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

Excipients: Hypromellose 2208 (100 mPa.s) 200,000 mg Hypromellose 2910 (50 mPa.s) 150.000 mg 137.500 mg of microcrystalline cellulose, colloidal silicon dioxide 2.500 mg Magnesium stearate 10.000 mg;

film sheath[Hypromellose 2910 (6 mPa.s) 15,000 mg, giproloza (hydroxypropyl) 5.820 mg Talc 5.778 mg Titanium dioxide 3.261 mg yellow iron oxide (iron oxide) 0.141 mg] or [dry mixture to a film coating comprising hypromellose 2910 (6 mPa.s) (50%), giproloza (hydroxypropylcellulose) (19.4%), talc (19.26%), titanium dioxide (10.87%), yellow iron oxide (ferric 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:

Klaritromitsii is a semisynthetic antibiotic macrolides and has antibacterial action by interacting with 50S ribosomal subunit and suppressing the synthesis of protein bacteria, sensitive to it.

Clarithromation is highly effective in vitro for both standard laboratory strains of bacteria and those isolated from patients in clinical practice. It is highly active against a wide range of aerobic and anaerobic, gram-positive and gram-negative microorganisms. The minimum inhibitory concentrations (MPC) of clarithromycin for most pathogens are less than the erythromycin MPC on average per 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, Listeria monocytogenes;

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

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

- mycobacteria: Mycobacterium avium complex (MAC): Mycobacterium avium,Mycobacterium intracellulare, Mycobacterium leprae, Mycobacterium kansasii, Mycobacterium chelonae, Mycobacterium fortuitum.

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 clarithromycin in clinical practice has not been confirmed by clinical studies, and practical significance remains unclear):

- aerobic Gram-positive microorganisms: Streptococcus 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;

- anaerobic gram-negative microorganisms: Bacteroides melaninogenicus;

- spirochetes: Borrelia burgdorferi, Treponema pallidum;

- Campylobacteria: Campylobacter jejuni.

The main metabolite of clarithromycin in the human body is the microbiologically active metabolite 14-hydroxyclarithromycin (14-OH-clarithro mycin). The microbiological activity of the metabolite is the same as that of clarithromycin, 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. 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

Clarithromycin is metabolized in the cytochrome P4503A system (isoenzyme CYP3A) of the liver. Absolute bioavailability is about 50%. 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

Research in vitro showed that on average about 70% of clarithromycin binds to human plasma proteins at drug concentrations of 0.45-4.5 μg / ml. With an increase in the concentration of up to 45.0 μg / ml, the binding of clarithromycin decreased to 41%, which may indicate saturation of the binding sites. This phenomenon was observed only at drug concentrations that are significantly higher than therapeutic concentrations.

Healthy

In patients taking 500 mg of clarithromycin in the form of prolonged-release tablets once a day during meals, the maximum concentration (C_mOh) of clarithromycin and 14-OH-clarithromycin in blood plasma was 1.3 and 0.48 μg / ml, respectively. The half-life (T_1/2) of clarithromycin and its metabolite were 5.3 and 7.7 hours, respectively. When receiving a single dose of clarithromycin in the form of long-acting tablets 1000 mg (2 x 500 mg) C_mOh clarithromycin and its hydroxylated metabolite reached 2.4 μg / ml and 0.67 μg / ml, respectively. T_1/2clarithromycin at a dose of 1000 mg was 5.8 hours, while a similar figure for 14-OH-clarithromycin was 8.9 hours. Time to reach the maximum concentration (TC_mOh) with the administration of both 500 mg and 1000 mg was approximately 6 hours. FROM_mOh 14-OH-clarithromycin did not increase in proportion to the dose of clarithromycin, while T_1/2 both 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-hydroxylated and N-detylated products at high doses indicates a non-linear metabolism of clarithromycin, which becomes more pronounced at high doses.

About 40% of the clarithromycin that enters the body is excreted by the kidneys. The intestine displays about 30%.

Patients

Clarithromycin and its metabolite 14-OH-clarithromycin rapidly penetrate into tissues and body fluids. There are limited patient data indicating that the concentration of clarithromycin in the cerebrospinal fluid for oral administration is negligible (i.e., only 1-2% of the plasma concentration at normal blood-brain barrier permeability). Concentrations in tissues are usually several times higher than in plasma.

Pharmacokinetics in specific patient groups

Dysfunction of the liver

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

Renal impairment

When the renal function is impaired, C_mOh and the minimum concentration (C_min) clarithromycin in blood plasma, T_1/2, area under the pharmacokinetic curve "concentration-time" (AUC) of clarithromycin and its metabolite 14-OH-clarithromycin. 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 metabolite 14-OH-clarithromycin 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).

Contraindications:

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

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

- severe renal failure - creatinine clearance (CC) less than 30 ml / min;

- 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");

- 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 the 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 developed with the use of clarithromycin (see section "Special instructions");

- the period of breastfeeding;

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

- porphyria;

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

Carefully:

- Renal failure of moderate 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 section "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 blockers of "slow" calcium channels, which are 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 the use of clarithromycin during pregnancy and lactation has not been established.

The use of the drug in pregnancy (especially in the first trimester) is possible only in the absence of alternative therapy, and the prospective benefit for the mother exceeds the potential risk to the fetus.

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:

Inside.

Clarithromycin CP tablets can not be broken or chewed, they must be swallowed whole.

Adults and children over 12 years of age: 1 tablet (500 mg) 1 time per day with meals.

In severe infections, the dose is increased to 2 tablets (1000 mg) 1 time per day with meals.

The usual duration of treatment is 5-14 days.

The exception is community-acquired pneumonia and sinusitis, which require treatment for 6 to 14 days.

Renal impairment

In patients with severe renal failure (QC less than 30 ml / min), the use of clarithromycin is contraindicated.In patients with impaired renal function of medium degree (QC from 30 to 60 ml / min), the dose of the drug is halved. The maximum daily dose is 500 mg (1 tablet).

Side effects:

Adverse reactions 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), unknown (side effects from the post-marketing application experience, the frequency can not be estimated based on available data).

Allergic reactions

Often - a rash.

Infrequent anaphylactoid reaction¹, hypersensitivity, dermatitis bullous¹, itching, hives, maculopapular rash.

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

From the nervous system

Often - a headache, insomnia.

Infrequent - loss of consciousness¹, dyskinesia¹, dizziness, drowsiness, tremor, anxiety, increased excitability, cry.

Unknown - cramps,psychotic disorders, confusion, depersonalization, depression, disorientation, hallucinations, dream disturbances ("nightmarish" dreams), paresthesia, mania.

From the skin

Often - intense 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

Infrequent - muscle spasm, musculoskeletal stiffness¹, myalgia.

Unknown - rhabdomyolysis^*, myopathy, increased myasthenia gravis symptoms gravis.

From the digestive system

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

Often - esophagitis¹, gastroesophageal reflux disease, gastritis, proctalgia, stomatitis, glossitis, bloating, constipation, dry mouth, belching, flatulence, cholestasis, hepatitis, including cholestatic and hepatocellular.

Unknown - acute pancreatitis, discoloration of the tongue and teeth, liver failure, cholestatic jaundice.

From the respiratory system

Infrequent - asthma¹, epistaxis, thromboembolism of the pulmonary artery¹.

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 Often - vasodilation.

Infrequent - atrial flutter, lengthening of the interval QT on an electrocardiogram, atrial fibrillation¹, extrasystole¹, cardiac arrest¹.

It is unknown: ventricular tachycardia, including "pirouette" type.

Laboratory indicators

Often - a deviation in the hepatic test.

Infrequent - increasing the concentration of creatinine¹, increased urea concentration¹, a change in the albumin-globulin ratio¹, leukopenia, neutropenia, eosinophilia, thrombocythemia, increased activity: alanine aminotransferase (ALT), aspartate aminotransferase (ACT), gammaglutamyltransferase (GGT), alkaline phosphatase (FA), lactate dehydrogenase (LDH).

It is unknown - agranulocytosis, thrombocytopenia, an increase in the value of the international normalized ratio (MNO), prolongation of prothrombin time, a change in the color of urine, an increase in the concentration of bilirubin in the blood.

General disorders

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

Infectious and parasitic diseases

Infrequently - cellulite¹, candidiasis, gastroenteritis, secondary infections (including vaginal).

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 dry mouth.

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.

* In some reports of rhabdomyolysis clarithromycin was taken together with other drugs, the reception of which is known to be associated with the development of rhabdomyolysis (statins, fibrates, colchicine or allopurinol).

¹ Reports of these adverse reactions were obtained during clinical trials, as well as post-marketing use of clarithromycin in the form of lyophilizate for the preparation of a solution for infusion.

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 an overdose, remove the unabsorbed preparation 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 plasma, which is typical for other drugs of the macrolide group.

Interaction:

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

Cisapride, pimozide

When combined, it is possible to: increase the concentration of cisapride / pimozide, increase the interval QT, the occurrence of cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation, ventricular pirouette tachycardia.

Terfenadine and astemisole

When combined, it is possible: an increase in the concentration of terfenadine / astemizole in the blood, the occurrence of cardiac arrhythmias, an increase in the interval QT, ventricular tachycardia, ventricular fibrillation, and ventricular pirouette tachycardia.

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

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 observe the concentration of the isoenzyme inducer CYP3A In blood plasma, which can increase due to inhibition of the isoenzyme CYP3A clarithromycin. With the combined use of rifabutin and clarithromycin, an increase in the plasma concentration of rifabutin and a decrease in the plasma concentration of clarithromycin with an increased risk of uveitis have been observed.

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.

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.

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 clarithromycin (_Cssmin) 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_max 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 of clarithromycin, a dose reduction 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% (no more than one Clarithromycin CP per day). Patients with severe renal insufficiency (CC <30 mL / min) should not take Clarithromycin SR due to the inability to adequately correct (reduce) the dose (see "Contraindications"). In such patient groups, clarithromycin tablets of conventional release can be used. Ritonavir should not be taken together with clarithromycin in doses exceeding 1 g / day.

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 plasma 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 in patients receiving drugs that are substrates of the isoenzyme CYP3A, especially if the substrate isoenzyme CYP3A has a narrow therapeutic range (for example, carbamazepine), and / or is extensively metabolized by this enzyme. If necessary, dose adjustment of the drug taken together with Clarithromycin SR should be performed, and joint administration of some drugs is contraindicated (see section "Contraindications"). 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: alprazolam, astemizole, carbamazepine, cilostazol, cisapride, ciclosporin, disopyramide, ergot alkaloids, lovastatin, methylprednisolone, midazolam, omeprazole, indirect anticoagulants (for example, warfarin), pimozide, quinidine, rifabutin, sildenafil, simvastatin, tacrolimus, terfenadine, 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 macrolides, 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 plasma concentrations, 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 do not depend on the isoenzyme metabolism CYP3A (eg, fluvastatin).

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.

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.

Sildenafil, tadalafil, vardenafil

Each of these phosphodiesterase inhibitors is metabolized, at least in part, by 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 carbamezepine, 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 (isoenzyme 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 much higher concentrations of tolterodine in the blood plasma. 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 intravenous administration of midazolam was simultaneously administered clarithromycin, 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, an effect on the central nervous system (CNS) is possible, 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 isoenzyme 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 the cases described occurred with patients with renal insufficiency. 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.

The simultaneous use of clarithromycin and colchicine is contraindicated in patients with impaired liver or kidney function (see "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 the concentration of digoxin in the blood plasma in patients, to the development of clinical symptoms of digoxin poisoning, including potentially lethal arrhythmias. With the simultaneous administration of clarithromycin and digoxin, the concentration of digoxin in the blood plasma should be carefully monitored.

Zidovudine

Simultaneous oral administration of clarithromycin tablets of conventional release 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,this interaction is hardly possible with the use of clarithromycin intravenously. Studies of the interaction of clarithromycin in the form of long-acting tablets with zidovudine have not been conducted.

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 plasma 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 daily) may lead to an increase AUC atazanavir by 28%, 2-fold increase AUC clarithromycin, decrease AUC 14-OH-clarithromycin by 70%. Due to the wide therapeutic range of clarithromycin in patients with normal renal function, dose reduction is not required.In patients with moderate renal failure (CK 30-60 ml / min), the dose of clarithromycin should be reduced by 50%. 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_max 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.

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.

In the application of clarithromycin reported hepatic dysfunction (increased activity of "liver" enzymes in the blood plasma, hepatocellular and / or cholestatic hepatitis with jaundice or without). 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 regularly monitor the activity of plasma enzymes.

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, 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 with clarithromycin in 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 and machinery are absent. Consideration should be given to the potential for dizziness, vertigo, confusion and disorientation that may occur with this drug.

Care should be taken when driving vehicles and engaging in other potentially hazardous activities that require increased attention and speed of psychomotor reactions.

When these undesirable phenomena appear, one should refrain from performing these activities.

Form release / dosage:

Tablets of prolonged action, 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, or one bank, along with instructions for medical 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-002449

Date of registration:06.05.2014

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: & nbsp06.05.2014

Illustrated instructions

Instructions

Clarithromycin SR (Clarithromycin SR)