Romiklar - 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 is highly effective 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.

Enterobacteriaceae and Pseudomonas spp. as well as other non-lactose-fermenting 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 (MAC) - complex, including: 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 clarithromycin in clinical practice has not been confirmed by clinical studies, and practical significance remains unclear):

Aerobic Gram-positive microorganisms:

Streptococcus agalactiae

Streptococcus spp. group C, F, G

Streptococcus spp. groups Viridans

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 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:

Healthy

In clinical studies in healthy volunteers clarithromycin were administered once in doses of 75, 125, 250 and 500 mg in a volume of 100 ml in the form of infusion for 30 minutes, as well as in doses of 500, 750 or 1000 mg in 250 ml for more than 60 minutes. The equilibrium maximum concentrations (C_mOh) 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_mOh 14-OH-clarithromycin were 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 final period / 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 increasing doses changed disproportionately, i.e. there was a nonlinear dependence of the values AUC from 22.29 h.mkg / ml to 53.26 h.mkg / ml with the administration of doses of 500-1000 mg for 60 min respectively. Data AUC 14-OH-clarithromycin were varied from 8.16 p.m.kg / ml to 14.76 p.m.kg / ml when the same doses were administered per 60 min infusion.

In 7-day clinical trials clarithromycin were administered multiple times at doses of 125 and 250 mg in the form of 100 ml infusion for more than 30 minutes and at doses of 500 mg and 750 mg in a volume of 250 ml for more than 60 minutes every 12 hours. In this study, the maximum concentration of C_mOh increased from 5.5 μg / ml at a dose of 500 mg to 8.6 μg / ml - 750 mg. In the equilibrium state, the final half-life 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_mOh 14-OH-clarithromycin in the equilibrium state after doses of 500 mg and 750 mg increased from 1.02 μg / ml to 1.37 μg / ml. The final phase of the half-life for this metabolite in groups administered 500 mg or 750 mg was 7.9 hours and 5.4 hours, respectively. The pharmacokinetics of 14-OH-clarithromycin did not depend on the dose.

Patients

Clarithromycin and 14-OH-clarithromycin are well distributed in tissues and body fluids. Concentrations of the drug in human tissues and serum are presented in the table.

CONCENTRATION (a dose of 250 mg after 12 hours)
Type of fabric	Tissue (μg / mg)	Plasma (μg / ml)
Tissue of tonsils	1,6	0,8
Pulmonary tissue	8,8	1,7

Dysfunction of the liver

In patients with moderate and severe impairment of the functional state of the liver, but with preserved renal function, no clarithromycin dose adjustment is required. The equilibrium concentration in blood plasma and the 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 minimum and maximum content of clarithromycin in the blood plasma increases, the half-life, the area under the concentration-time curve of clarithromycin and 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 level of clarithromycin and its 14-OH-clarithromycin in the blood was higher, and excretion is slower than in the group of young people. It is believed that the changes in pharmacokinetics in elderly patients are primarily related to changes in creatinine clearance and the functional state of the kidneys, and not with the age of the patients.

Patients with mycobacterial infections

The equilibrium concentrations of clarithromycin and 14-OH-clarithromycin in patients with HIV infection who received clarithromycin in the form of tablets for 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 maximum concentration of C_mOh usually 2-4 μg / ml and 5-10 μg / ml, respectively. When the drug was used at higher doses, the half-life was longer than in healthy people who received clarithromycin in usual doses. The increase in plasma concentration and the duration of the half-life with the appointment of clarithromycin at higher doses is consistent with the known non-linearity of the pharmacokinetics of the drug.

Indications:

Infectious-inflammatory diseases caused by microorganisms sensitive to clarithromycin:

- infections of the upper respiratory tract (pharyngitis, tonsillitis);

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

- infections of the skin and subcutaneous tissue;

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

- concurrent use of clarithromycin with colchicine in patients with impaired renal and hepatic function who take P-glycoprotein inhibitors or potent inhibitors of the isoenzyme inducer CYP3A4;

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

- Cholestatic jaundice / hepatitis, caused by the use of clarithromycin (in the anamnesis), severe hepatic insufficiency, which occurs simultaneously with renal insufficiency, hypokalemia;

- children's age till 18 years;

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

- the period of breastfeeding.

Carefully:

- Renal failure of severe and moderate severity;

- liver dysfunction;

- myasthenia gravis (possibly increased symptoms);

- simultaneous use with drugs, inducing and metabolizing isoenzyme CYP3A4 (rifampicin, phenytoin, carbamazepine, phenobarbital and others), benzodiazepines (alprazolam, triazolam, midazolam for intravenous administration), antiarrhythmic drugs of class IA and III, blockers of "slow" calcium channels (verapamil, amlodipine, diltiazem), which are metabolized by the inducer of the isoenzyme SURZA4;

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

- pregnancy.

Pregnancy and lactation:

Use in pregnancy 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.

If you need to use the drug during lactation, you should decide whether to abort breastfeeding.

Dosing and Administration:

For intravenous infusion.

The recommended dose of clarithromycin IV is 1.0 g per day, divided into two equal doses, each of which is administered after dissolution in an appropriate solvent drip during 60 min and more.

Intramuscular and bolus administration is prohibited..

Patients with mycobacterial infections

Data on the use of clarithromycin intravenously in patients with reduced immunity are absent. In HIV-infected patients clarithromycin was applied inside.

Adult patients with localized or disseminated infections caused by Mycobacterium chelonae, Mycobacterium fortuitum, Mycobacterium kansasii, Mycobacterium intracellulare, Mycobacterium avium the recommended dose of clarithromycin is 1.0 g per day in two stages of administration.

Patients with impaired renal function (creatinine clearance less than 30 ml / min or a serum creatinine concentration of more than 3.3 mg / 100 ml), the dose is reduced by a factor of 2. Intravenous administration of the drug in severe patients continues for 2-5 days with the subsequent transfer of the patient by the doctor's decision to take clarithromycin inwards.

Preparation of the infusion solution:

1. Add 10 ml of water for injection into a vial containing 500 mg of the drug. To avoid precipitation after dissolution, only water for injection is needed. Do not use solvents containing preservatives or inorganic salts. Each 1 ml of the prepared solution contains 50 mg of clarithromycin. When storing the prepared solution at a temperature of 5 ° C to 25 ° C it is allowed to use it within 24 hours.

2. The prepared solution (500 mg / 10 ml of water for injection) should be mixed with 250 ml of one of the solutions listed below, after which, in the absence of any sediment, intravenously infusion: 5% dextrose solution in Ringer's lactate solution, 5% glucose solution, solution Ringer's lactate, a 5% dextrose solution in 0.3% solution of sodium chloride, a solution of Normosol-M in a 5% dextrose solution, a solution of Normosol-R in a 5% dextrose solution, 5% dextrose solution in a 0.45% solution of sodium chloride, 0.9% sodium chloride solution.

The resulting solution of the drug is recommended to be used immediately after its preparation.

It is forbidden to mix the intravenous infusion solution of clarithromycin withmedicinal or chemical substances due to possible physical or chemical stability of the solution.

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 the post-marketing application experience, the frequency can not be estimated based on available data).

From the cardiovascular system:

often - vasodilation;

rarely - cardiac arrest, atrial fibrillation, lengthening of the interval QT on an electrocardiogram, atrial flutter, extrasystole;

unknown - ventricular tachycardia, including the type of "pirouette", hemorrhage.

From the digestive system:

often - diarrhea, vomiting, dyspepsia, nausea, abdominal pain;

rarely - esophagitis, gastritis, stomatitis, glossitis, constipation, dry mouth, eructation, flatulence;

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

From the nervous system:

often - headache, insomnia;

rarely - dizziness, drowsiness, tremor, anxiety, loss of consciousness, dyskinesia;

unknown - convulsions, psychotic disorders, confusion, depersonalization, depression, disorientation, hallucinations, dreaming ("nightmarish" dreams), mania.

From the musculoskeletal system:

rarely - musculoskeletal stiffness, increased myasthenia gravis symptoms gravis;

unknown - myopathy.

From the urinary system:

unknown - renal failure, interstitial nephritis.

From the respiratory system:

rarely - asthma, thromboembolism of the pulmonary artery.

From the sense organs:

rarely - dysgeusia (distortion of taste sensations), vertigo, hearing impairment, ringing in the ears;

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

Allergic reactions:

often - a rash;

rarely - itching, hives, anaphylactoid reaction, hypersensitivity, bullous dermatitis;

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

Change in laboratory indicators:

often - a deviation in the hepatic test;

rarely - an increase in the concentration of creatinine in the blood,increased urea concentration in the blood, changes in the albumin-globulin ratio, leukopenia, elevated alanine aminotransferase, elevated aspartate aminotransferase;

unknown - agranulocytosis, thrombocytopenia, hypoglycemia, an increase in the international standardized ratio, lengthening prothrombin time, a change in the color of urine.

From the skin and subcutaneous fat:

often - intense sweating;

unknown - acne, purple Shenlaine-Genocha.

From the side of metabolism and nutrition:

rarely - anorexia, decreased appetite.

General disorders:

very often phlebitis at the injection site;

often - pain at the injection site, inflammation at the injection site;

rarely - asthenia.

Infectious and parasitic diseases:

rarely - cellulite, candidiasis, vaginal infection;

it is unknown - pseudomembranous colitis, erysipelas, erythrasma.

Overdose:

In case of an overdose, the use of clarithromycin should be discontinued and an appropriate supportive and symptomatic therapy should be initiated.

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.

Hemodialysis and peritoneal dialysis do not have a significant effect on the level of clarithromycin in the serum, 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 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 astemisole

When combined, it is possible to increase 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.

Ergotamine / dihydroergotamine

When combined, the following effects are possible,related to acute poisoning with drugs of the ergotamine group: 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), 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, there was an increase in the plasma level of rifabutin and a decrease in the serum level 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, 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, lower the level of clarithromycin in the plasma and weaken the therapeutic effect, and at the same time increase the level 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 may decrease with the combined use of clarithromycin and enzyme inducers.

Etravirine

The effect of clarithromycin decreases with 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 (POPPY), the general activity with respect to this pathogenic factor may change, therefore alternative treatment should be considered for the treatment of IAS.

Fluconazole

The simultaneous administration 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 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_mOhclarithromycin 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, 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 simultaneous reception of clarithromycin and some drugs that reduce glucose levels, 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 level is recommended.

Action of clarithromycin on other drugs

Antiarrhythmic drugs (quinidine and disopyramide)

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

Interactions due to the isoenzyme CYP3A

The combined administration of clarithromycin, which is known to inhibit the isozyme isoenzyme inducer CYP3A, and drugs, primarily metabolized by isoenzyme CYP3A, can be associated with a mutual increase in their concentrations, which can enhance or prolong both the therapeutic and side effects. Clarithromycin should be used with caution for patients receiving drugs that are substrates of isoenzyme CYP3A, especially if these drugs have a narrow therapeutic range (for example, carbamazepine), and / or 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 serum 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, oral 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

Like other macrolides, clarithromycin increases concentrations of HMG-CoA reductase inhibitors (eg, lovastatin and simvastatin). Contraindicated in the combined use of clarithromycin with lovastatin or simvastatin (see 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).

Oral anticoagulants

With the simultaneous administration of warfarin and clarithromycin, bleeding and a marked increase in MNO 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 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 carried out through 2D6 isoform of cytochrome P450 (CYP2D6). However, in the part of the population deprived of isoenzyme CYP2D6, metabolism occurs through isoenzyme CYP3A. In this population, suppression of the isoenzyme CYP3A leads to significantly higher serum concentrations of tolterodine. In a population with a low level of metabolism via an isoenzyme inducer CYP2D6, a dose reduction of tolterodine in the presence of inhibitors of the isoenzyme CYP3A, such as clarithromycin.

Triazolobenzodiazepines (for example, alprazolam, midazolam, triazolam)

When joint use of midazolam and clarithromycin in the form of 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 are metabolized by the CYP3A isoenzyme, 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 co-administration, it is recommended to follow the symptoms of the CNS disorder.

Interactions with other drugs

Colchicine

Colchicine is a substrate as an isoenzyme CYP3A, and the carrier protein, P-glycoprotein (Pgp). It is known that clarithromycin and other macrolides inhibit 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. 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.

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 use of digoxin and clarithromycin can also lead to an increase in serum digoxin concentration. Some patients experienced significant clinical symptoms of digoxin poisoning, including potentially fatal arrhythmias. When co-administered with clarithromycin and digoxin, the concentration of digoxin in the serum should be carefully monitored.

Zidovudine

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

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

Such 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 valproate

There are data on the interactions of isoenzyme inhibitors CYP3A (including clarithromycin) with drugs that are not metabolized by isoenzyme CYP3A (phenytoin and valproate). For these drugs, when combined with clarithromycin, the determination of their serum levels is recommended. There are reports of increased serum levels of phenytoin and valproate.

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 for this. Clarithromycin in doses exceeding 1000 mg per day, can not be used in conjunction 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 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, compared with the administration of saquinavir alone. Values AUC and C_mOh clarithromycin were approximately 40% higher than with monotherapy with clarithromycin. When these two drugs are used together for a limited time in the doses / formulations mentioned above, dose adjustment is not required. The results of a study of drug interactions using saquinavir in soft gelatin capsules may not correspond to the effects observed with saquinavir in hard gelatin capsules. The results of the study of drug interactions with monotherapy of saquinavir may not correspond to the effects observed with saquinavir / ritonavir therapy. When taking saquinavir together with ritonavir, the potential effect of ritonavir on clarithromycin.

Verapamil

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

Special instructions:

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

When applying clarithromycin, hepatic dysfunction was reported (elevation of hepatic enzyme levels, hepatocellular and / or cholestatic hepatitis). There are also cases of hepatic insufficiency with a fatal 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 Clostridium difficile. Pseudomembranous colitis caused by Clostridium difficile, It is necessary to suspect all patients experiencing the appearance of diarrhea after using antibacterial agents. After the course of antibiotic therapy, careful medical supervision of the patient is necessary. Cases of pseudomembranous colitis after 2 months after taking antibiotics were described.

In connection with the danger of lengthening the interval QT Clarithromycin is used with caution in patients with coronary heart disease, severe heart failure, hypomagnesemia, severe bradycardia (less than 50 beats / min), and also in patients taking antiarrhythmic drugs 1A grade (quinidine, procainamide) and III class (dofetilide, amiodarone, sotalol). It is necessary to regularly monitor the electrocardiogram for increasing the interval QT. B When combined with warfarin or other indirect anticoagulants, monitoring of MNO and prothrombin time is necessary.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 are most often caused Staphylococcus aureus and Streptococcus pyogenes while both pathogens 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), 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 when it is impossible to apply penicillin treatment.

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

In the case of acute hypersensitivity reactions, such as anaphylactic reaction, Stevens-Jones 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.

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.

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

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

Form release / dosage:

Lyophilizate for the preparation of concentrate for the preparation of a solution for infusions, 500 mg.

Packaging:

500 mg of the active substance in the form of lyophilized mass is placed in a vial of colorless glass, sealed with a stopper of bromobutyl rubber, crimped with an aluminum ring or an aluminum cap "flipoff".

Solvent (water for injection): 10 ml into a vial of colorless glass.

1 bottle with the drug and 1 ampoule with a solvent, along with instructions for use, are placed in a cardboard box.

Storage conditions:

In a dry, the dark place at a temperature of no higher than 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:LP-002487

Date of registration:04.06.2014

The owner of the registration certificate:Mustafa Nevzat Ilach Sanai A.Sh.Mustafa Nevzat Ilach Sanai A.Sh. Turkey

Manufacturer: & nbsp

MUSTAFA NEVZAT ILAC SANAYII, A.S. Turkey

Representation: & nbspASFARMA-ROS LLCASFARMA-ROS LLCRussia

Information update date: & nbsp04.06.2014

Illustrated instructions

Instructions

Romiklar® (Romiclar®)