Clarithromycin Zentiva - instructions for use, dose, side effects, contraindications

Excipients: core: croscarmellose sodium 35.00 / 70.00 mg, pregelatinized starch 65.00 / 130.00 mg, microcrystalline cellulose 85.30 / 170.60 mg, silica colloidal dioxide 7.20 / 14.40 mg, povidone K-30 20 , 00 / 40.00 mg, stearic acid 12.50 / 25.00 mg, talc 17.50 / 35.00 mg, magnesium stearate 7.50 / 15.00 mg; film sheath: giprolose 1.00 / 2.00 mg, hypromellose (viscosity 15 cps) 13.00 / 26.00 mg, propylene glycol 8.60 / 17.20 mg, sorbitan oleate modified 1.00 / 2.00 mg, vanillin 0, 55 / 1.10 mg, titanium dioxide 3.00 / 6.00 mg, quinoline yellow dye 0.50 / 0.50 mg, sorbic acid 0.55 / 1.10 mg.

Description:

Tablets 250 mg: oval biconvex tablets of yellow color, covered with a film membrane.

Tablets 500 mg: oblong biconvex tablets of yellow color, covered with a film membrane, with a risk on one side.

View of the break: from white to almost white.

Pharmacotherapeutic group:antibiotic-macrolide

ATX: & nbsp

J.01.F.A.09 Clarithromycin

Pharmacodynamics:

Clarithromycin is a semisynthetic bacteriostatic antibiotic of the second-generation macrolide group of a broad spectrum of action.

The antimicrobial effect of the drug is due to binding 50S subunit membrane ribosome microbial cells and suppression of protein synthesis of microorganisms. Clarithromycin showed high activity in vitro for both standard laboratory strains and those isolated from patients during clinical practice.

It is highly effective against many aerobic and anaerobic Gram-positive and Gram-negative microorganisms located both extracorporeally and intracellularly. The drug is active against: aerobic Gram-positive microorganisms: Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Listeria monocytogenes; aerobic gram-negative microorganisms: Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella (Branhamella) catarrhalis, Neisseria gonorrhoeae, Legionella pneumophila, Helicobacter pylori; other microorganisms: Mycoplasma pneumoniae, Chlamydia pneumoniae (TWAR); Mycobacterium: Mycobacterium leprae, Mycobacterium kansasii, Mycobacterium chelonae, Mycobacterium fortuitum, Mycobacterium avium complex (MAC), Mycobacterium avium, Mycobacterium intracellulare.

Clarithromycin exerts its action in vitro and for most of the following microorganisms (however, the safety and efficacy of using clarithromycin in clinical practice is not supported by clinical studies, and practical remains unclear): aerobic Gram-positive microorganisms: Staphylococcus agalactiae, Streptococci (groups C, F, G), Viridans group streptococci; aerobic gram-negative microorganisms: Bordetella pertussis, Pasteurella multocida; anaerobic Gram-positive microorganisms: Clostridium perfringens, Peptococcus niger, Propionibacterium acnes; aerobic gram-negative microorganisms: Bacteroides melaninogenicus; Spirochetes: Borrelia burgdorferi, Treponema pallidum; Campylobacteria: Campylobacter jejuni.

The production of p-lactamase does not affect the activity of clarithromycin. Clarithromycin insensitive Enterobacteriaceae, Pseudomonas spp., and other non-lactose-degrading gram-negative bacteria.

It is possible to develop cross-resistance to clarithromycin and other antibiotics of the macrolide group, as well as to lincomycin and clindamycin.

The main metabolite of clarithromycin in the human body is the microbiologically active metabolite 14-hydroxyclarithromycin.

The microbiological activity of the metabolite is the same as that of the starting material, or 1-2 times weaker in respect of most microorganisms, except for Haemophilus influenzae, in respect of which the efficiency of the metabolite is 2 times higher. The starting material and its main metabolite exert either an additive or a synergistic effect on Haemophilus influenzae at conditions in vitro and in vivo depending on the strain of bacteria.

Bactericidal action against Helicobacter pylori higher at neutral pH than with acid.

Most strains of staphylococcus aureus resistant to methicillin and oxacillin are resistant to clarithromycin.

Pharmacokinetics:

Ingestion clarithromycin quickly and actively absorbed. Absolute bioavailability is about 50%. Food slows down absorption, without significantly affecting bioavailability. With repeated intake of cumulation drug is not found, and the nature of metabolism in the human body has not changed. The connection with plasma proteins is 65-75%. After a single dose, 2 peaks of maximum concentration (C_mOh). The second peak is due to the ability of the drug to accumulate in the gallbladder, followed by a gradual or rapid intake into the intestine and absorption. Time to reach the maximum concentration with a single dose of 500 mg of clarithromycin - 2-3 hours.

Metabolism and excretion. Clarithromycin is metabolized in the cytochrome P450 system with the participation of the CYP3A isoenzyme, is an inhibitor of the CYP3A4, CYP3A5, CYP3A7 isoenzymes. After oral administration, 20% of the dose is rapidly hydroxylated in the liver to form the main metabolite, 14-hydroxyclarithromycin, which has a pronounced antimicrobial activity against Haemophilus influenzae.

In the equilibrium state, the concentration of 14-hydroxyclarithromycin does not increase in proportion to the doses of clarithromycin, and the half-life (T_1/2) of clarithromycin and its main metabolite increase with increasing dose. The non-linear nature of the pharmacokinetics of clarithromycin is associated with a decrease in the formation of 14-hydroxyclarithromycin and N-detylated metabolites when higher doses are used, which indicates the non-linearity of clarithromycin metabolism when taken in high doses.

In most cases, the minimum inhibitory concentration (MIC) of clarithromycin is 2 times lower than the minimum inhibitory concentration of erythromycin. The minimum inhibitory concentration of the metabolite is equal to or twice the minimum inhibitory concentration of the parent compound, the exception being Haemophilus influenzae, in respect of which the metabolite is 2 times more active than the original compound.

With a regular intake of 250 mg / day, the equilibrium concentrations (C_ss) unchanged drug and its main metabolite - 1 and 0,6 μg / ml, respectively; the half-life is 3-4 hours and 5-6 hours, respectively. When the dose is increased to 500 mg / day, the equilibrium concentrations of the unchanged drug and its metabolite in plasma - 2, 7-2.9 and 0.83-0.88 μg / ml, the elimination half-life is 4.8-5 hours and 6, 9-8.7 hours, respectively. Clarithromycin and 14-hydroxyclarithromycin penetrates well into all tissues and body fluids. After oral administration of clarithromycin, its content in the cerebrospinal fluid remains low (with normal blood-brain barrier permeability 1-2% of serum level). In therapeutic concentrations, it accumulates in the lungs, skin and soft tissues (in them concentrations in 10 times the concentration in the blood serum).

Excreted by the kidneys and intestines (20-30% - in unchanged form, the rest - in the form of metabolites). With a single intake of 250 mg and 1200 mg, kidneys are allocated 37.9% and 46%, through the intestines - 40.2% and 29.1%, respectively.

Pharmacokinetics in special clinical cases

In patients with moderate and severe impairment of liver function, but with a preserved renal function, there is no need to adjust the dose of clarithromycin, the equilibrium concentrations and the systemic clearance of clarithromycin do not differ from those in healthy patients, the equilibrium concentrations of 14-hydroxyclarithromycin in people with impaired liver function are lower than in healthy individuals.

In patients with impaired renal function increase the maximum and minimum concentrations in blood plasma, half-life, AUC clarithromycin and 14-hydroxyclarithromycin. The elimination constant and excretion in the urine are reduced. The degree of changes in these parameters depends on the degree of impaired renal function.

In elderly patients the concentration of clarithromycin and 14-hydroxyclarithromycin in the blood was higher, and excretion was slower than in young people. It is believed that the changes in pharmacokinetics in elderly patients are primarily related to changes in creatinine clearance and the functional state of the kidneys, rather than with the age of the patients.

The equilibrium concentrations of clarithromycin and 14-hydroxyclarithromycin in patients with HIV infectionwho received clarithromycin in usual doses (500 mg 2 times / day) were similar to those in healthy people. However, when using clarithromycin at higher doses, which may be required for the treatment of mycobacterial infections, the concentrations of antibiotic can significantly exceed the usual ones. In patients with HIV infection who took clarithromycin in a dose of 1 g / day and 2 g / day in 2 doses, the maximum equilibrium concentration was usually 2-4 μg / ml and 5-10 μg / ml, respectively.When the drug was used at higher doses, the half-life was longer than in healthy people who received clarithromycin in usual doses. The increase in plasma concentrations and the duration of the half-life with the appointment of clarithromycin at higher doses is consistent with the known non-linearity of the pharmacokinetics of the drug.

Combined treatment with omeprazole

With the appointment of clarithromycin 500 mg 3 times / day in combination with omeprazole at a dose of 40 mg / day there is an increase in the half-life, AUC_0-24 omeprazole. In all patients receiving combination therapy, compared with those receiving one omeprazole, there was an increase AUC0-24 omeprazole by 89% and half-life of omeprazole by 34%. In clarithromycin, the maximum and minimum concentrations and AUC_0-∞ increased accordingly by 10%, 27% and 15% compared to the data when only clarithromycin without omeprazole. In the equilibrium state of the concentration of clarithromycin in the gastric mucosa through 6 h after admission in the group receiving the combination of drugs, 25 times greater than those compared to those receiving one clarithromycin. The concentrations of clarithromycin in the stomach tissues through 6 h after taking two drugs in 2 times exceeded the data obtained in the group of patients who received one clarithromycin.

Indications:

Infectious-inflammatory diseases caused by microorganisms sensitive to clarithromycin:

- infections of the lower respiratory tract (such as bronchitis, pneumonia);

- upper respiratory tract infections (such as pharyngitis, sinusitis);

- infections of the skin and soft tissues (folliculitis, erysipelas, cellulitis (inflammation of the subcutaneous tissue));

- eradication Helicobacter pylori and a decrease in the frequency of recurrences of duodenal ulcers;

- common or localized mycobacterial infections caused by Mycobacterium avium, Mycobacterium intracellulare; localized infections caused by Mycobacterium fortuitum, Mycobacterium kansasii and Mycobacterium chelonae;

- prevention of the spread of infection caused by Mycobacterium avium (MAC), HIV-infected patients with lymphocyte content Cd4 (T-helper lymphocytes) no more than 100 at 1 mm³.

Contraindications:

- Hypersensitivity to the components of the drug and other macrolides;

- simultaneous reception of clarithromycin with the following drugs: astemizole, cisapride, pimozide, terfenadine (see Fig.section "Interaction with other drugs");

- simultaneous reception of clarithromycin with ergot alkaloids, for example, ergotamine, dihydroergotamine (see section "Interaction with other drugs");

- simultaneous reception of clarithromycin with midazolam for oral administration (see section "Interaction with other drugs");

- patients with a history of lengthening the interval QT, ventricular arrhythmia or ventricular tachycardia of the "pirouette" type;

- patients with hypokalemia (risk of lengthening the interval QT);

- patients with severe hepatic insufficiency, which occurs simultaneously with renal insufficiency;

- simultaneous reception of clarithromycin with inhibitors of HMG-CoA reductase (statins), which are largely metabolized by isoenzyme CYP3A4 (lovastatin, simvastatin), due to an increased risk of myopathy, including rhabdomyolysis (see section "Interaction with other drugs");

- simultaneous reception of clarithromycin with colchicine in patients with impaired liver or kidney function;

- patients with a history of cholestatic jaundice / hepatitis who developed with the use of clarithromycin (see Fig.section "Special instructions");

- porphyria;

- the period of breastfeeding;

- children under 12 years.

Carefully:

- Renal failure of moderate to severe severity;

- hepatic failure of moderate to severe severity;

- myasthenia gravis gravis (possibly increased symptoms);

- simultaneous reception of clarithromycin with benzodiazepines, such as alprazolam, triazolam, midazolam for intravenous use (see "Interaction with Other Drugs");

- simultaneous reception with drugs that are metabolized by isoenzyme CYP3A, eg, carbamazepine, cilostazol, ciclosporin, disopyramide, methylprednisolone, omeprazole, indirect anticoagulants (for example, warfarin), quinidine, rifabutin, sildenafil, tacrolimus, vinblastine (see the section "Interaction with other drugs");

- simultaneous reception with drugs that induce isoenzyme CYP3A4, for example, rifampicin, phenytoin, carbamazepine, phenobarbital, St John's wort (see "Interaction with other medicines");

- simultaneous reception with calcium channel blockers, which is metabolized by isoenzyme CYP3A4 (e.g., verapamil, amlodipine, diltiazem);

- patients with coronary heart disease (CHD), severe heart failure, hypomagnesemia, severe bradycardia (less than 50 beats per minute), as well as patients taking antiarrhythmic drugs at the same time IA class (quinidine, procainamide) and III class (dofetilide, amiodarone, sotalol);

- pregnancy.

Pregnancy and lactation:

The safety of clarithromycin during pregnancy and lactation has not been studied, therefore during pregnancy clarithromycin prescribe only if there is no alternative therapy if the intended benefit exceeds the possible risk to the fetus.

Clarithromycin penetrates into breast milk, so if it is necessary to prescribe the drug during lactation, breastfeeding should be stopped.

Dosing and Administration:Inside, the tablets are taken regardless of food intake.

For the treatment of infections of the respiratory tract, skin and soft tissues in adults and children older than 12 years, the average dose for oral administration is 250 mg 2 times a day. Clarithromycin in a dose of 500 mg 2 times a day is used in more severe cases. The usual duration of treatment is 5-14 days.The exception is community-acquired pneumonia and sinusitis, which require treatment from 6 up to 14 days.

With mycobacterial infections, except tuberculosis, recommended a dose of clarithromycin 500 mg 2 times a day. With common infections caused by MAC, in patients with AIDS treatment should be continued until there are clinical and microbiological evidence of its usefulness. Clarithromycin should be administered in combination with other antimicrobial agents active against these pathogens. The duration of treatment is determined by the doctor.

To prevent the spread of infections caused by Mycobacterium avium complex, prescribe 500 mg 2 times / day.

For eradication Helicobacter pylori prescribe a combination therapy with three drugs. The first scheme: clarithromycin - 500 mg 2 times / day, lansoprazole - 30 mg 2 times / day and amoxicillin - 1 g 2 times / day for 10 days. The second scheme: clarithromycin - 500 mg 2 times / day, amoxicillin - 1 g 2 times / day and omeprazole - 20 mg 2 times / day for 7-10 days.

In patients with chronic renal insufficiency (creatinine clearance less than 30 ml / min or serum creatinine concentration more than 3.3 mg / 100 ml), the dose is reduced by 2 times, or the interval between doses is increased by 2 times.The maximum duration of the drug in this group should not exceed 14 days.

Side effects:

The incidence of adverse reactions described below was determined respectively the following (classification of the World Health Organization): very frequent (≥10%); frequent (≥1% and <10%); infrequent (≥0,1% and <1%); rare (≥0,01% and <0,1%); very rare (<0,01 %); unknown (side effects from experience postmarketing application; frequency can not be estimated on the basis of available data).

Disorders from the gastrointestinal tract: frequent - diarrhea, vomiting, indigestion, nausea, pain in the abdomen; infrequent - gastritis, stomatitis, glossitis, bloating, constipation, dry mouth, eructation, flatulence; unknown - acute pancreatitis, discoloration of the tongue and teeth (usually restored by professional cleaning at the dentist).

Disturbances from the liver and bile ducts: frequent - violations of the liver; infrequent - cholestasis, a transient increase in the concentration in the blood plasma: alanine aminotransferase (ALT), aspartate aminotransferase (ACT), gamma glutamyl transferase (GGT), alkaline phosphatase, lactate dehydrogenase (LDH), cholestatic hepatitis; unknown - hepatic insufficiency, jaundice, hepatocellular hepatitis.

Impaired nervous system: frequent - headaches; infrequent - dizziness, drowsiness, tremor; unknown - convulsions, paresthesia, agevzia (loss of taste sensations), parosmia, anosmia.

Disorders of the psyche: frequent - insomnia; infrequent - anxiety; unknown - psychotic disorders, confusion, depersonalization, depression, disorientation, hallucinations, dream disturbances ("nightmarish" dreams).

Heart Disease: infrequent - atrial flutter, lengthening interval QT on an electrocardiogram (as in other macrolides); unknown - ventricular tachycardia, ventricular arrhythmia of the type "pirouette".

Vascular disorders: it is unknown - hemorrhages.

Hearing disorders and labyrinthine disorders: infrequent - vertigo, hearing impairment, ringing in the ears; unknown - hearing loss that occurs after drug withdrawal.

From the side of the urinary system: unknown - interstitial nephritis, kidney failure.

Infectious and parasitic diseases: infrequent - candidiasis, vaginal infection; it is unknown - pseudomembranous colitis, erysipelas, erythrasma, with prolonged or repeated use of the drug, development of superinfection (development of resistance of microorganisms) is possible.

Immune system disorders: infrequent - hypersensitivity reaction; unknown - anaphylactic reaction.

Violations of the blood and lymphatic system: infrequent - leukopenia, neutropenia, eosinophilia; unknown - agranulocytosis, thrombocytopenia.

Disorders from the metabolism and nutrition: infrequent - anorexia, worsening of appetite; unknown - hypoglycemia.

Disturbances from the skin and subcutaneous tissues: frequent - skin rash, intense sweating; infrequent - itching, hives; Unknown - Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS-syndrome), acne, purple Shenlaine-Genocha.

Disturbances from the musculoskeletal and connective tissue: infrequent - myopathy, increased myasthenia gravis symptoms gravis.

General disorders and disorders at the site of administration: infrequent - malaise, asthenia, pain in the chest, chills, fatigue.

Laboratory and instrumental data: unknown-thrombocytosis, an increase in the value of the international normalized ratio (INR), prolongation of prothrombin time, a change in the color of urine.

Overdose:

Symptoms: abdominal pain, nausea, vomiting, diarrhea, possibly a headache, confusion.

Treatment: in case of an overdose, an immediate gastric lavage should be performed and symptomatic treatment should be prescribed. Hemodialysis and peritoneal dialysis do not lead to a significant change in the level of clarithromycin in the blood serum.

Interaction:

The use of the following drugs together with clarithromycin is contraindicated in connection with the possibility of developing serious side effects

Cisapride, pimozide, terfenadine and astemizole

With the simultaneous use of clarithromycin with cisapride / pimozide / terfenadine / astemizole, an increase in the concentration of the latter in the blood plasma was reported, which may lead to an increase in the interval QT and the occurrence of cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation, and ventricular pirouette tachycardia (see "Contraindications").

Alkaloids of ergot

Postmarketing studies show that with the combined use of clarithromycin with ergotamine or dihydroergotamine, the following effects associated with acute poisoning with drugs of the ergotamine group are possible: vascular spasm, ischemia of limbs and other tissues, including the central nervous system.Simultaneous use of clarithromycin and ergot alkaloids is contraindicated (see section "Contraindications").

The effect of other drugs on clarithromycin

Preparations that are inducers CYP3A (eg, rifampicin, phenytoin, carbamazepine, phenobarbital, St. John's wort pitted), can induce the metabolism of clarithromycin. This can lead to a subtherapeutic concentration of clarithromycin, which leads to a decrease in its effectiveness. In addition, it is necessary to observe the concentration of the ACh3A-inductor in the blood plasma, which can increase due to inhibition CYP3A clarithromycin. With the combined use of rifabutin and clarithromycin, there was an increase in plasma rifabutin concentration and a decrease in serum concentration of clarithromycin with an increased risk of uveitis. The following drugs have a proven or suspected effect on the concentration of clarithromycin in the blood plasma; In the case of their combined use with clarithromycin, dosage adjustment or alternate treatment may be required.

Efavirenz, nevirapine, rifampicin, rifabutin and rifapentin

Strong inductors of the cytochrome P450 system, such as efavirenz, nevirapine, rifampicin, rifabutin and rifapentin can accelerate the metabolism of clarithromycin and thus reduce the concentration of clarithromycin in the plasma and weaken the therapeutic effect, and at the same time increase the concentration of 14-hydroxycylarithromycin metabolite, also being microbiologically active. Since the microbiological activity of clarithromycin and 14-hydroxyclarithromycin differs in relation to different bacteria, the therapeutic effect may decrease with the combined use of clarithromycin and enzyme inducers.

Etravirine

The concentration of clarithromycin decreases with the use of etravirine, but the concentration of the active metabolite of 14-hydroxyclarithromycin increases. Since 14-hydroxyclarithromycin has a low activity against infections Mycobacterium avium complex (MAC), the overall activity against these pathogens may change, therefore alternative treatment should be considered for MAC treatment.

Fluconazole

Joint administration of fluconazole at a dose of 200 mg daily and clarithromycin at a dose of 500 mg twice daily for 21 healthy volunteer led to an increase in the average value of the minimum equilibrium concentration of clarithromycin (C_min) and AUC by 33% and 18%, respectively. At the same time, the combined administration did not significantly affect the average equilibrium concentration of the active metabolite of 14-hydroxyclarithromycin.

Correction of the dose of clarithromycin in the case of concurrent administration of fluconazole is not required.

Ritonavir

A pharmacokinetic study showed that a joint intake of ritonavir at a dose of 200 mg every eight hours and clarithromycin at a dose of 500 mg every 12 hours led to a marked suppression of the metabolism of clarithromycin. With the joint administration of ritonavir C_mOh clarithromycin increased by 31%, C_min increased by 182% and AUC increased by 77%. A complete inhibition of the formation of 14-hydroxyclarithromycin was noted. Due to the wide therapeutic range of clarithromycin, a reduction in its dose in patients with normal renal function is not required. In patients with renal insufficiency it is advisable to consider the following options for dose adjustment: with a QC of 30-60 ml / min, the dose of clarithromycin should be reduced by 50%; with QC less than 30 ml / min, the dose of clarithromycin should be reduced by 75%. Ritonavir should not be taken together with clarithromycin in doses exceeding 1 g / day.

Oral hypoglycemic agents / insulin

With the combined use of clarithromycin and oral hypoglycemic agents and / or insulin, pronounced hypoglycemia can be observed. Against the background of simultaneous reception of clarithromycin and some drugs that reduce the concentration of glucose, such as nateglinide, pioglitazone, repaglinide and rosiglitazone, there may be an inhibition of the isoenzyme CYP3A clarithromycin, which may result in hypoglycemia. Careful monitoring of glucose concentration is recommended.

Action of clarithromycin on other drugs

Antiarrhythmic drugs (quinidine and disopyramide)

Possible occurrence of ventricular tachycardia of the "pirouette" type when combined use of clarithromycin and quinidine or disopyramide. When concurrently taking clarithromycin with these drugs should regularly monitor the electrocardiogram for increasing the interval QT, and the serum concentrations of these drugs should be monitored.

Interactions due to the isoenzyme CYP3A

Joint reception of clarithromycin, which is known to inhibit isoenzyme CYP3A, and drugs, primarily metabolized by isoenzyme CYP3A, can be associated with a mutual increase in their concentrations, which can enhance or prolong both the therapeutic and side effects. Clarithromycin should be used with caution for patients receiving drugs that are substrates of isoenzyme CYP3A, especially if these drugs have a narrow therapeutic range (for example, carbamazepine), and / or are extensively metabolized by this enzyme. If necessary, a dose adjustment of the drug taken with clarithromycin should be performed. Also, if possible, monitoring of plasma concentrations of drugs primarily metabolized by isoenzyme CYP3A.

Metabolism of the following drugs / classes is carried out by the same isoenzyme CYP3A, as the metabolism of clarithromycin, for example, alprozolam, carbamazepine, cilostazol, ciclosporin, disopyramide, methylprednisolone, midazolam, omeprazole, indirect anticoagulants (for example, warfarin), quinidine, rifabutin, sildenafil, tacrolimus, triazolam and vinblastine. Also to the isoenzyme CYP3A agonists include the following drugs, contraindicated for joint use with clarithromycin: astemizole, cisapride, pimozide, terfenadine, lovastatin, simvastatin and ergot alkaloids (see the section "Contraindications"). To drugs interacting in a similar way through other isoenzymes within the cytochrome P450 system, phenytoin, theophylline and valproic acid.

Inhibitors of HMG-CoA reductase (statins)

The combined administration of clarithromycin with lovastatin or simvastatin is contraindicated (see the section "Contraindications") due to the fact that these statins are largely metabolized by the isoenzyme CYP3A4, and combined use with clarithromycin increases their concentration in blood plasma, which leads to an increased risk of myopathy, including rhabdomyolysis. There have been reports of rhabdomyolysis in patients taking clarithromycin together with these drugs. If it is necessary to use clarithromycin, you should stop taking lovastatin or simvastatin for the duration of therapy.

Clarithromycin should be used with caution in combination therapy with statins.In case of need of joint admission, it is recommended to take the lowest dose of statin. It is necessary to use statins that are not dependent on metabolism CYP3A (eg, fluvastatin).

Indirect anticoagulants

With the concomitant administration of warfarin and clarithromycin, bleeding is possible, a marked increase in INR and prothrombin time. In the case of combined use with warfarin or other indirect anticoagulants, it is necessary to monitor INR and prothrombin time.

Omeprazole

Clarithromycin (500 mg every 8 hours) was tested in healthy adult volunteers in combination with omeprazole (40 mg daily). With the combined use of clarithromycin and omeprazole, equilibrium plasma concentrations of omeprazole were increased (C_max, AUC_0-24 and T_1/2 increased by 30%, 89% and 34% respectively). The average pH value of the stomach for 24 hours was 5.2 when taking omeprazole alone and 5.7 when taking omeprazole together with clarithromycin.

Sildenafil, tadalafil and vardenafil

Each of these phosphodiesterase inhibitors is metabolized, at least in part, by the participation of an isoenzyme CYP3A. In the same time CYP3A can be inhibited in the presence of clarithromycin. The combined use of clarithromycin with sildenafil, tadalafil or vardenafil may lead to an increase in the inhibitory effect on phosphodiesterase. When using these drugs together with clarithromycin should consider the possibility of reducing the dose of sildenafil, tadalafil and vardenafil.

Theophylline, carbamazepine

With the combined use of clarithromycin and theophylline or carbamazepine, an increase in the concentration of these drugs in the systemic circulation is possible.

Tolterodin

Primary metabolism of tolterodine is via isoenzyme CYP2D6 cytochrome P450. However, in the part of the population deprived of isoenzyme CYP2D6, metabolism occurs through CYP3A. In this population, suppression of the isoenzyme CYP3A leads to significantly higher serum concentrations of tolterodine. In a population with a low level of metabolism via isoenzyme CYP2D6, a dose reduction of tolterodine in the presence of inhibitors of the isoenzyme CYP3A, such as clarithromycin.

Benzodiazepines (eg, alprozolam, midazolam, triazolam)

When combined with midazolam and clarithromycin tablets (500 mg twice daily), an increase in the area under the concentration-time curve (AUC) midazolam: 2.7 times after intravenous administration of midazolam and 7 times after oral administration. It is necessary to avoid joint ingestion of midazolam and clarithromycin. If, together with clarithromycin, the intravenous form of midazolam is used, the patient's condition should be carefully monitored for possible dose adjustment. The same precautions should be applied to other benzodiazepines, which are metabolized by the isoenzyme CYP3A, including triazolam and alprazolam. For benzodiazepines, the excretion of which is independent of CYP3A (temazepam, nitrazepam, lorazepam), clinically significant interaction with clarithromycin is unlikely.

With the combined use of clarithromycin and triazolam, the central nervous system (CNS) may be affected, for example, drowsiness and confusion. In this regard, in the case of joint application, it is recommended to follow the symptoms of the CNS disorder.

Interactions with other drugs

Colchicine

Colchicine is a substrate as an isoenzyme CYP3A, and the carrier protein, P-glycoprotein (Pgp). It is known that clarithromycin and other macrolides inhibit CYP3A and Pgp. When co-administered with clarithromycin and colchicine, inhibition Pgp and / or CYP3A can lead to an increase in the action of colchicine. It should monitor the development of clinical symptoms of colchicine poisoning. Post-marketing reports on cases of colchicine poisoning during its simultaneous administration with clarithromycin are registered, more often in elderly patients. Some of these cases occurred with patients suffering from kidney failure. As reported, some cases ended in a fatal outcome. In patients with normal renal and hepatic function, a dose of colchicine should be lowered with simultaneous use with clarithromycin. Simultaneous use of clarithromycin and colchicine is contraindicated in patients with impaired liver or kidney function (see section "Contraindications").

Digoxin

It is assumed that digoxin is a substrate Pgp. It is known that clarithromycin inhibits Pgp. When co-administered with clarithromycin and digoxin, inhibition Pgp clarithromycin may lead to an increase in the action of digoxin. The combined administration of digoxin and clarithromycin may also lead to an increase in plasma digoxin concentrations. Some patients experienced significant clinical symptoms of digoxin poisoning, including potentially fatal arrhythmias. When co-administered with clarithromycin and digoxin, the concentration of digoxin in the serum should be carefully monitored.

Zidovudine

Simultaneous oral administration of tablets clarithromycin and zidovudine by adult HIV-infected patients may lead to a decrease in the equilibrium concentration of zidovudine.

Because the clarithromycin influences the absorption of zidovudine when taken orally, interactions can be largely avoided by taking clarithromycin and zidovudine with an interval of 4 hours.

Similar interaction was not observed in HIV-infected children who took a children's suspension of clarithromycin with zidovudine or dideoxyinosine. Because the clarithromycin may interfere with the absorption of zidovudine when administered simultaneously in adults in adults,Such interaction is hardly possible with the use of clarithromycin intravenously.

Phenytoin and valproic acid

There are data on the interactions of isoenzyme inhibitors CYP3A (including clarithromycin) with drugs that are not metabolized by CYP3A (phenytoin and valproic acid). For these drugs, when combined with clarithromycin, it is recommended to determine their plasma concentrations, since there are reports of their increase.

Bi-directional drug interactions

Atazanavir

Clarithromycin and atazanavir are both substrates and isoenzyme inhibitors CYP3A. There is evidence of bi-directional interaction of these drugs. The combined use of clarithromycin (500 mg twice daily) and atazanavir (400 mg once a day) can lead to a twofold increase in the effect of clarithromycin and a decrease in the effect of 14-hydroxycylarithromycin by 70%, with an increase AUC atazanavir by 28%. Due to the wide therapeutic range of clarithromycin, reducing its dose in patients with normal renal function is not required.In patients with moderate renal failure (CK 30-60 ml / min), the dose of clarithromycin should be reduced by 50%. In patients with QC less than 30 ml / min, the dose of clarithromycin should be reduced by 75% using the appropriate dosage form of clarithromycin. Clarithromycin in doses exceeding 1000 mg per day, can not be used in conjunction with protease inhibitors.

Calcium channel blockers

With the simultaneous use of clarithromycin and calcium channel blockers, which are metabolized by the isoenzyme CYP3A4 (e.g., verapamil, amlodipine, diltiazem), you should be careful, since there is a risk of arterial hypotension. Plasma concentrations of clarithromycin, as well as calcium channel blockers, can increase with simultaneous application. Arterial hypotension, bradyarrhythmia and lactic acidosis are possible with concurrent administration of clarithromycin and verapamil.

Itraconazole

Clarithromycin and itraconazole are substrates and inhibitors of the isoenzyme CYP3A, which determines the bi-directional interaction of drugs. Clarithromycin can increase the concentration of itraconazole in the plasma, while itraconazole can increase the plasma concentration of clarithromycin. Patients simultaneously taking itraconazole and clarithromycin, should be carefully examined for signs of increased or prolonged pharmacological effects of these drugs.

Saquinavir

Clarithromycin and saquinavir are substrates and inhibitors CYP3A, which determines the bi-directional interaction of drugs. Simultaneous use of clarithromycin (500 mg twice daily) and saquinavir (in soft gelatin capsules, 1200 mg three times a day) in 12 healthy volunteers caused an increase AUC and C_mOhsaquinavir by 177% and 187%, respectively, compared with the administration of saquinavir alone. Values AUC and C_mOh clarithromycin were approximately 40% higher than with monotherapy with clarithromycin. When these two drugs are used together for a limited time in the doses / formulations mentioned above, dose adjustment is not required. The results of a study of drug interactions using saquinavir in soft gelatin capsules may not correspond to the effects observed with saquinavir in hard gelatin capsules.The results of the study of drug interactions with saquinavir monotherapy may not correspond to the effects observed with saquinarine / ritonavir therapy. When taking saquinavir together with ritonavir, the potential effect of ritonavir on clarithromycin.

Special instructions:

Long-term use of antibiotics can lead to the formation of colonies with an increased number of bacteria and fungi that are not sensitive to clarithromycin. With the development of superinfection, appropriate therapy should be prescribed.

When applying clarithromycin, hepatic dysfunction was reported (increased concentration of hepatic enzymes in the blood plasma, hepatocellular and / or cholestatic hepatitis with or without jaundice). Hepatic dysfunction can be severe, but is usually reversible. There are cases of hepatic insufficiency with a fatal outcome, mainly associated with the presence of serious concomitant diseases and / or simultaneous use of other medications. When signs and symptoms of hepatitis such as anorexia, jaundice, darkening of the urine, itching, tenderness of the abdomen during palpation, it is necessary to immediately stop the treatment with clarithromycin.In the presence of chronic liver diseases it is necessary to carry out regular monitoring of serum enzymes.

In the treatment of nearly all antibacterial agents, including clarithromycin, described cases of pseudomembranous colitis, the severity of which can range from mild to life-threatening. Antibiotic drugs can change the normal intestinal microflora, which can lead to growth FROM.difficile. Pseudomembranous colitis caused by Clostridium difficile, It is necessary to suspect all patients experiencing the appearance of diarrhea after using antibacterial agents. After the course of antibiotic therapy, careful medical supervision of the patient is necessary. Cases of pseudomembranous colitis after 2 months after taking antibiotics were described.

Clarithromycin should be used with caution in patients with ischemic heart disease (CHD), severe heart failure, hypomagnesemia, severe bradycardia (less than 50 beats / min), and also with simultaneous use with antiarrhythmic drugs IA class (quinidine, procainamide) and III class (dofetilide, amiodarone, sotalol).With these conditions and with simultaneous reception of clarithromycin with these drugs, the electrocardiogram should be monitored regularly to increase the interval QT.

It is possible to develop cross-resistance to clarithromycin and other antibiotics of the macrolide group, as well as to lincomycin and clindamycin.

Given the growing resistance Streptococcus pneumoniae to macrolides, it is important to conduct sensitivity testing in the appointment of clarithromycin to patients with community-acquired pneumonia. With hospital pneumonia clarithromycin should be used in combination with appropriate antibiotics.

Infections of the skin and soft tissues of mild and moderate severity are most often caused Staphylococcus aureus and Streptococcus pyogenes. In this case, both pathogens can be resistant to macrolides. Therefore, it is important to carry out a sensitivity test.

Macrolides can be used for infections caused by Corynebacterium minutissimum (erythrasma), diseases acne vulgaris and erysipelas, as well as in situations where penicillin can not be used.

In case of acute hypersensitivity reactions, such as anaphylactic reaction, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS-syndrome), purpura Shenlaine-Henoch, it is necessary to immediately stop taking clarithromycin and begin appropriate therapy.

In patients receiving clarithromycin, reported worsening of myasthenia gravis symptoms gravis.

In the case of combined use with warfarin or other indirect anticoagulants, it is necessary to monitor MNO and prothrombin time (see section "Interaction with other drugs").

Effect on the ability to drive transp. cf. and fur:

During the period of treatment, care must be taken when driving vehicles and engaging in other potentially hazardous activities requiring increased attention and speed of psychomotor reactions. It is necessary to take into account the presence of reports of the appearance of vertigo, disorientation and confusion in patients with the use of clarithromycin.

Form release / dosage:

Tablets, film-coated, 250 mg, 500 mg.

Packaging:

7 tablets in a PVC / A blisterl.

2 blisters per cardboard pack together with instructions for use.

Storage conditions:

At a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LS-000106

Date of registration:27.03.2012

The owner of the registration certificate:Zentiva Saalyk Yuryunleri Sanayi ve Tidjaret A.Sh.Zentiva Saalyk Yuryunleri Sanayi ve Tidjaret A.Sh. Turkey

Manufacturer: & nbsp

ZENTIVA SAGLIK URUNLERI SANAYI VE TICARET, A.S. Turkey

Representation: & nbspZENTIVA PHARMA, LLCZENTIVA PHARMA, LLC

Information update date: & nbsp17.09.2014

Illustrated instructions

Instructions

Clarithromycin Zentiva (Clarithromycin Zentiva)