Clarbact - instructions for use, doses, side effects, contraindications

Excipients: cellulose microcrystalline 175.77 / 203.92 mg, corn starch 33.60 / - mg, pregelatinized starch 35.00 / 70.00 mg, polyvinylpyrrolidone (PVPK-30) 7.50 / 9.45 mg, talc 9.60 / 12.60 mg, sodium carboxymethyl starch 11.20 / 12.60 mg, silicon colloidal dioxide 4.80 / 6.30 mg, stearic acid 9.60 / 12.60 mg, magnesium stearate 4.80 / 6.30 mg;

shell composition: hydroxypropylmethylcellulose 5.69 / 7.27 mg, titanium dioxide 4.70 / 6.27 mg, talc 2.18 / 3.00 mg, polyethylene glycol 6000 1.51 / 2.00 mg, lemon flavor 0.30 / 0 , 50 mg, peppermint powder, 3.63 / 5.00 mg, methylene chloride, isopropyl alcohol.

Description:

Tablets capsular-shaped, coated with a coat from white to almost white, with a dividing risk on one side.

Type of tablet on the break: the core is white or almost white, covered with a shell.

Pharmacotherapeutic group:Antibiotic-macrolide

ATX: & nbsp

J.01.F.A.09 Clarithromycin

Pharmacodynamics:

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

Clarithromycin demonstrated high activity in vitro in relation to both standard laboratory strains of bacteria and those isolated from patients during clinical practice. It shows high activity against many 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 one log₂ breeding.

Clarithromycin in vitro highly active in relation to Legionella pneumophila, Mycoplasma pneumoniae. 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 Enterobacteriaceae and Pseudomonas spp. As well as other non-fermenting lactose, gram-negative bacteria are not sensitive to clarithromycin.

The activity of clarithromycin against most strains listed below microorganisms is proved both in conditions 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,

- Neisseria gonorrhoeae,

- Legionella pneumophila.

Othermicroorganisms:

- Mycoplasma pneumoniae,

- Chlamydia pneumoniae (TWAR).

Mycobacteria:

- Mycobacterium leprae,

- Mycobacterium kansasii,

- Mycobacterium chelonae,

- Mycobacterium fortuitum,

- Mycobacterium avium complex (MAC) - a complex that includes: 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 Helicobacter pylori to clarithromycin was studied on isolates Helicobacter pylori, isolated from 104 patients prior to initiation of drug therapy. In 4 patients, strains resistant to clarithromycin were isolated Helicobacter pylori, in 2 patients - strains with moderate resistance, in the remaining 98 patients, isolates Helicobacter pylori were sensitive to clarithromycin.

Clarithromycin exerts its effect in conditions 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-clarithromycin).

The microbiological activity of the metabolite is the same as that of the starting material, or 2 times weaker in respect of most microorganisms. The exception is Haemophilus influenzae, in relation to which the efficiency of the metabolite is twice as high. The starting compound and its main metabolite exert either an additive or a synergistic effect onHaemophilus influenzae in conditions in vitro and in vivo depending on the strain of bacteria.

Pharmacokinetics:

Clarithromycin is well and rapidly absorbed in the gastrointestinal tract. Absolute bioavailability is about 50%. With repeated administration of a dose of the cumulation drug is practically not detected, and the nature of metabolism in the human body has not changed. The intake of food immediately before taking the drug increased the bioavailability of the drug by an average of 25%. Clarithromycin can be applied before meals or during meals.

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 binding sites. This is observed only at concentrations many times greater than the therapeutic concentration.

Clarithromycin and the metabolite of clarithromycin 14-OH-clarithromycin penetrates well into body fluids and tissues, due to high intracellular concentration, a concentration exceeding the concentration in the blood plasma is reached in the tissues. The highest concentrations were found in the liver and lungs.

When using clarithromycin in a dose of 250 mg 2 times a day, the maximum equilibrium concentration (C_SSmax) clarithromycin and 14-OH-clarithromycin in plasma was achieved after 2-3 days and was 1 μg / ml and 0.6 μg / ml, respectively. The half-life (T_1/2) of clarithromycin and its main metabolite was 3-4 hours and 5-6 hours, respectively.

When using clarithromycin in a dose of 500 mg 2 times a day C_ssmax clarithromycin 14-OH-clarithromycin in plasma was achieved after taking the 5th dose and averaged 2.7-2.9 μg / ml and 0.88-0.83 μg / ml, respectively. T_1/2clarithromycin and its main metabolite was 4.5-4.8 hours and 6.9-8.7 hours, respectively. C_ssmax 14-OH-clarithromycin did not increase in proportion to the dose of clarithromycin, while the half-life of both clarithromycin and its hydroxylated metabolite tended to increase with increasing dosage. Such nonlinear pharmacokinetics of clarithromycin in combination with a decrease in the formation of 14-hydroxylated and N-detylated products at high dosages indicates a non-linear metabolism of clarithromycin, which becomes more pronounced at high dosages.

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

Dysfunction of the liver

In patients with moderate and severe impairment of the functional state of the liver, 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.

Impaired renal function

If the renal function is impaired, the maximum (C_max) 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 was no difference in both groups. Thus, the main effect on the pharmacokinetic parameters of clarithromycin is the function of the kidneys, not age.

Patients with mycobacterial infections

The equilibrium concentrations of clarithromycin and 14-OH-clarithromycin in patients with HIV infection who used clarithromycin in usual doses (500 mg twice a day) were similar to those of 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 1000 mg / day or 2000 mg / day in two doses, the equilibrium values of C_max usually 2-4 μg / ml and 5-10 μg / ml, respectively. When using the drug in more high doses T_1/2compared with that of healthy people who received clarithromycin in usual doses. An increase in plasma concentration and an elongation of the half-life with clarithromycin at higher doses is associated with the non-linear pharmacokinetics of clarithromycin.

Combined treatment with omeprazole

Clarithromycin, 500 mg 3 times a day, in combination with omeprazole at a dose of 40 mg / day contributes to an increase T_1/2 and AUC₀-₂₄ omeprazole. In all patients who received combination therapy, compared with those receiving one omeprazole, there was an increase of 89% AUC_0-₂₄ and by 34% T_1/2 omeprazole. In clarithromycin C_max, FROM_minand AUC_0-∞ respectively, increased by 10%, 27% and 15% respectively% compared with data when only clarithromycin without omeprazole. In the equilibrium state of the concentration of clarithromycin in the gastric mucosa 6 hours after admission in the group receiving the combination, 25 times greater than those, but compared with those receiving one clarithromycin. The concentrations of clarithromycin in the stomach tissues 6 hours after taking 2 drugs were 2 times higher than those obtained in the group of patients receiving one clarithromycin.

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 (MAS)_, HIV-infected patients with lymphocyte counts Cd4 (T-helper lymphocytes) not more than 100 in 1 mm³;

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

- odontogenic infections.

Contraindications:

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

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

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

- simultaneous reception of clarithromycin with ergotamine or dihydroergotamine (see section "Interaction with other medicinal products");

- simultaneous reception of clarithromycin with colchicine;

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

- simultaneous reception of clarithromycin with ticagrelor or ranolazine (see section "Interaction with other medicinal products");

- hypokalemia (risk of lengthening the interval QT);

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

- severe hepatic failure, occurring concomitantly with renal insufficiency;

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

- porphyria;

- the period of breastfeeding;

- age up to 12 years (efficacy and safety not established).

Carefully:

- Renal failure of moderate to severe severity;

- hepatic insufficiency of moderate and severe severity;

- simultaneous reception of clarithromycin with benzodiazepines, such as alprazolam, triazolam, midazolam for intravenous use (see section "Interaction with other medicinal products");

- simultaneous reception of clarithromycin with other ototoxic drugs "especially aminoglycosides (see section" Interaction with other medicinal drugs ");

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

- simultaneous administration with drugs inducing the isoenzyme CYP3A4, for example, rifampicin, phenytoin, carbamazepine, phenobarbital, St John's wort (see "Interaction with other medicinal products");

- simultaneous reception of clarithromycin with statins that do not depend on the metabolism of the isoenzyme CYP3A (for example, fluvastatin) (see the section "Interaction with other medicinal products");

- simultaneous reception with blockers of "slow" calcium channels, which is metabolized by the isoenzyme CYP3A4 (for example, 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 IA class (quinidine, procainamide) and III class (dofetilide, amiodarone, sotalol);

- pregnancy.

Pregnancy and lactation:

The safety of using clarithromycin during pregnancy and breastfeeding has not been established. Application in pregnancy (especially in the first trimester) is possible only in the absence of alternative therapy, and the potential The benefit to the mother exceeds the potential risk to the fetus.

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

Dosing and Administration:

For oral administration. Regardless of food intake.

Adults and children over 12 let: 250 mg of clarithromycin twice a day. In the case of a more severe course of infection, the dose is increased to 500 mg twice a day. The usual duration of treatment is from 5 to 14 days. The exception is community-acquired pneumonia and sinusitis, which require treatment for 6 to 14 days.

Doses for the treatment of mycobacterial infections other than tuberculosis

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

Treatment of disseminated MAC infection in AIDS patients should continue as long as there is clinical and microbiological efficacy, Clarithromycin Combinations with other antimicrobial agents active against these pathogens should also be used. The duration of treatment for other non-tuberculous 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 2 times a day.

With odontogenic infections The dose of clarithromycin is 250 mg 2 times a day for 5 days.

For eradication H. pylori.

In patients with peptic ulcer caused by infection H. pylori, clarithromycin can be used 500 mg twice a day in combination with other antimicrobials and proton pump inhibitors for 7-14 days, in accordance with national and international recommendations for the treatment of infection H. pylori.

Patients with renal insufficiency

Patients with a creatinine clearance greater than 30 mL / min are not required to adjust the dose. Patients with creatinine clearance less than 30 ml / min are prescribed half of the usual dose of clarithromycin, i.e. 250 mg once a day or, with more severe infections, but 250 mg twice a day. Treatment of such patients continues no more than 14 days.

Elderly patients

In elderly patients with severe renal insufficiency, a dose adjustment is necessary. In general, elderly patients may be more prone to effects such as pirouette tachycardia, arrhythmia than younger patients.

Side effects:

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 (adverse reactions from postmarketing experience, frequency can not be estimated from available data).

Allergic reactions: Mr.Often - hypersensitivity, itching, urticaria; Mr.it is known - anaphylactic reaction, angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS-syndrome).

From the nervous system: hasto - headache, insomnia; Mr.Often - dizziness, drowsiness, tremor, anxiety; Mr.it is known - convulsions, psychotic disorders, confusion, depersonalization, depression, disorientation, hallucinations, dreaming ("nightmarish" dreams), paresthesia, mania.

From the skin: hasto - intense sweating; Mr.it is known - acne, hemorrhage.

From the urinary system: nit is known - renal failure, interstitial nephritis.

From the side of metabolism and nutrition: nOften - anorexia, decreased appetite.

From the side of the musculoskeletal system: unknown - myopathy.

From the digestive system: often - diarrhea, vomiting, indigestion, nausea, pain in the abdomen; Mr.Often - gastritis, stomatitis, glossitis, bloating, constipation, dryness of the oral mucosa, eructation, flatulence, cholestasis, hepatitis incl. cholestatic or hepatocellular; Mr.it is known - acute pancreatitis, discoloration of the tongue and teeth, hepatic insufficiency, cholestatic jaundice.

From the sense organs: hasto - dysgeusia, perversion of taste; Mr.Often - vertego, hearing impairment, ringing in the ears; Mr.it is known - deafness, agevzia (loss of taste sensations), parosmia, anosmia.

From the side of the cardiovascular system: nOften - interval lengthening QT on an electrocardiogram, atrial flutter; Mr.it is known - ventricular tachycardia, including the "pirouette" type.

Laboratory indicators: hourshundred - deviation in the hepatic test; Mr.Often - leukopenia, neutropenia, eosinophilia; increased activity in the blood of alanine aminotransferase (ALT), aspartate aminotransferase (ACT), gammaglutamyltransferase (GGT), alkaline phosphatase, lactate dehydrogenase (LDH); Mr.it is known - agranulocytosis, thrombocytopenia, an increase in the value of the international normalized ratio (INR), prolongation of prothrombin time, a change in the color of urine, an increase in the concentration of bilirubin in the blood.

General disorders: infrequently - malaise, asthenia, pain in the chest, chills, fatigue.

Infectious and parasitic diseases: nOften - candidiasis; Mr.it is known - pseudomembranous colitis, erysipelas.

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 of ACT and ALT in blood. There have also been cases of undesirable phenomena with a low occurrence frequency, 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 violations from the gastrointestinal tract.

Treatment: when an overdose should be removed unabsorbed drug from the gastrointestinal tract and conduct symptomatic therapy. Hemodialysis and peritoneal dialysis do not have a significant effect on the concentration of clarithromycin in plasma, 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 and astemizole

With the simultaneous administration 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

With the combined use of clarithromycin with ergotamine or dihydroergotamine, the following effects associated with acute poisoning with drugs of the ergotamine troupe were reported: 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").

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 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 other statins. It is recommended to use statins that do not depend on the isoenzyme metabolism CYP3A (eg, fluvastatin). In case of necessity of joint reception, it is recommended to take the smallest dose of statics. It should monitor the development of signs and symptoms of myopathy.

The effect of other drugs on clarithromycin

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.

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, while increasing the concentration of the 14-OH-clarithromycin metabolite, which is also 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 inducers of cytochrome P450 isoenzymes.

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 Mycobacterium avium complex (MAC), the overall activity against these pathogens may change, therefore, for treatment MAC alternative treatment should be considered.

Fluconazole

It was reported that 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 average value of the minimum equilibrium concentration of clarithromycinCssmin) 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-OH-clarithromycin. Correction of the dose of clarithromycin in the case of concurrent administration of fluconazole is not required.

Ritonavir

It was reported that 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 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 used 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.

There have been reports of cases of hypoglycemia in the joint use of clarithromycin and disopyramide. It is necessary to monitor the concentration of glucose in the blood with the simultaneous use of clarithromycin and disopyramide

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 hypoglycemic drugs (for example, 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.

Interactions caused by the isoenzyme СUR3А

The combined administration of clarithromycin, which is known to inhibit the CYP3A isoenzyme, and drugs primarily metabolized by the CYP3A isoenzyme, 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 these drugs have a narrow therapeutic range (for example, carbamazepine), and / or are extensively metabolized by this isoenzyme. 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 the CYP3A isoenzyme should be carried out.

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 agonists of the isoenzyme CYP3A are the following drugs that are 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 manner through other isoenzymes within the cytochrome P450 system are phenytoin, theophylline and valproic acid.

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

In the study of clarithromycin (500 mg every 8 hours) in healthy adult volunteers in combination with omeprazole (40 mg daily), it was reported that equilibrium plasma concentrations of omeprazole were increased; FROM_max, AUCo-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. 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 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 2D6 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 much higher concentrations of tolterodine in 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 (eg, alprozolam, midazolam, triazolam)

When combined with midazolam and clarithromycin tablets (500 mg twice daily), there was an increase AUC midazolam: 2.7 times after intravenous administration of midazolam and 7 times after oral administration. Simultaneous reception of clarithromycin with midazolam for oral administration is contraindicated. 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 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.

Interactions with other drugs

Aminoglycosides

With the simultaneous use of clarithromycin with other ototoxic drugs, especially aminoglycosides,care must be taken to monitor the function of the vestibular and hearing aids both during therapy and after its termination.

Colchicine

Colchicine is a substrate as an isoenzyme CYP3A, and the carrier protein of the 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 increase in the action of colchicine. It should monitor the development of clinical symptoms of colchicine poisoning. It has been reported cases of colchicine poisoning during its simultaneous administration with clarithromycin, 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. Simultaneous use of clarithromycin and colchicine is contraindicated (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. With the simultaneous administration of clarithromycin and digoxin, the concentration of digoxin in the blood plasma should be carefully monitored.

Zidovudine

Simultaneous reception of tablets of clarithromycin and zidovudine by adult HIV-infected patients can 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. Such an interaction was not observed in HIV-infected children taking a children's suspension of clarithromycin, with zidovudine or dideoxyinosine. Because the clarithromycin can interfere with the absorption of zidovudine when administered simultaneously in adults in adults, this interaction is hardly possible with the use of clarithromycin intravenouslynano.

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 both substrates and inhibitors of the CYP3A isoenzyme. There is evidence of bi-directional interaction of these drugs. The combined use of clarithromycin (500 mg twice daily) and atazanavir (400 mg once per 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 in Atazanavir AUC by 28%. a broad therapeutic range of clarithromycin is reduced in patients with normal renal function.In patients with moderate renal insufficiency (CK 30-60 ml / min), the dose of clarithromycin should be reduced by 50%.In patients with SC less than 30 ml / min, the dose of clarithromycin should be reduced by 75%. 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 is 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 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. It was reported that the 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_mOh saquinavir by 177% and 187% respectively, in comparison 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 a colony with an increased number of insensitive bacteria and fungi. When superinfection is necessary to appoint appropriate therapy.

Hepatotoxicity

With the use of clarithromycin, hepatic dysfunction was reported (increased activity of hepatic enzymes in the blood, 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 collapsed with the presence of serious concomitant diseases and / or simultaneous use of other medicines. 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 disease, regular monitoring of enzymes in the blood plasma is necessary.

Interval lengthening QT

The use of clarithromycin is associated with lengthening of the interval QT, in rare cases there was also the occurrence of arrhythmia. There are spontaneous reports of cases of tachycardia such as "pirouette" in patients who took clarithromycin. There are reports of deaths. Clarithromycin should be used with caution in patients with coronary heart disease (CHD), severe heart failure, hypomagnesemia, severe bradycardia (less than 50 beats / min), and 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. In general, elderly patients may be more prone to such effects as lengthening the interval QT under the action of clarithromycin.

Pneumonia

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

Infections of the skin and soft tissues

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.

Diarrhea caused by Clostridium difficile

In the treatment of almost all antibacterial agents, including clarithromycin, cases of diarrhea caused by Clostridium difficile (CDAD), the severity of which can range from mild to life-threatening. Antibiotic drugs can change the normal intestinal microflora, which can lead to growth C. difficile.

FROM. difficile toxins A and B, which contribute to the development of CDAD. Hypertoxin, which produces strains C. difficile, leads to an increase in morbidity and mortality. There may be a need for colectomy. CDAD 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, since cases of development CDAD 2 months after taking antibiotics.

In case of suspicion or confirmation of availability CDAD therapy with clarithromycin is discontinued. It is necessary to carry out therapy aimed at replenishment of fluid loss and electrolyte balance; food enriched with protein; treatment with antibiotics, to which strains are sensitive C. difficile and examination by a surgeon, based on clinical indications. Contraindicated use of drugs that inhibit intestinal motility,

Hypersensitivity reactions

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), you must immediately stop taking clarithromycin and begin appropriate therapy.

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

It is also necessary to take into account the possibility of developing cross-resistance to clarithromycin and other antibiotics of the macrolide group, as well as to lincomycin and lindamycin.

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

Form release / dosage:

The coated tablets are 250 mg and 500 mg.

Packaging:

For 4 or 10 tablets in aluminum foil / PVC blisters.

1 blister for 10 tablets or 1, 7 or 10 blisters for 4 tablets together with instructions for use are placed in a cardboard box.

Storage conditions:

In a dry, dark place at a temperature below 25 ° C.

Keep out of the reach of children.

Shelf life:

2 of the year.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:П N015373 / 01

Date of registration:29.12.2008 / 06.03.2015

Expiration Date:Unlimited

The owner of the registration certificate:Ipka Laboratories Ltd.Ipka Laboratories Ltd. India

Manufacturer: & nbsp

IPCA LABORATORIES, Ltd. India

Representation: & nbspIPKA LABORATORIES LTD. IPKA LABORATORIES LTD. India

Information update date: & nbsp11.01.2018

Illustrated instructions

Instructions

Clarcart (Clarbact)