenafily, tadalafily or vardenafily can lead to increase in the inhibiting impact on phosphodiesterase. At use of these drugs together with klaritromitsiny it is necessary to consider the possibility of reduction of a dose of a sildenafil, a tadalafil and vardenafit.

Theophylline, carbamazepine. At combined use of a klaritromitsin and theophylline or carbamazepine increase in concentration of these drugs in a system blood-groove is possible.

Tolterodin. Primary metabolism of a tolterodin is carried out through an isoenzyme 2D6 of P450 (CYP2D6) cytochrome. However regarding the population deprived of CYP2D6 isoenzyme, metabolism happens through CYP3A isoenzyme. In this group of the population suppression of an isoenzyme of CYP3A results in much higher concentration of a tolterodin in plasma. In population with a low metabolic rate through an isoenzyme of CYP2D6 the dose decline of a tolterodin in the presence of inhibitors of an isoenzyme CYP3A, such as кларитромицин can be required.

Benzodiazepines (for example, to alprazola, midazolam, to triazoles). At combined use of midazolam and tablets of a klaritromitsin (500 mg twice a day) increase in AUC midazolam was noted: by 2,7 times after intravenous administration of midazolam and by 7 times after oral administration. Joint oral administration of midazolam and a klaritromitsin is contraindicated. If together with klaritromitsiny the intravenous form of midazolam is applied, it is necessary to control carefully a condition of the patient for possible dose adjustment. The same precautionary measures should be applied also to other benzodiazepines which are metabolized by CYP3A isoenzyme, including triazoles and alprazola. For benzodiazepines which removal does not depend on CYP3A isoenzyme (temazepam, nitrazepam, lorazepam) clinically significant interaction with klaritromitsiny is improbable. When sharing a klaritromitsin and triazolam impact on the central nervous system (CNS), for example, drowsiness and confusion of consciousness is possible. In this regard, in case of combined use, it is recommended to watch symptoms of disturbance of TsNS.

Interactions with other drugs. Colchicine. Colchicine is substrate of both CYP3A isoenzyme, and protein carrier, the R-glycoprotein (Pgp). It is known that кларитромицин and other macroleads inhibit an isoenzyme of CYP3A and Pgp. At joint reception of a klaritromitsin and colchicine the inhibition of Pgp and/or an isoenzyme of CYP3A can lead to strengthening of effect of colchicine. It is necessary to control development of clinical symptoms of poisoning with colchicine. Post-marketing messages on cases of poisoning with colchicine at its concomitant use with klaritromitsiny are registered, is more often at elderly patients. Some of the described cases happened to patients with a renal failure. As it was reported, some cases came to an end with a lethal outcome. At patients with normal function of kidneys and a liver it is necessary to reduce a colchicine dose at simultaneous use with klaritromitsiny. Simultaneous use of a klaritromitsin and colchicine is contraindicated to patients with the broken function of a liver or kidneys (see the section "Contraindications"),

Digoxin. It is supposed that digoxin is Pgp substrate. It is known what кларитромицин inhibits Pgp. At joint reception of a klaritromitsin and digoxin Pgp inhibition klaritromitsiny can lead to strengthening of effect of digoxin. Joint reception of digoxin and a klaritromitsin can also lead to increase in plasma concentration of digoxin. At some patients considerable clinical symptoms of poisoning with digoxin, including potentially lethal arrhythmias were noted. At joint reception of a klaritromitsin and digoxin it is necessary to control carefully concentration of digoxin in a blood plasma.

Zidovudine. Concomitant oral administration of tablets of a klaritromitsin and zidovudine by adult HIV-positive patients can lead to decrease in equilibrium concentration of a zidovudine. As кларитромицин influences absorption of a zidovudine at oral administration, interaction can be avoided substantially, accepting кларитромицин and a zidovudine at an interval of the 4th hour. Similar interaction was not observed at the HIV-positive children accepting children's suspension of a klaritromitsin with a zidovudine or didezoksiinoziny. As кларитромицин can interfere with absorption of a zidovudine at their concomitant use inside at adult patients, similar interaction is hardly possible when using a klaritromitsin intravenously.

Phenytoinum and valproic acid. There are data on interactions of inhibitors of an isoenzyme of CYP3A (including кларитромицин) with drugs which are not metabolized by means of CYP3A isoenzyme (Phenytoinum and valproic acid). For these drugs, at combined use with klaritromitsiny, definition of their plasma concentration as there are messages on their increase is recommended.

Bidirectional interaction of drugs. Atazanavir. Klaritromitsin and атазанавир are both substrates, and CYP3A isoenzyme inhibitors. There is an evidence of bidirectional interaction of these drugs. Combined use of a klaritromitsin (twice a day) and an atazanavira (400 mg once a day) can lead 500 mg to double increase in influence of a klaritromitsin and reduction of influence 14-(R) - a klaritromitsina for 70%, with increase in AUC of an atazanavir by 28%. Thanks to the broad therapeutic range of a klaritromitsin of reduction of its dose with normal renal function it is not required from patients. At patients with a moderate renal failure (KK of 30-60 ml/min.) the dose of a klaritromitsin has to be reduced by 50%. At patients with KK less than 30 ml/min. a dose of a klaritromitsin should be lowered by 75%, using for this purpose the corresponding dosage form of a klaritromitsin. Klaritromitsin in the doses exceeding 1000 mg a day it is impossible to apply together with inhibitors of proteases.

Blockers of "slow" calcium channels. At simultaneous use of a klaritromitsin and blockers of "slow" calcium channels which it is metabolized by CYP3A4 isoenzyme (for example, verapamil, амлодипин, diltiazem) it is necessary to be careful as there is a risk of developing of arterial hypotension. Plasma concentration of a klaritromitsin, also as well as blockers of "slow" calcium channels, can increase at simultaneous use. Arterial hypotension, a bradyarrhythmia and lactoacidosis are possible at a concomitant use of a klaritromitsin and verapamil.

Itrakonazol. Klaritromitsin and итраконазол are substrates and inhibitors of an isoenzyme CYP3A that defines bidirectional interaction of drugs. Klaritromitsin can increase concentration of an itrakonazol in plasma while итраконазол can increase plasma concentration of a klaritromitsin. The patients who are at the same time accepting итраконазол and кларитромицин should be inspected carefully on existence of symptoms of strengthening or increase in duration of pharmacological effects of these drugs.

Sakvinavir. Klaritromitsin and саквинавир are substrates and inhibitors of an isoenzyme CYP3A that defines bidirectional interaction of drugs. Simultaneous use of a klaritromitsin (500 mg twice a day) and a sakvinavira (in soft gelatin capsules, 1200 mg three times a day) caused increase in AUC and Cmax of a sakvinavir by 177% and 187% in 12 healthy volunteers respectively in comparison with reception of a sakvinavir separately. AUC and Cmax values of a klaritromitsin were about 40% higher, than at monotherapy klaritromitsiny. At combined use of these two drugs during limited time in the doses/structures stated above dose adjustment is not required. Results of a research of medicinal interactions with use of a sakvinavir in soft gelatin capsules can not correspond to the effects observed at use of a sakvinavir in solid gelatin capsules. Results of a research of medicinal interactions at monotherapy sakvinaviry can not correspond to the effects observed at therapy sakvinarinom/ritonaviry. At reception of a sakvinavir together with ritonaviry it is necessary to consider potential influence of a ritonavir on кларитромицин.

Contraindications:

- hypersensitivity to a klaritromitsin, other antibiotics of group of macroleads and other components of drug;

- a concomitant use of a klaritromitsin with the following drugs: астемизол, цизаприд, Pimozidum, терфенадин, ergotamine, dihydroergotamine;

- a concomitant use of a simvastatin, a lovastatin, midazolam for intake;

- a concomitant use of colchicine at patients with a renal failure or a liver;

- existence at patients of lengthening of an interval of QT in the anamnesis, ventricular arrhythmia or ventricular tachycardia like "pirouette";

- hypopotassemia;

- cholestatic jaundice / hepatitis, developed at use of a klaritromitsin (in the anamnesis);

- the heavy liver failure proceeding along with a renal failure;

- porphyria;

- hypopotassemia;

- breastfeeding period;

- children's age up to 12 years (taking into account a dosage form and a dosage).

With care. A renal failure of average and heavy degree, a liver failure of average and heavy degree, gravis myasthenia, a concomitant use with benzodiazepines (to alprazola, triazoles, midazolam for intravenous administration), the drugs inducing CYP3A4 isoenzyme (for example, the rifampicin, Phenytoinum, carbamazepine, phenobarbital, a St. John's Wort which is made a hole), blockers of "slow" calcium channels which are metabolized by CYP3A4 isoenzyme (for example, verapamil, амлодипин, diltiazem); coronary heart disease, heavy heart failure, hypomagnesiemia, the expressed bradycardia (heart rate less than 50 beats/min), concomitant use of the antiarrhytmic drugs IA of a class (quinidine, procaineamide) and the III class (дофетилид, Amiodaronum, соталол), pregnancy. The concomitant use with drugs which are metabolized by CYP3A isoenzyme, for example, carbamazepine цилостазол, cyclosporine, Disopyramidum, Methylprednisolonum, омепразол, indirect anticoagulants (for example, warfarin), quinidine, рифабутин, sildenafit, такролимус, vinblastine.

Overdose:

Symptoms: abdominal pain, nausea, vomiting, diarrhea.

Treatment: gastric lavage, maintenance therapy. Is not removed at haemo - or peritoneal dialysis.

Storage conditions:

In the dry, protected from light place at a temperature not above 25 °C. To store in the place, unavailable to children. A period of validity - 2 years. Not to use after a period of validity.

Issue conditions:

According to the recipe

Packaging:

Dosage of 250 mg: on 7, 10 or 12 tablets in a blister strip packaging from a film of the polyvinyl chloride and printing aluminum foil varnished. On 1 or 2 blister strip packagings together with the instruction on a medical use in a cardboard pack.

Dosage of 500 mg: on 5, 7 or 10 tablets in a blister strip packaging from a film of the polyvinyl chloride and printing aluminum foil varnished. On 1 or 2 blister strip packagings together with the instruction on a medical use in a cardboard pack.