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

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

Clarithromycin showed high activity in vitro against standard and isolated cultures of bacteria. 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 less than the erythromycin MPC.

Clarithromycin in vitro highis effective in respect Legionella pneumophila, Mycoplasma pneumoniae. Has a bactericidal effect against Helicobacter pylori, this activity of clarithromycin is higher at neutral pH than with acid.

Enterobacteriaceae and Pseudomonas spp. As well as other non-fermenting lactose, gram-negative bacteria are not sensitive to clarithromycin.

Shown, that clarithromycin has antibacterial action against the following pathogens:

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

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

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

- mycobacteria: Mycobacterium leprae, Mycobacterium kansasii, Mycobacterium chelonae, Mycobacterium fortuitum, Mycobacterium avium complex (MAO-complex, which 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 H. pylori to clarithromycin was studied on isolates H. pylori, isolated from 104 patients, before the beginning of drug therapy. In 4 patients, strains resistant to clarithromycin were isolated H. pylori, in 2 strains with intermediate resistance, in the remaining 98 patients, isolates H. 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;

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

- anaerobic Gram positivee 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 1-2 times weaker in respect of most microorganisms. The exception is H. influenzae, in relation to which the efficiency of the metabolite is twice as high. The starting material and its main metabolite exert either an additive or a synergistic effect on H. influenzae in conditions in vitro and in vivo depending on the culture of the bacteria.

Pharmacokinetics:

Clarithromycin was administered to healthy volunteers for 30 min, and once in doses of 75, 125, 250, 500 mg in a volume of 100 ml in the form of infusion over 30 min, and at doses of 500, 750 or 1000 mg in a volume of 250 ml during more than 60 min. The equilibrium maximum concentrations (C max) of clarithromycin were from 5.16 μg / ml to 9.40 μg / ml after infusion of 500 mg and 1000 mg of clarithromycin for 60 min, respectively. FROM max 14-OH-clarptromomcin was 0.66 μg / ml after infusion of 500 mg and 1.06 μg / ml after administration of 1000 mg of clarithromycin for 60 min.

In the equilibrium state, the terminal half-life of clarithromycin depends on the dose of the drug and is from 3.8 hours to 4.5 hours when doses from 500 mg to 1000 mg are administered per 60 minutes, respectively. The half-life of 14-OH-clarithromycin after the administration of the same doses of 500 mg and 1000 mg in 60 minutes is 7.3 hours and 9.3 hours, respectively, which confirms about the same dependence that increases with an increase in the dose of clarithromycin.

In the equilibrium state, the area under the "concentration-time" curve (AUC) with an increase in the dose varies disproportionately, i.e. there is a nonlinear dependence of the value AUC from 22.29 h x mcg / ml to 52.26 h x mcg / ml with doses of 500-1000 mg for 60 min, respectively. Data AUC 14-OH-clarithromycin is varied from 8.16 h x μg / ml to 14.76 h ug / ml when the same doses are administered in 60 min.

Clarithromycin was administered to healthy volunteers multiple times at doses of 125 and 250 mg in totalb100 ml infusion for more than 30 minutes, and at doses of 500 and 750 mg in a volume of 250 ml for more than 60 minutes every 12 hours. The equilibrium values of C_maxIncreased from 5.5 μg / ml at a dose of 500 mg to 8.6 μg / ml - 750 mg. In the equilibrium state, the terminal elimination half-life when administered at a dose of 500 mg and 750 mg of clarithromycin after more than 60 minutes of infusion was 5.3 hours and 4.8 hours, respectively. FROM_max 14-OH-Clarithromycin in the equilibrium state when applied at a dose of 500 mg and 750 mg increased from 1.02 μg / ml to 1.37 μg / ml. The terminal phase of the half-life for this metabolite in healthy volunteers administered 500 mg and 750 mg was 7.9 hours and 5.4 hours, respectively. The pharmacokinetics of 14-OH-clarithromycin is dose independent.

Clarithromycin and its metabolite are well distributed in tissues and body fluids.

Tissue concentrations in the serum of patients are presented in the table:

Concentration (a dose of 250 mg after 12 hours)
Type of fabric	Cloth (μg / g)	Serum (μg / ml)
Tonsils	1,6	0,8
Lungs	8,8	1,7

Dysfunction of the liver

In patients with moderate to severe hepatic / renal function impairment, clarithromycin dose adjustment is not required. The equilibrium concentration in the blood plasma and the systemic clearance of clarithromycin do not differ from these indices in healthy volunteers. The equilibrium concentration of 14-OH-clarithromycin in people with hepatic impairment is lower, than in healthy people.

Renal impairment

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

Indications:

Infectious-inflammatory diseases caused by microorganisms sensitive to clarithromycin:

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

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

- infections of the skin and soft tissues (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.

Contraindications:

- Simultaneous use of clarithromycin with the following drugs: astemizole, cisapride, pimozide, terfenadine, ergotamine, dihydroergotamine, lovastatin, simvastatin, midazolam (for oral administration) (see section "Interaction with other drugs");

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

- simultaneous application with colchicine;

- simultaneous application with ticagrelor or ranolazine;

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

- hypokalemia;

- patients with a history of cholestatic jaundice / hepatitis, developed with the use of clarithromycin;

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

- the period of breastfeeding;

- age to 18 years (efficacy and safety not established).

Carefully:

- Renal and / or liver failure of moderate to severe severity, simultaneous use with benzodiazepines (alprazolam, triazolam, midazolam for intravenous administration), isozyme inducing drugs CYP3A4 (rifampicin, phenytoin, carbamazepine, phenobarbital, St. John's wort), blockers of "slow" calcium channels, which are metabolized by isoenzyme CYP3A4 (e.g., verapamil, amlodipine, diltiazem);

- with drugs that are metabolized by isoenzyme CYP3A4 (carbamazepine, cilostazol, ciclosporin, disopyramide, methylprednisolone, omeprazole, indirect anticoagulants, quinidine, rifabutin, sildenafil, tacrolimus, vinblastine);

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

- simultaneous application with other ototoxic drugs, especially aminoglycosides; simultaneous use with statins that do not depend on the isoenzyme metabolism CYP3A (eg, fluvastatin).

Pregnancy and lactation:

The safety of using clarithromycin during pregnancy and lactation is not established.

Application in pregnancy (especially in the first trimester) is possible in those cases where there is no safer alternative, and the risk to the mother associated with the diseases themselves exceeds the potential risk to the fetus.

Clarithromycin is excreted in breast milk. If it is necessary to use during lactation, breastfeeding should be discontinued.

Dosing and Administration:

Intravenously drip.

Intramuscular administration of the drug and application in the form of a bolus is prohibited.

Adults: the recommended dose of clarithromycin intravenously is 1 g day divided into two equal doses, each of which is administered after dissolution in a suitable solvent by dropping for 60 min or more.

To patients of advanced age the drug is administered in the same doses as in adults.

Patients with mycobacterial infections: Data on the use of clarithromycin intravenously in patients with reduced immunity are not available. In HIV-infected patients clarithromycin was applied inside. Adult patients with localized or disseminated infections caused by Mycobacterium avium, Mycobacterium inlracellulare, Mycobacterium chelonae, Mycobacterium fortuitum, Mycobacterium kansasii the recommended dose of clarithromycin is 1 g per day and two administrations.

Intravenous administration of the drug continues for 2-5 days with the subsequent transfer of the patient to the use of clarithromycin inward.

Patients with impaired renal function (creatinine clearance less than 30 ml / min), the dose of clarithromycin is reduced by a factor of 2 from the usual recommended dose.

Preparation of a solution for infusions

Add 10 ml of sterile water for injection into a vial of 500 mg of lyophilized powder. It is recommended to use only sterile water, because Another solvent may cause precipitation. Do not use solvents containing preservatives or inorganic salts.

Note: the reconstituted solution of the preparation contains a sufficient amount of preservative and has a concentration of 50 mg / ml of clarithromycin.

The reconstituted solution of the drug should be used immediately after its preparation. Do not apply the drug immediately after obtaining its reconstituted solution, it is recommended to keep it for no more than 24 hours at a temperature of 2 ° C to 8 ° C in aseptic conditions.

Before administration, the reconstituted solution of the drug (500 mg in 10 ml of water for injection) should be added to not less than 250 ml of one of the following solutions for intravenous administration: 5% dextrose solution in Ringer's lactate solution, 5% dextrose solution, Ringer's lactate solution, 5% dextrose solution in 0.3% sodium chloride solution, 5% dextrose solution in 0.45% sodium chloride solution, 0.9% sodium chloride solution.

The resulting solution of the drug is recommended to be used immediately after its preparation. If the resulting solution can not be used immediately, it should be stored under aseptic conditions. If the solution is not used immediately, it is recommended to keep it for no more than 24 hours at a temperature of 2 ° C to 8 ° C in aseptic conditions. After this period, further storage and use of the solution of clarithromycin IV is not recommended.

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

From the cardiovascular system: often - vasodilation; infrequently - cardiac arrest, atrial fibrillation, QT interval elongation on electrocardiogram, atrial flutter, extrasystole; unknown - ventricular tachycardia, including the type of "pirouette", hemorrhage.

From the digestive system: often - diarrhea, vomiting, dyspepsia, nausea, abdominal pain; infrequently - esophagitis, gastritis, stomatitis, glossitis, constipation, dry mouth, eructation, flatulence; unknown - acute pancreatitis, discoloration of the tongue and teeth, hepatic insufficiency with fatal outcome, cholestatic jaundice.

From the nervous system: often - dysgeusia, headache, perversion of taste, insomnia; infrequently - dizziness, drowsiness, tremor, anxiety, loss of consciousness, dyskinesia; unknown - convulsions, psychotic disorders, mania, paresthesia, confusion, depersonalization, depression, disorientation, hallucinations, dreaming ("nightmarish" dreams).

From the musculoskeletal system: infrequent - musculoskeletal stiffness; unknown - myopathy.

From the urinary system: unknown - renal failure, interstitial nephritis.

From the respiratory system: infrequently - asthma, thromboembolism of the pulmonary artery.

From the sense organs: infrequently - vertigo, hearing impairment, ringing in the ears; unknown - deafness, agevzia (loss of taste sensations), parosmia, anosmia.

Allergic reactions: often - a rash; infrequently - itching, hives, anaphylactoid reaction, hypersensitivity, bullous dermatitis; unknown - anaphylactic reaction, angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS-syndrome).

Change in laboratory indicators: often - a deviation in the hepatic test; infrequently, an increase in the concentration of creatinine in the blood, an increase in the concentration of urea and bilirubin in the blood, a change in the albumin-globulin ratio, leukopenia, increased activity of alanine aminotransferase, aspartate aminotransferase; unknown - agranulocytosis, thrombocytopenia, hypoglycemia, an increase in the international standardized ratio (INR), prolongation of prothrombin time, a change in the color of urine.

From the skin and subcutaneous fat: often - intense sweating; it is unknown - acne.

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

General disorders: very often - phlebitis at the injection site; often - pain at the injection site, inflammation and injection site; infrequently, asthenia.

Infectious and parasitic diseases: infrequently - cellulite, candidiasis, vaginal infection; unknown - 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 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: in 2-3% of patients who received clarithromycin in a dose of 1000 mg daily, there was a significant increase in the activity of AST 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: increased manifestations of the described side effects, disorders of the digestive system.

There are no reports of cases of overdose with intravenous administration of clarithromycin. In case of an overdose, there may be an increase in manifestations, described dose-dependent side effects;

Treatment: the introduction of the IV drug should be discontinued and appropriate symptomatic therapy should be started. Clarithromycin is not removed by hemo- or peritoneal dialysis.

Interaction:

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

Cisapride and 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 astemizole

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

Ergotamine / dihydroergotamine

When combined, 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.

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 CYP3A - an 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. The following drugs have a proven or suspected effect on the concentration of clarithromycin; In the case of their joint use with clarithromycin, vines may need to be adjusted or alternatives can be switched to alternative treatment.

Efavirenz, nevirapine, rifampicin, rifabutin and rifapentin

Strong inducers of the cytochrome system of the isoenzyme 1450, such as efavirenz, nevirapine, rifampicin, rifabutin and rifapentin can accelerate the metabolism of clarithromycin and thus reduce the concentration of clarithromycin in the plasma and weaken the therapeutic effect, and at the same time increase the concentration of 14-OH-clarithromycin metabolite, also being microbiologically active. Since the microbiological activity of clarithromycin and 14-OH-clarithromycin is different for different bacteria,The therapeutic effect can be reduced by 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 with respect to the complex Mycobacterium avium (MAC), the overall activity against this microorganism may change, therefore alternative treatment should be considered for the treatment of IAS.

Fluconazole

The simultaneous use of fluconazole at a dose of 200 mg daily and clarithromycin 500 mg twice daily in 21 healthy volunteers resulted in an increase in the minimum mean equilibrium concentration of clarithromycin (C_min) and AUC by 33% and 18%, respectively. At the same time, the combined use did not significantly affect the average equilibrium concentration of the active metabolite of 14-OH-clarithromia. Correction of the dose of clarithromycin in the case of concomitant use of fluconazole is not required.

Ritonavir

A pharmacokinetic study showed that the combined use 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. When combined use of ritonavir C_max clarithromycin increased by 31%, C_max 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, dosage 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: in case of creatinine clearance of 30-60 ml / min, the dose of clarithromycin should be reduced by 50%; when creatinine clearance is less than 30 ml / min, the dose of clarithromycin should be reduced by 75%. Ritonavir should not be taken together with clarithromycin in doses exceeding 1 g / day.

Oral hypoglycemic agents / insulin

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

Action of clarithromycin on other drugs

Antiarrhythmic drugs (quinidine and disopyramide)

Possible occurrence of ventricular tachycardia such as "pirouette" with the joint appointment of clarithromycin and quinidine or disopyramide. With the simultaneous use of clarithromycin with these drugs should regularly monitor the electrocardiogram for increasing the interval QT, and the serum concentrations of these drugs should be monitored.

When postregistered use, cases of development of hypoglycemia with simultaneous use of clarithromycin and disopyramide were reported. It is necessary to monitor the concentration of glucose in the blood with the simultaneous use of clarithromycin and disopyramide.

Interactions caused by isoenzymes of SURZA

The combined use of clarithromycin, which is known to inhibit isoenzymes CYP3A, and drugs primarily metabolized by isoenzymes of CUR3A, can be associated with a mutual increase in their concentrations, which can enhance or prolong both the therapeutic and side effects. Clarithromycin should be administered with caution to patients receiving drugs that are substrates of the isoenzyme CUR3A, especially if the substrate isoenzyme CYP3A has a narrow therapeutic range (for example, carbamazepine), and / or is extensively metabolized by this enzyme. If necessary, a dose adjustment of the drug taken with clarithromycin should be performed. Also, if possible, monitoring of the serum concentration of drugs, primarily metabolized by the isoenzyme СUR3A, should be carried out. Metabolism of the following drugs / classes is carried out by the same isoenzyme CUR3A, that 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 manner through other isoenzymes within the cytochrome isoenzyme 1450 system, phenytoin, theophylline and valproic acid.

Simultaneous use of drugs astemizole, cisapride, ergot alkaloids, lovastatin, simvastatin, pimozide, terfenadine with clarithromycin is contraindicated.

Inhibitors of HMG-Co A-reductase

Like other macrolides, clarithromycin increases concentrations of HMG-CoA reductase inhibitors (eg, lovastatin and simvastatin). Contraindicated the joint use of clarithromycin with lovastatin or simvastatin (see the section "Contraindications"), Patients should be examined to exclude signs and symptoms of myopathy. There are rare reports of the development of rhabdomyolysis in patients who received therapy with atorvastatin or rosuvastatin in combination with clarithromycin. When combined therapy with clarithromycin should be used atorvastatin or rosuvastatin in the minimum possible doses or use statins that do not depend on the isoenzyme metabolism CYP3A (eg, fluvastatin or pravastatin).

Indirect anticoagulants

With the combined use of warfarin and clarithromycin, bleeding and a marked increase in INR and prothrombin time are possible. Regularly monitor MNO and prothrombin time.

Omeprazole

Clarithromycin (500 mg every 8 hours) was tested in healthy adult volunteers in combination with omeprazole (40 mg daily).In the joint appointment of clarithromycin and omeprazole, equilibrium plasma concentrations of omeprazole were increased (C_max, AUC_0-24 and T1/2 increased by 30%, 89% and 34% respectively). The mean pH of the stomach for 24 hours was 5.2 with omeprazole alone and 5.7 with omeprazole in conjunction with clarithromycin.

Sildenafil, tadalafil and vardenafil

Each of these phosphodiesterase inhibitors is metabolized, at least in part, by the participation of an isoenzyme CYP3 A. 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 prescribing these drugs together with clarithromycin, one 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 carried out through 2D6 isoform of cytochrome isoenzyme 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 significantly higher serum concentrations of tolterodine. In a population with a low concentration 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, newts)

With the joint administration of 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. It is necessary to avoid joint oral administration of midazolam and clarithromycin. If intravenous administration of midazolam is simultaneously assigned clarithromycin, the patient's condition should be carefully monitored for possible dose adjustment. The same precautions should also be applied to other benzodiazepines that metabolize 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, exposure to the central nervous system (DPS) is possible, for example, drowsiness and confusion. In this regard, in the case of co-administration, 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, P-glycoprotein (Pgp). It is known that clarithromycin and other macrolides inhibit isoenzyme CYP3A and Pgp. When combined with clarithromycin and colchicine, inhibition Pgp and / or isoenzyme CYP3A can lead to an increase in the action of colchicine.

Simultaneous use with colchicine is contraindicated.

Post-marketing reports on cases of colchicine poisoning with its simultaneous use 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.

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

Digoxin

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

Зidovudine

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

Because the clarithromycin influences the absorption of zidovudine by oral administration, 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 unlikely to be possible with the use of clarithromycin IV.

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 that their serum concentration be determined. There are reports of increased serum concentrations of phenytoin and valproic acid.

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, patients who have normal renal function do not need a dose reduction. In patients with moderate renal insufficiency (creatinine clearance 30-60 ml / min), the dose of clarithromycin should be reduced by 50%. In patients with creatinine clearance less than 30 ml / min, the dose of clarithromycin should be reduced by 75% using the appropriate form of clarithromycin. Clarithromycin in doses exceeding 1000 mg per day, can not be used, before writing the isoenzyme CYP3A4, isoenzyme CYP2D6 together with protease inhibitors.

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. Simultaneous administration 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, compared with saquinavir alone. Values AUC and C_mOh clarithromycin were approximately 40% higher than with monotherapy with clarithromycin. If these two drugs are co-administered 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 monotherapy of saquinavir may not correspond to the effects observed with saquinavir / ritonavir therapy. When saquinavir is used together with ritonavir, the potential effect of ritonavir on clarithromycin.

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.

Special instructions:

Prolonged 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, hepatic dysfunction was reported (increased hepatic enzyme concentrations, hepatocellular and / or cholestatic hepatitis). There are also cases of hepatic insufficiency with a legal outcome, mainly associated with the presence of serious co-morbidities and / or simultaneous use of other drugs. If there are signs of hepatitis such as anorexia, jaundice, darkening of the urine, pruritus, tenderness of the abdomen during palpation, it is necessary to immediately stop the treatment with clarithromycin.

In the presence of chronic liver diseases it is necessary to carry out regular monitoring of serum enzymes.

In the treatment of nearly all antibacterial agents, including clarithromycin, described cases of pseudomembranous colitis, the severity of which can range from mild to life-threatening. Antibacterial drugs can damage the normal intestinal microflora, which can lead to growth C. difficile.

Pseudomembranous colitis caused by Clostridium difficile, It is necessary to suspect all patients experiencing the appearance of diarrhea after using antibacterial agents.After the course of antibiotic therapy, careful medical supervision of the patient is necessary. The cases of development of pseudomembranous colitis after 2 months after the application of antibiotics were described. The drug is 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 1A (quinidine, procainamide) and III class (dofetilide, amiodarone, sotalol). With these conditions and with the simultaneous use of clarithromycin with these drugs, the electrocardiogram should be monitored regularly to increase the interval QT.

It is possible to develop cross-resistance to clarithromycin and other antibiotics of the macrolide group, as well as to lincomycin and clindamycin. Given the growing resistance Streptococcus pneumoniae to macrolides, it is important to conduct sensitivity testing in the appointment of clarithromycin to patients with community-acquired pneumonia. With hospital pneumonia clarithromycin should be used in combination with appropriate antibiotics.

Infections of the skin and soft tissues of minor and moderate severity more often all caused Staphylococcus aureus and Streptococcus pyogenes while both the pathogen can be resistant to macrolides. Therefore, it is important to carry out a sensitivity test.

When beta-lactam antibiotics are contra-indicated (for example, with allergies), you can use other antibiotics, such as clindamycin, as antibiotics of the first choice.

Macrolides can be used for infections caused by Corynebacterium minutissimum, diseases acne vulgaris and erysipelas, as well as in those 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), it is necessary to immediately stop using clarithromycin and begin appropriate therapy.

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

Data on the effect of clarithromycin on the ability to drive vehicles and mechanisms, no. 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.

Form release / dosage:

Lyophilizate for solution for infusion, 500 mg.

Packaging:

For 500 mg of active ingredient in a glass bottle of colorless glass I of hydrolytic class, sealed with a stopper of bromobutyl rubber and crimped with an aluminum cap.

On 1 bottle together with the instruction on application place in a pack a cardboard.

For hospitals: 5, 10, 48 bottles, together with an equal number of instructions for use, are placed in a cardboard box.

Storage conditions:

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

Keep out of the reach of children.

Shelf life:

4 years.

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

Terms of leave from pharmacies:On prescription

Registration number:LP-002904

Date of registration:12.03.2015 / 06.07.2015

Expiration Date:12.03.2020

The owner of the registration certificate:JODAS EKSPOIM, LLC JODAS EKSPOIM, LLC Russia

Manufacturer: & nbsp

JODAS EXPOIM, Pvt. Ltd. India

Representation: & nbspJodas Expoim, Open CompanyJodas Expoim, Open Company

Information update date: & nbsp24.01.2018

Illustrated instructions

Instructions

Clarithromycin-J (Clarithromycin-DJ)