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

Excipients: lactose monohydrate 230.0 mg, microcrystalline cellulose 160.0 mg, giprolose (hydroxypropylcellulose) 50.0 mg, croscarmellose sodium 30.0 mg, silicon dioxide colloid 20.0 mg, magnesium stearate 10.0 mg;

film sheath: [hypromellose 15,000 mg, giprolose (hydroxypropylcellulose) 5,820 mg, talc 5,778 mg, titanium dioxide 3,261 mg, iron oxide yellow (iron oxide) 0.141 mg] or [dry film coat containing hypromellose (50%), giprolose (hydroxypropylcellulose) (19 , 4%), talc (19.26%), titanium dioxide (10.87%), iron oxide yellow (iron oxide) (0.47%)] 30,000 mg.

Description:

Oval biconvex tablets, covered with a film coating of yellow color. On the cross section, the nucleus is white or almost white in color.

Pharmacotherapeutic group:antibiotic-macrolide

ATX: & nbsp

J.01.F.A.09 Clarithromycin

Pharmacodynamics:

Clarithromycin is a semisynthetic antibiotic of the macrolide group and has an antibacterial effect, interacting with 50S ribosomal subunit and suppressing the synthesis of protein bacteria, sensitive to it.

Clarithromycin showed high activity in vitro for both standard laboratory strains of bacteria and those isolated from patients in clinical practice. It is highly effective against many aerobic and anaerobic Gram-positive and Gram-negative microorganisms. The minimum inhibitory concentrations (MPC) of clarithromycin for most pathogens are smaller than the erythromycin MPC on average by one log2 breeding. Has a bactericidal effect against Helicobacter pylori, this activity of clarithromycin is higher at neutral pH than with acid.

In addition, data in vitro and in vivo indicate that clarithromycin acts on clinically significant species of mycobacteria.

In studies in vitro shown, that clarithromycin highly active in relation to Legionella pneumophila and Mycoplasma pneumoniae. but Enterobacteriaceae, Pseudomonas spp. and other non-fermenting lactose, gram-negative microorganisms are immune to the action of clarithromycin.

The activity of clarithromycin against most strains listed below as microorganisms has been proven in vitro, and in clinical practice for the diseases listed in the section "Indications for use":

- aerobic Gram-positive microorganisms: Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes;

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

- other microorganisms: Mycoplasma pneumoniae, Chlamydia pneumoniae (TWAR);

- mycobacteria: Mycobacterium avium complex (MAC): Mycobacterium avium, Mycobacterium intracellulare.

The production of beta-lactamase does not affect the activity of clarithromycin. Most strains of staphylococcus aureus resistant to methicillin and oxacillin are resistant to clarithromycin.

Helicobacter pylori

Sensitivity N. pylori to clarithromycin was studied on isolates N. pylori, isolated from 104 patients prior to initiation of drug therapy. In 4 patients, strains resistant to clarithromycin were isolated N. pylori, in 2 cases - strains with moderate resistance, in the remaining 98 patients, isolates N. pylori were sensitive to clarithromycin.

Clarithromycin exerts its action in vitro and for most strains of the following microorganisms (however, the safety and efficacy of using clarithromycin in clinical practice has not been confirmed by clinical studies and the practical significance remains unclear):

- aerobic Gram-positive microorganisms: Streptococcus agalactiae, Streptococci (groups C, F, G), Viridans group streptococci, Listeria monocytogenes;

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

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

- anaerobic gram-negative microorganisms: Bacteroides melaninogenicus;

- spirochetes: Borrelia burgdorferi, Treponema pallidum;

- mycobacteria: Mycobacterium leprae, Mycobacterium kansasii, Mycobacterium chelonae, Mycobacterium fortuitum;

- Campylobacteria: Campylobacter jejuni.

The main metabolite of clarithromycin in the human body is the microbiologically active metabolite 14-hydroxyclarithromycin (14-OH-clarithromycin). The microbiological activity of the metabolite is the same as that of the parent compound, or 1-2 times weaker in respect of most microorganisms. The exception is N. influenzae, in respect of which the efficiency of the metabolite is twice as high.

The starting compound (clarithromycin) and its metabolite in combination can have both additive and synergistic effects on N. influenzae in vitro and in vivo, depending on the strain of bacteria.

Pharmacokinetics:

Suction

The drug is rapidly absorbed in the gastrointestinal tract. The absolute bioavailability of clarithromycin is about 50%. Clarithromycin metabolized in the cytochrome P450 3A system (CYP3A) of the liver. When taking repeated doses of the preparation, cumulation was practically not detected, and the character of metabolism in the human body did not change.

Distribution, metabolism and excretion

In vitro

Clarithromycin binds to plasma proteins by 70% at a concentration of 0.45 to 4.5 μg / ml. At a concentration of 45 μg / ml, binding is reduced to 41%, probably as a result of saturation of the binding sites. This phenomenon was observed only at drug concentrations that are significantly higher than therapeutic concentrations.

Healthy

When using clarithromycin in a dose of 250 mg 2 times a day, the maximum equilibrium concentrations (C_max) of clarithromycin and 14-hydroxyclarithromycin in blood plasma were achieved after 2-3 days and were 1 μg / ml and 0.6 μg / ml, respectively. The half-lives of the initial drug and its main metabolite were 3-4 hours and 5-6 hours, respectively.

When using clarithromycin in a dose of 500 mg 2 times a day, the maximum equilibrium concentrations (C_max) of clarithromycin and 14-hydroxyclarithromycin in blood plasma were achieved after taking the 5th dose and averaged 2.7-2.9 μg / ml and 0.88-0.83 μg / ml, respectively. The half-lives of the initial preparation and its main metabolite were 4.5-4.8 hours and 6.9-8.7 hours, respectively.

FROM_max 14-hydroxyclarithromycin did not increase in proportion to the dose of clarithromycin, while the half-life as clarithromycin,and its hydroxylated metabolite tended to increase with increasing dose. Such nonlinear pharmacokinetics of clarithromycin in combination with a decrease in the formation of 14-hydroxyclarithromycin and N-detylated metabolite at high doses indicates a non-linear metabolism of clarithromycin, which becomes more pronounced at high doses.

The kidneys excreted about 37.9% after oral administration of clarithromycin at a dose of 250 mg and 46% after taking clarithromycin at a dose of 1200 mg; intestine is about 40.2% and 29.1%, respectively.

Patients

Clarithromycin and 14-hydroxyclarithromycin rapidly penetrate into the tissues and body fluids. There are limited patient data indicating that the concentration of clarithromycin in the cerebrospinal fluid is insignificant when taken orally (1-2% of the serum concentration with normal blood-brain barrier permeability). Concentration in tissues is usually several times higher than in serum.

Patients with hepatic impairment

In patients with moderate to severe hepatic impairment, but with preserved renal function, correction of the dose of clarithromycin is not required.Equilibrium concentration in blood plasma and systemic clearance of clarithromycin does not differ in patients of this group and healthy patients. The equilibrium concentration of 14-hydroxyclarithromycin in people with impaired liver function is lower than in healthy people.

Patients with impaired renal function

If the renal function is impaired, the minimum and maximum concentrations of clarithromycin in the blood plasma increase, the half-life, the area under the concentration-time curve of clarithromycin and the 14-OH metabolite. The elimination constant and excretion by the kidneys decrease. The degree of changes in these parameters depends on the degree of impaired renal function.

Elderly patients

In elderly patients, the concentration of clarithromycin and its 14-OH metabolite in the blood was higher, and excretion was slower than in the group of young people. However, after correction in view of renal clearance of creatinine, there were no differences in both groups.

Thus, the main effect on the pharmacokinetic parameters of clarithromycin is the function of the kidneys, not age.

Indications:

Infectious-inflammatory diseases caused by microorganisms sensitive to clarithromycin:

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

- infections of the upper respiratory tract and ENT organs (such as pharyngitis, sinusitis);

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

- disseminated or localized mycobacterial infections caused by Mycobacterium avium and Mycobacterium intracellulare;

- localized infections caused by Mycobacterium chelonae, Mycobacterium fortuitum and Mycobacterium kansasii;

- prevention of the spread of infection caused by the complex Mycobacterium avium (MAC), HIV-infected patients with lymphocyte content Cd4 (T-helper lymphocytes) not more than 100 in 1 mm³;

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

- odontogenic infections.

Contraindications:

- Hypersensitivity to clarithromycin, other components of the drug and other antibiotics of the macrolide group;

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

- simultaneous reception of clarithromycin with ergot alkaloids, for example,

ergotamine, dihydroergotamine (see the section "Interaction with other drugs");

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

- interval lengthening QT (including in the anamnesis), ventricular arrhythmia or ventricular tachycardia of the "pirouette" type;

- hypokalemia (risk of lengthening the interval QT);

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

- simultaneous reception of clarithromycin with inhibitors of HMG-CoA reductase,

which are largely metabolized by the isoenzyme CYP3A4 (lovastatin, simvastatin), due to the increased risk of myopathy (see section "Interaction with other drugs");

- simultaneous reception of clarithromycin with colchicine in patients with impaired liver or kidney function (see section "Interaction with other drugs");

- Cholestatic jaundice / hepatitis in history, developed with the use of clarithromycin (see section "Special instructions");

- the period of breastfeeding;

- children under 12 years of age (safety and efficacy not established);

- porphyria;

- lactose intolerance, lactase deficiency, glucose-galactose malabsorption.

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 of clarithromycin 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 of clarithromycin with preparations inducing isoenzyme CYP3A4, for example, rifampicin, phenytoin, carbamazepine, phenobarbital, St John's wort (see "Interaction with other medicines");

- simultaneous reception of clarithromycin with blockers of "slow" calcium channels, which are metabolized by isoenzyme CYP3A4 (e.g., verapamil, amlodipine, diltiazem);

- ischemic heart disease (CHD), severe heart failure, hypomagnesemia, severe bradycardia (less than 50 beats / min), and simultaneous use of antiarrhythmic drugs IA class (quinidine, procainamide) and III class (dofetilide, amiodarone, sotalol);

- pregnancy.

Pregnancy and lactation:

The safety of clarithromycin during pregnancy and during breastfeeding has not been established.

Use during pregnancy (especially in the first trimester) is only possible if the potential benefit to the mother exceeds the potential risk to the fetus and / or there is no safer alternative therapy.

If pregnancy occurs during the use of the drug, the patient should be warned about possible risks to the fetus.

Clarithromycin is excreted along with breast milk. If you need to take clarithromycin, breastfeeding should be discontinued.

Dosing and Administration:

The drug is taken orally, regardless of food intake.

When appointing clarithromycin at a dose of 250 mg should take the drug Clarithromycin capsules 250 mg.

The usual recommended dose of clarithromycin for adults and children over 12 years is 250 mg twice a day. In more severe cases, the dose is increased to 500 mg twice a day.

Usually the duration of treatment is from 5 to 14 days, with community-acquired pneumonia and sinusitis - from 6 to 14 days.

Patients with renal insufficiency

Patients with creatinine clearance less than 30 ml / min are recommended to have half the usual dose of clarithromycin, i.e. 250 mg once a day or, for more severe infections, 250 mg twice a day. The maximum daily dose is 500 mg. Treatment of such patients continues no more than 14 days.

Doses for the treatment of mycobacterial infections other than tuberculosis

With mycobacterial infections, a dose of clarithromycin 500 mg 2 times a day is recommended.

Treatment of disseminated MAC infections in patients with AIDS should continue as long as there is clinical and microbiological efficacy. Clarithromycin should be used in combination with other antimicrobial agents active against these pathogens.

The duration of treatment of other non-tuberculosis mycobacterial infections is determined by the doctor.

For the prevention of infections caused by MAC

The recommended dose of clarithromycin for adults is 500 mg twice a day.

With odontogenic infections The dose of clarithromycin is 250 mg twice a day for 5 days.

For eradication Helicobacter pylori

Combination treatment with three drugs:

- clarithromycin 500 mg twice a day in combination with lansoprazole 30 mg twice a day and amoxicillin 1000 mg twice a day for 10 days;

- clarithromycin 500 mg twice a day in combination with amoxicillin 1000 mg twice a day and omeprazole 20 mg twice a day for 7-10 days.

Combination treatment with two drugs:

- clarithromycin 500 mg 3 times daily in combination with omeprazole at a dose of 40 mg / day for 14 days with the use of omeprazole at a dose of 20-40 mg / day for the next 14 days;

- clarithromycin 500 mg 3 times daily in combination with lansoprazole 60 mg / day for 14 days.

Side effects:

Side effects are presented depending on the effect on organs and organ systems.

Classification of adverse reactions according to the frequency of development (number of reported cases / number of patients): very often (> 1/10), often (> 1/100, <1/10), infrequently (> 1/1000, <1/100), is unknown (the frequency can not be estimated from the available data).

Allergic reactions

Often - skin rash.

Infrequent - hypersensitivity, skin itching, hives.

Unknown - anaphylactic reaction, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS-syndrome), skin hyperemia.

From the nervous system

Often - a headache, insomnia.

Infrequent - dizziness, drowsiness, tremors, anxiety.

Unknown - convulsions, psychotic disorders, confusion, depersonalization, depression, disorientation, hallucinations, dreaming ("nightmarish" dreams), fear, anxiety, paresthesia, mania.

From the skin

Often - increased sweating.

Infrequently - acne, purple Shenlaine-Henoch, hemorrhage.

From the urinary system

Unknown - renal failure, interstitial nephritis.

From the side of metabolism and nutrition

Infrequent - anorexia, decreased appetite.

It is unknown - hypoglycemia.

From the side of the musculoskeletal system

Unknown - myopathy, increased myasthenia gravis symptoms gravis.

From the digestive system

Often - diarrhea, vomiting, dyspepsia, nausea, pain in the abdomen.

Infrequently - gastritis, stomatitis, glossitis, bloating, constipation, dryness of the oral mucosa, belching, flatulence, cholestasis, hepatitis, including cholestatic and hepatocellular.

Unknown - acute pancreatitis, discoloration of the tongue and teeth, hepatic insufficiency, cholestatic jaundice, gastralgia, candidiasis of the oral cavity.

From the sense organs

Often - dysgeusia, a perversion of taste.

Infrequently - vertigo, hearing impairment, ringing in the ears.

Unknown - deafness, agevzia (loss of taste sensations), parosmia, anosmia.

From the side of the cardiovascular system

Infrequent - atrial flutter, lengthening of the interval QT on an electrocardiogram.

It is unknown - ventricular tachycardia, including the "pirouette" type.

Laboratory indicators

Often - a deviation in the hepatic test.

Infrequently, - increasing the concentration of creatinine, leukopenia, neutropenia, eosinophilia, increased activity in blood: alanine aminotransferase (ALT), aspartate aminotransferase (ACT), gammaglutamiltransferazy (GGT), alkaline phosphatase (ALP), lactate dehydrogenase (LDG).

Unknown - agranulocytosis, thrombocytopenia, increase the value of international normalized ratio (INR), prolonged prothrombin time, changes in urine color, hyperbilirubinemia.

General disorders

Infrequent - malaise, asthenia, pain in the chest, chills, fatigue.

Infectious and parasitic diseases

Infrequently, candidiasis.

It is unknown - pseudomembranous colitis, erysipelas, erythrasma.

Patients with depressed immunity

In patients with AIDS and other immunodeficiency clarithromycin at higher doses for a long time to treat mycobacterial infections, it is often difficult to distinguish the undesirable effects of the drug from the symptoms of HIV infection or a concomitant disease.

The most frequent adverse events in patients taking a daily dose of clarithromycin equal to 1000 mg were: nausea, vomiting, taste distortion, abdominal pain, diarrhea, rash, flatulence, headache, constipation, hearing impairment, increased activity ACT and ALT in the blood. There have also been cases of adverse events with a low incidence, such as shortness of breath, insomnia and dryness of the oral mucosa.

In patients with suppressed immunity, laboratory indicators were evaluated, analyzing their significant deviations from the norm (a sharp increase or decrease). Based on this criterion, 2-3% of patients who received clarithromycin in a dose of 1000 mg daily, there was a significant increase in activity ACT and ALT in the blood, as well as a decrease in the number of leukocytes and platelets.A small number of patients also reported an increase in the concentration of residual urea nitrogen.

Overdose:

Symptoms

Taking a large dose of clarithromycin can cause symptoms of disorders from the gastrointestinal tract. In one patient with bipolar disorder in the history after the administration of 8 g of clarithromycin, changes in the mental state, paranoid behavior, hypokalemia and hypoxemia are described.

Treatment

In case of overdose, remove the nonabsorbed drug from the gastrointestinal tract (gastric lavage, taking activated charcoal, etc.) and perform symptomatic therapy. Hemodialysis and peritoneal dialysis does not have a significant effect on the concentration of clarithromycin in the blood serum, which is typical for other drugs of the macrolide group.

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, 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, ventricular pirouette tachycardia (see "Contraindications"),

Alkaloids of ergot

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 the section "Contraindications"),

The effect of other drugs on clarithromycin

The following drugs have a proven or suspected effect on the concentration of clarithromycin. In the case of their combined use with clarithromycin, dosage adjustment or alternate treatment may be required.

Preparations that are inducers of isoenzyme 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 monitor the concentration of the CUR3A inductor in the blood plasma, which can increase due to inhibition of the isoenzyme 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.

Efavirenz, nevirapine, rifampicin, rifabutin, rifapentin

Strong inductors of the cytochrome P450 system, such as efavirenz, nevirapine, rifampicin, rifabutin and rifapentin can accelerate the metabolism of clarithromycin and, thus, lower the concentration of clarithromycin in the blood plasma and weaken the therapeutic effect, and at the same time increase the concentration of 14-OH-clarithromycin metabolite, also being microbiologically active. Since the microbiological activity of clarithromycin and 14-OH-clarithromycin differs with respect 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-OH-clarithromycin increases. Since 14-OH-clarithromycin has a low activity against infections MAC, the overall activity against these pathogens may change, therefore, for treatment MAC alternative treatment should be considered.

Fluconazole

The simultaneous administration of fluconazole at a dose of 200 mg daily and clarithromycin at a dose of 500 mg twice daily in 21 healthy volunteers resulted in an increase in the minimum mean equilibrium concentration of clarithromycinC_min) and AUC by 33% and 18% respectively. At the same time, joint administration did not significantly affect the average equilibrium concentration of the active metabolite of 14-OH-clarithromycin. 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 suppression of the formation of 14-OH-clarithromycin was noted. Due to the wide therapeutic range, dose reduction in patients with normal renal function is not required. In patients with renal insufficiency it is advisable to consider the following dose adjustment options: when creatinine clearance is 30-60 ml / min, the dose of clarithromycin should be reduced by 50%. Ritonavir should not be taken together with clarithromycin in doses exceeding 1 g / day.

Oral hypoglycemic drugs / 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

Possible occurrence of ventricular tachycardia such as "pirouette" with the combined use of clarithromycin and antiarrhythmic drugs IA class (quinidine, procainamide) and III class (dofetilide, amiodarone, sotalol). 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 caused by isoenzymes CYP3A

Joint reception of clarithromycin, which is known to inhibit isoenzymes CYP3A, and drugs, primarily metabolized by isoenzymes 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 serum concentrations of drugs primarily metabolized by isoenzyme CYP3A.

Also to CYP3A agonists include the following drugs, contraindicated for joint use with clarithromycin: astemizole, cisapride, pimozide,

terfenadine, lovastatin, simvastatin and ergot alkaloids (see section "Contraindications"), The metabolism of the following drugs / classes is carried out by the same isoenzyme CYP3A, as the metabolism of clarithromycin: alprazolam, carbamazepine, cilostazol, ciclosporin, disopyramide, methylprednisolone, midazolam, omeprazole, indirect anticoagulants (for example, warfarin), quinidine, rifabutin, sildenafil, tacrolimus, triazolam and vinblastine. 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)

Like other macrolide antibiotics, clarithromycin increases concentrations of HMG-CoA reductase inhibitors (eg, lovastatin and simvastatin).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 serum concentrations, which leads to an increased risk of myopathy. 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 independent of the isoenzyme 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 in the stomach for 24 hours was 5.2 when taking omeprazole alone and 5.7 when taking omeprazole together with clarithromycin.

Sildenafil, tadalafil, vardenafil

Each of these phosphodiesterase inhibitors is metabolized, at least in part, with the participation of an isoenzyme CYP3A. At the same time, isoenzyme 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 these drugs are used together, 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 carried out through 2D6 isoform of cytochrome P450 (CYP2D6).However, in the part of the population deprived of isoenzyme CYP2D6, metabolism occurs through isoenzyme CYP3A. In this population, suppression of the isoenzyme CYP3A leads to significantly higher concentrations of tolterodine in the blood serum. 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 (e.g., alprazolam, midazolam, triazolam)

When combined with midazolam and clarithromycin (500 mg twice daily), there was an increase AUC midazolam: 2.7 times after intravenous administration of midazolam and 7 times after oral administration. It is necessary to avoid joint oral administration 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, alprazolam. For benzodiazepines, the excretion of which does not depend on the isoenzyme 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. Interaction with other drugs Colchicine

Colchicine is a substrate as an isoenzyme CYP3A, and the carrier protein responsible for excretion of the drug, P-glycoprotein (Pgp). It is known that clarithromycin and other macrolides inhibit isoenzyme CYP3A and Pgp. When co-administered with clarithromycin and colchicine, inhibition Pgp and / or CYP3A can lead to an enhanced effect of colchicine. 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.

It should monitor the development of clinical symptoms of colchicine poisoning.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 substratum for 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. Joint reception of digoxin and clarithromycin can also lead to an increase in serum digoxin concentration in patients. Some patients experienced clinical symptoms of digoxin poisoning, including potentially fatal arrhythmias. When the combined use of clarithromycin and digoxin should be carefully monitored the concentration of digoxin in the serum.

Zidovudine

Simultaneous ingestion of clarithromycin and zidovudine in adults with HIV-infected patients may lead to a decrease in the equilibrium concentration of zidovudine. Because the clarithromycin influences the absorption of zidovudine when ingested, 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, this 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 isoenzyme CYP3A (phenytoin and valproic acid). For these drugs, when combined with clarithromycin, it is recommended to determine their serum concentrations, since there are reports of their increase.

Bi-directional drug interactions

Atazanavir

Clarithromycin and atazanavir are substrates and inhibitors of the isoenzyme 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 reduction in the effect of 14-OH-clarithromycin 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 insufficiency (creatinine clearance 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.

Blocks of "slow" calcium channels

With the simultaneous use of clarithromycin and blockers of "slow" calcium channels, 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 blockers of "slow" calcium channels, 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 blood 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 of the isoenzyme 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_max saquinavir by 177% and 187%, respectively, compared with the administration of saquinavir alone. Value 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 saquinavir / ritonavir therapy. When taking saquinavir together with ritonavir, the potential effect of ritonavir on clarithromycin.

Verapamil

With a joint admission with clarithromycin, arterial hypotension, bradyarrhythmia, lactate acidosis are possible.

Special instructions:

Most strains of staphylococci, resistant to methicillin and oxacillin, are resistant to clarithromycin.

Long-term use of antibiotics can lead to the formation of colonies with an increased number of insensitive bacteria and fungi. When superinfection is necessary to appoint appropriate therapy.

When clarithromycin was used, cases of hepatic dysfunction were reported (increased hepatic enzyme activity 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 conduct regular monitoring of the activity 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. Antibacterial drugs can change the normal intestinal microflora, which can lead to an increase in C. difficile. Pseudomembranous colitis caused by Clostridium difficile, it is necessary to suspect in all patients experiencing the appearance of diarrhea after the use of 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 pneumonia to antibiotics of the macrolide group, it is important to conduct sensitivity testing for 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 give 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:

Data on the effect of clarithromycin on the ability to drive vehicles and mechanisms are not available.

Care should be taken when driving vehicles and mechanisms, taking into account the potential for dizziness, vertigo, confusion and disorientation that may occur when using this drug.

When there are undesirable phenomena from the central nervous system should refrain from performing these activities.

Form release / dosage:

Tablets, film-coated, 500 mg.

Packaging:

5, 7, 10 or 14 tablets in a contoured cell pack of a polyvinylchloride film and aluminum foil.

5, 7, 10 or 14 tablets in a can of high-density polyethylene.

1 or 2 contour packs of 5 or 7 tablets, 1 circuit pack of 10 or 14 tablets each, or one bank along with instructions for use in a pack of cardboard.

Storage conditions:

In the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:LP-002709

Date of registration:13.11.2014 / 30.06.2015

Expiration Date:13.11.2019

The owner of the registration certificate:VERTEKS, AO VERTEKS, AO Russia

Manufacturer: & nbsp

VERTEKS, AO Russia

Representation: & nbspVERTEKS CJSC VERTEKS CJSC Russia

Information update date: & nbsp30.06.2015

Illustrated instructions

Instructions

Clarithromycin (Clarithromycin)