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

Excipients: carbomer (carbopol 974P) 75.0 mg, povidone K90 17.5 mg, hypromelose phthalate 152.1 mg, castor oil 16.1 mg, silicon dioxide 5.0 mg, maltodextrin 285.7 mg, sucrose 2748.3 mg, titanium dioxide 35.7 mg, xanthan gum 3.8 mg, fruit flavoring 35.7 mg, potassium sorbate 20.0 mg, citric acid anhydrous 4.2 mg.

Description:

White or almost white granular powder with a fruity aroma. When shaken with water, a white or almost white opaque suspension with a fruity aroma.

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 showed high activity in vitro in relation to both standard laboratory strains of bacteria and those isolated from patients in the course of 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 per log₂breeding.

Clarithromycin in vitro highly active in relation to Legionella pneumophila, Mycoplasma pneumoniaeIt 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-lactose-fermenting gram-negative bacteria, are not sensitive to clarithromycin.

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

Aerobic Gram-positive microorganisms

Staphylococcus aureus

Streptococcus pneumoniae

Streptococcus pyogenes

Listeria monocytogenes

Aerobic Gram-negative microorganisms

Haemophilus influenzae

Haemophilus parainfluenzae

Moraxella catarrhalis

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 cases - strains with moderate resistance, in the remaining 98 patients, isolates H.pylori were sensitive to clarithromycin. Clarithromycin has an effect 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-positive microorganisms

Clostridim 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 strain of bacteria.

Pharmacokinetics:

Suction

The first data on pharmacokinetics were obtained in the study of clarithromycin tablets. The drug is rapidly absorbed in the gastrointestinal tract. Absolute bioavailability of 500 mg of clarithromycin tablets is approximately 50%. Food somewhat delayed the onset of absorption and the formation of the active metabolite of 14-OH-clarithromycin, but did not affect the bioavailability of the drug.

Distribution, metabolism and excretion

In vitro

In studies in vitro Clarithromycin binding to plasma proteins averaged about 70% at clinically significant concentrations from 0.45 to 4.5 μg / ml.

Healthy

Bioavailability and pharmacokinetics of clarithromycin suspension were studied in healthy adults and children. With a single admission in adults, the bioavailability of the suspension was equivalent to that for tablets (in both cases, the dose was 250 mg) or slightly higher. As in the case of tablets, food somewhat delayed the absorption of the clarithromycin suspension, but did not affect the overall bioavailability of the drug. The maximum concentration (C_mOh), the area under the "concentration-time" curve (AUC) and half-life (T_1/2) of clarithromycin were 0.95 μg / ml, 6.5 μg.h / ml and 3.7 hours, respectively, when taking a child's suspension (after a meal), and 1.1 mg / ml when taking a 250 mg tablet (on an empty stomach) 6.3 μg.h / ml and 3.3 hours, respectively.

When receiving a clarithromycin suspension at a dose of 250 mg every 12 hours in adults, the equilibrium concentrations in the blood were reached by taking a fifth dose. The pharmacokinetics parameters were as follows: C_mOh- 1.98 μg / ml, AUC - 11.5 μg.h / ml, time to reach the maximum concentration (T_mOh) - 2.8 hours and T_1/2 - 3.2 hours for clarithromycin and 0.67, 5.33, 2.9 and 4.9 for 14-OH-clarithromycin, respectively.

In healthy people, serum concentrations reached a maximum within 2 hours after ingestion on an empty stomach.When taking the drug in the form of tablets at a dose of 250 mg every 12 hours, the peak equilibrium concentrations of clarithromycin in the blood serum were achieved within 2-3 days and were approximately 1 μg / ml. Appropriate peak concentrations for a dose of 500 mg every 12 hours were from 2 μg / ml to 3 μg / ml.

The half-life of clarithromycin was 3-4 hours with 250 mg tablets taken every 12 hours, but increased to 5-7 hours after administration of 500 mg every 12 hours. The maximum equilibrium concentration of the main metabolite, 14-OH-clarithromycin, is about 0.6 μg / ml, and the elimination half-life when taken at a dose of 250 mg every 12 hours is 5-6 hours. When taking clarithromycin at a dose of 500 mg every 12 hours, the maximum equilibrium concentration of 14-OH-clarithromycin is slightly higher (up to 1 μg / ml), and the elimination half-life is about 7 hours. When both doses are used, the equilibrium concentrations of the metabolite are usually achieved within 2-3 days. When using clarithromycin at a dose of 250 mg every 12 hours, approximately 20% of the dose is excreted by the kidneys unchanged. When taking clarithromycin at a dose of 500 mg every 12 hours, approximately 30% of the dose is removed by the kidneys unchanged.The renal clearance of clarithromycin is substantially independent of the dose and approximately equal to the normal glomerular filtration rate. The main metabolite, determined in urine, is 14-OH-clarithromycin, the proportion of which is 10-15% from the dose (250 or 500 mg every 12 hours).

Patients

Clarithromycin and its metabolite 14-OH-clarithromycin rapidly penetrate into tissues and body fluids. Tissue concentrations are usually several times higher than serum concentrations. The table gives examples of tissue and serum concentrations:

Concentrations (250 mg every 12 hours)
Type of fabric	Tissue (μg / g)	Serum (μg / ml)
Tonsils	1,6	0,8
Lungs	8,8	1,7

In children who needed oral antibiotic treatment, clarithromycin showed high bioavailability, while the profile of his pharmacokinetics was similar to that of adults taking the same dosage form. The drug is quickly and well absorbed in children. Food somewhat delays the absorption of clarithromycin, but does not significantly affect its bioavailability or pharmacokinetic properties. The equilibrium parameters of the pharmacokinetics of clarithromycin achieved after 5 days (ninth dose) were as follows: FROM_max - 4.60 μg / ml, AUC - 15.7 μg.h / ml and T_mOh - 2.8 hours; the corresponding values for the metabolite of 14-OH-clarithromycin were 1.64 μg / ml, 6.69 μg.h / ml and 2.7 hours, respectively. The calculated half-lives of clarithromycin and its metabolite are 2.2 and 4.3 hours, respectively.

In patients with otitis media, 2.5 hours after receiving the fifth dose (7.5 mg / kg twice daily), the mean concentrations of clarithromycin and its metabolite in the middle ear fluid were 2.53 and 1.27 μg / g. Concentrations of the drug and its metabolite were twice as high as serum concentrations.

Impaired liver function

The equilibrium concentrations of clarithromycin in patients with impaired hepatic function do not differ from those in healthy people, while the concentrations of 14-OH-clarithromycin were lower. The decrease in the formation of 14-OH-clarithromycin in patients with impaired liver function was at least partially offset by an increase in renal clearance of clarithromycin in comparison with that in healthy individuals.

Impaired renal function

The pharmacokinetics of clarithromycin also changed in patients with impaired renal function who received the drug in repeated doses of 500 mg.In such patients, plasma concentrations, half-life, maximum concentration (C_mOh), the minimum concentration (C_max) and AUC clarithromycin and its metabolite were higher than in healthy people. The deviations of these parameters correlated with the degree of renal failure: with more pronounced impairment of renal function, the differences were more significant (see section "Dosing and Administration").

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 for renal clearance of creatinine (CC), 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 received clarithromycin in usual doses (tablets for adults, suspension for children), were similar to those in healthy people. However, when taking clarithromycin in higher doses,which may be required for the treatment of mycobacterial infections, the concentration of antibiotic can significantly exceed the usual.

In children with HIV infection, who took clarithromycin in a dose of 15-30 mg / kg / day in two doses, the equilibrium values of C_max typically comprised between 8 and 20 μg / ml. However, in children with HIV infection who received a suspension of clarithromycin at a dose of 30 mg / kg / day in two divided doses, C_mOh reached 23 μg / ml. When taking the drug at higher doses, the half-life was longer than in healthy people who received clarithromycin in usual doses. An increase in plasma concentration and an elongation of the elimination half-life when using clarithromycin at higher doses is associated with the non-linear pharmacokinetics of the drug.

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;

- acute otitis media.

Contraindications:

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

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

- simultaneous reception of clarithromycin with ergot alkaloids, for example, ergotamine, dihydroergotamine (see section "Interaction with other medicinal products");

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

- simultaneous reception of clarithromycin with inhibitors of HMG-CoA reductase (statins), which are largely metabolized by isoenzyme CYP3A4 (lovastatin, simvastatin), due to the increased risk of myopathy, including rhabdomyolysis (see "Interaction with Other Drugs");

- simultaneous reception of clarithromycin with colchicine;

- simultaneous reception of clarithromycin with ticagrelor or ranolazine;

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

- hypokalemia (risk of lengthening the interval QT);

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

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

- congenital intolerance to fructose, insufficiency of sucrose-isomaltase, glucose-galactose malabsorption syndrome;

- porphyria;

- the period of breastfeeding.

Carefully:

- Renal failure of moderate to severe severity;

- hepatic insufficiency of moderate and severe degree;

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

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

- simultaneous reception with drugs that are metabolized by the isoenzyme CYP3A, 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 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 are 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), and patients taking antiarrhythmic drugs of the IA class simultaneously (quinidine, procainamide) and III class (dofetilide, amiodarone, sotalol);

- Pregnancy;

- diabetes (the preparation contains sucrose).

Pregnancy and lactation:

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

The use of clarithromycin in pregnancy (especially in the first trimester) is possible only if there is no alternative therapy, and the potential benefit to the mother exceeds the potential risk to the fetus.

Clarithromycin is excreted in breast milk. If you need to take during lactation, breastfeeding should be stopped.

Dosing and Administration:

For oral administration. The ready-made suspension can be taken regardless of food intake, including milk.

Preparation for use: the water is gradually added to the vial before labeling and shaken to obtain 60 ml of a suspension containing 125 mg of clarithromycin in 5 ml. The finished suspension can be stored for 14 days at room temperature (15 ° C to 30 ° C). Before each reception, the suspension should be shaken well.

Dose for non-mycobacterial infections

The recommended daily dose of clarithromycin suspension in non-mycobacterial infections in children is 7.5 mg / kg 2 times a day (maximum - 500 mg 2 times a day). The usual duration of treatment is 5-10 days, depending on the pathogen and the severity of the condition.

The table shows recommendations for dosing in children taking into account the body weight:

Body weight *, kg	Single dose at reception of 2 times a day, ml (7.5 mg / kg 2 times a day)
8-11	2,5
12-19	5
20-29	7,5
30-40	10

* In children with a body weight <8 kg, the dose is selected by weight (approximately 7.5 mg / kg 2 times a day)

Dose for mycobacterial infections

In children with disseminated or localized mycobacterial infections (M avium, M. intracellular, M. chelonae, M. fortuitum, M. kansasii) the recommended daily dose of clarithromycin is 7.5-15 mg / kg 2 times a day.

Treatment with clarithromycin should be continued as long as the clinical effect remains. Clarithromycin should be administered in combination with other antimicrobial agents active against these pathogens.

The table gives recommendations for dosing in children with mycobacterial infections with regard to body weight:

Body weight *, kg	Single dose at reception of 2 times a day, ml
Body weight *, kg	7.5 mg / kg 2 times a day	15 mg / kg 2 times a day
8-11	2,5	5
12-19	5	10
20-29	7,5	15
30-40	10	20

* In children with a body weight <8 kg, the dose is selected by weight (7.5-15 mg / kg 2 times in day)

Dose for patients with impaired renal function

In children less than 30 ml / min, the dose of clarithromycin should be halved (eg, 125 mg per day or 125 mg twice daily for more severe infections).In such cases, the course of treatment should not exceed 14 days, although the usual duration of treatment is 5-10 days.

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

Allergic reactions

Often: rash.

Infrequently: anaphylactoid reaction¹, hypersensitivity, dermatitis bullous¹, itching, urticaria, maculopapular rash³.

The frequency is unknown: anaphylactic reaction, angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptomatology (DRESS syndrome).

From the nervous system

Often: headache, insomnia.

Infrequently: loss of consciousness¹, dyskinesia¹, dizziness, drowsiness, tremor, anxiety, increased excitability³.

Frequency is unknown: convulsions, psychotic disorders, confusion, depersonalization, depression, disorientation, hallucinations, dream disturbances ("nightmarish" dreams), paresthesia, mania.

From the skin

Often: intense sweating.

The frequency is unknown: acne, hemorrhage.

From the urinary system

Frequency unknown: renal failure, interstitial nephritis.

From the side of metabolism and nutrition

Infrequent: anorexia, decreased appetite.

From the side of the musculoskeletal system

Infrequently: muscle spasm³, musculoskeletal stiffness¹, myalgia².

Frequency unknown: rhabdomyolysis² *, myopathy.

From the digestive system

Often: diarrhea, vomiting, indigestion, nausea, pain in the abdomen.

Infrequently: esophagitis¹, gastroesophageal reflux disease², gastritis, proctalgia², stomatitis, glossitis, bloating⁴, constipation, dry mouth, eructations, flatulence, cholestasis⁴, hepatitis incl. cholestatic or hepatocellular⁴.

The frequency is unknown: acute pancreatitis, discoloration of the tongue and teeth, hepatic insufficiency, cholestatic jaundice.

From the respiratory system

Infrequently: asthma¹, nose bleed² , pulmonary embolism¹.

From the sense organs

Often: dysgeusia, a taste perversion.

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

The frequency is unknown: deafness, agevia (loss of taste sensations), parosmia, anosmia.

From the side of the cardiovascular system

Often: vasodilation¹.

Infrequent: cardiac arrest¹, atrial fibrillation¹, prolongation of QT interval on electrocardiogram, extrasystole¹, atrial flutter.

The frequency is unknown: ventricular tachycardia, including the "pirouette" type.

Laboratory indicators

Often: deviation in the hepatic test.

Infrequent: increased creatinine concentration¹, increased urea concentration¹, a change in the albumin-globulin ratio¹, leukopenia, neutropenia⁴, eosinophilia⁴, thrombocythemia³, increased activity: alanine aminotransferase (ALT), aspartate aminotransferase (ACT), gamma glutamyl transferase (GGTP)⁴, alkaline phosphatase⁴, lactate dehydrogenase (LDH)⁴.

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

General disorders

Very often: phlebitis at the injection site¹.

Often: pain at the injection site¹, inflammation at the injection site¹.

Infrequently: malaise⁴, hyperthermia³, asthenia, chest pain⁴, chills⁴, fatigue⁴.

Infectious and parasitic diseases

Infrequently: cellulite¹, candidiasis, gastroenteritis², secondary infections (including vaginal)³.

The frequency is 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 of ACT and ALT in blood. There have also been cases of adverse events with a low incidence, such as shortness of breath, insomnia and dry mouth.

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

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

¹These adverse reactions were reported only with the use of Clacid®, a lyophilizate for the preparation of a solution for infusion.

²Reports of these adverse reactions were obtained only with the use of Clacid®, sustained-release tablets coated with a film coat.

³Reports of these adverse reactions were obtained only with the use of Clacid®, a powder for the preparation of a suspension for oral administration.

⁴ These adverse reactions were reported only with Clacid®, film-coated tablets.

Overdose:

Symptoms: taking a large dose of clarithromycin can cause symptoms of violations from the gastrointestinal tract.

In one patient with bipolar disorder in the history after the administration of 8 g of clarithromycin, changes in the mental state, paranoid behavior, hypokalemia and hypoxemia are described.

Treatment: when an overdose should be removed unabsorbed drug from the gastrointestinal tract (gastric lavage, taking activated charcoal, etc.) and conduct symptomatic therapy. Hemodialysis and peritoneal dialysis do not have a significant effect on the concentration 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, pimozide, terfenadine and astemizole

With the concomitant use of clarithromycin with cisapride, pimozide, terfenadine, or astemizole, an increase in plasma concentrations was reported, which may lead to prolongation of the QT interval and the occurrence of cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation, and ventricular pirouette tachycardia (see section "Contraindications"),

Alkaloids of ergot

Postmarketing studies show that with the combined use of clarithromycin with ergotamine or dihydroergotamine, the following effects associated with acute poisoning with drugs of the ergotamine group are possible: vascular spasm, ischemia of limbs and other tissues, including the central nervous system. Simultaneous reception of clarithromycin with ergot alkaloids is contraindicated (see section "Contraindications").

Inhibitors of HMG-CoA reductase (statins)

Simultaneous reception 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 the combined use with clarithromycin increases their serum 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, 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 are independent of the metabolism of the CYP3A isoenzyme (for example, fluvastatin). In case of need for joint intake, it is recommended to take the lowest dose of statin. It should monitor the development of signs and symptoms of myopathy.

The effect of other drugs on clarithromycin

Preparations that are inducers of the isoenzyme CYP3A (eg, rifampicin, phenytoin, carbamazepine, phenobarbital, St. John's wort pitted), can induce the metabolism of clarithromycin. This can lead to a subtherapeutic concentration of clarithromycin, which leads to a decrease in its effectiveness. In addition, it is necessary to monitor the concentration of the inductor of the CYP3A isoenzyme in the blood plasma, which can be increased due to inhibition of the CYP3A isoenzyme by 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 blood plasma; in the case of their joint application withclarithromycin may require dose adjustments or alternate treatment

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, and at the same time increase 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 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 low activity against Mycobacterium avium complex (MAC) infections, the overall activity against these pathogens may change, therefore alternative treatment should be considered for MAC treatment.

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 mean minimum 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_maxclarithromycin increased by 31%, C_minincreased 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 taken together with clarithromycin in doses exceeding 1 g / day.

Action of clarithromycin on other drugs

Antiarrhythmic drugs (quinidine and disopyramide)

Possible occurrence of ventricular tachycardia of the "pirouette" type when combined use of clarithromycin and quinidine or disopyramide. With concurrent administration of clarithromycin with these drugs, the electrocardiogram should be monitored regularly for prolonged QT intervals, and serum concentrations of these drugs should be monitored.

In post-marketing applications, cases of hypoglycemia were reported with the combined 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 (eg, sulfonylureas) and / or insulin, pronounced hypoglycemia can be observed. Simultaneous use of clarithromycin with some hypoglycemic drugs (for example, nateglinide, pioglitazone, repaglinide and rosiglitazone) can lead to inhibition of the CYP3A isoenzyme by clarithromycin, which can lead to hypoglycemia. Careful monitoring of glucose concentration is recommended.

Interactions caused by the isoenzyme CYP3A

The combined use 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 may 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 enzyme. If necessary, a dose adjustment of the drug taken with clarithromycin should be performed. Also, if possible, monitoring of serum concentrations of drugs that are primarily metabolized by the CYP3A isoenzyme should be conducted.

Metabolism of the following drugs / classes is carried out by the same isoenzyme CYP3A as the metabolism of clarithromycin,eg, alprazolam, carbamazepine, cilostazol, ciclosporin, disopyramide, methylprednisolone, midazolam, omeprazole, indirect anticoagulants (for example, warfarin), quinidine, rifabutin, sildenafil, tacrolimus, triazolam and vinblastine. Also, the agonists of the CYP3A isoenzyme 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"), drugs interacting in a similar way through other isoenzymes within the cytochrome P450 system include 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

Clarithromycin (500 mg every 8 hours) was tested in healthy adult volunteers in combination with omeprazole (40 mg daily).With the combined use of clarithromycin and omeprazole, equilibrium plasma concentrations of omeprazole were increased (C_max , AUC_0-24 uT_1/2increased 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 the CYP3A isoenzyme. At the same time, the CYP3A isoenzyme 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

The primary metabolism of tolterodine is via the 2D6 cytochrome P450 isoform (CYP2D6).However, in the part of the population devoid of the isoenzyme CYP2D6, the metabolism occurs through the isoenzyme CYP3A. In this population, suppression of the CYP3A isoenzyme results in significantly higher serum concentrations of tolterodine. In a population with a low level of metabolism via the CYP2D6 isozyme, a dose reduction of tolterodine may be required in the presence of CYP3A isoenzyme inhibitors such as clarithromycin.

Benzodiazepines (e.g., alprazolam, midazolam, triazolam)

When combined with midazolam and clarithromycin tablets (500 mg twice daily), augmentation of midazolam AUC was noted: 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 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 joint application, it is recommended to follow the symptoms of the CNS disorder.

Interactions with other drugs

Aminoglycosides

With the simultaneous administration 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 its termination.

Colchicine

Colchicine is a substrate for both the CYP3A isoenzyme and the P-glycoprotein carrier protein (Pgp). It is known that clarithromycin and other macrolides are inhibitors of the isoenzyme CYP3A and Pgp. When co-administered with clarithromycin and colchicine, inhibition of Pgp and / or isoenzyme CYP3A can lead to increased colchicine action. It should monitor the development of clinical symptoms of colchicine poisoning. Post-marketing reports on cases of colchicine poisoning during its simultaneous administration with clarithromycin are registered, more often in elderly patients.

Some of these cases occurred with patients suffering from kidney failure. As reported, some cases ended in a fatal outcome.

Simultaneous use of clarithromycin and colchicine is contraindicated (see section "Contraindications").

Digoxin

It is assumed that digoxin is the substrate of Pgp. It is known that clarithromycin inhibits Pgp. When co-administered with clarithromycin and digoxin, inhibition of Pgp with 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 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 reception of clarithromycin and zidovudine tablets orally by adult HIV-infected patients may lead to a decrease in the equilibrium concentration of zidovudine.

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

Similar interaction was not observed in HIV-infected children who took a children's suspension of clarithromycin with zidovudine or dideoxyinosine. Because the clarithromycin may interfere with the absorption of zidovudine when administered simultaneously in adults in adults, this interaction is hardly possible with the use of clarithromycin intravenously.

Phenytoin and valproic acid

There are data on the interactions of inhibitors of the isoenzyme CYP3A (including clarithromycin) with drugs that are not metabolized by the CYP3A isoenzyme (phenytoin and valproic acid). For these drugs, when combined with clarithromycin, it is recommended to determine their serum concentrations, since there are reports of their increase.

Bi-directional drug interactions

Atazanavir

Clarithromycin and atazanavir are 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 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 in Atazanavir AUC by 28%. 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 moderate renal failure (CK 30-60 ml / min), the dose of clarithromycin should be reduced by 50%. In patients with QC less than 30 ml / min, the dose of clarithromycin should be reduced by 75% using the appropriate dosage form of clarithromycin. Clarithromycin in doses exceeding 1000 mg per day, can not be used in conjunction with protease inhibitors.

Blocks of "slow" calcium channels

With the simultaneous use of clarithromycin and blockers of "slow" calcium channels, which are metabolized by the isoenzyme CYP3A4 (for example, 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 CYP3A isoenzyme, which determines the bi-directional interaction of the 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 CYP3A isoenzyme, which determines the bi-directional interaction of the drugs. The simultaneous use of clarithromycin (500 mg twice daily) and saquinavir (in soft gelatin capsules, 1200 mg three times daily) in 12 healthy volunteers caused an increase in AUC and C_maxsaquinavir by 177% and 187%, respectively, compared with the administration of saquinavir alone. The values of AUC and C_maxclarithromycin 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 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 (increased hepatic enzyme activity 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 related to 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 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. Antibiotic drugs can change 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.Cases of pseudomembranous colitis after 2 months after taking antibiotics were described.

Clarithromycin should be used with caution in patients with ischemic heart disease (CHD), severe heart failure, hypomagnesemia, severe bradycardia (less than 50 beats / min), and also with 1A antiarrhythmic drugs (quinidine, procainamide) and III class (dofetilide, amiodarone, sotalol). In these conditions and with the simultaneous administration of clarithromycin with these drugs, the electrocardiogram should be monitored regularly for prolongation of the QT interval.

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 increasing resistance of Streptococcus pneumoniae to macrolides, it is important to conduct sensitivity testing in the administration of clarithromycin to patients with community-acquired pneumonia. With hospital pneumonia clarithromycin should be used in combination with appropriate antibiotics.

Infections of the skin and soft tissues of mild and moderate severity are most often caused Staphylococcus aureusand 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 Coiynebacterium minutissimum, diseases acne vulgaris and erysipelas, as well as in those situations where penicillin can not be used.

In the case of acute hypersensitivity reactions, such as anaphylactic reaction, Stevens-Johnson syndrome, toxic epidermal necrolysis and drug rash with eosinophilia and systemic symptomatology (DRESS syndrome), 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").

When prescribing the drug to patients with diabetes it is necessary to take into account that Clacid®, a powder for the preparation of a suspension for ingestion of 125 mg / 5 ml, contains sucrose (1.05 ml of the suspension contains 0.055 XE or 0.55 g of sucrose).

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 that may occur when taking this drug.

Form release / dosage:

Powder for the preparation of a suspension for oral administration 125 mg / 5ml.

Packaging:

For 42.3 g of the drug in a plastic bottle, closing with a polypropylene cap. The label is marked on the vial in the form of a line.

1 bottle 60 ml complete with a dosage spoon or dosing syringe in a cardboard pack together with instructions for use.

Storage conditions:

Store in a dark place at a temperature of no higher than 30 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

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

Terms of leave from pharmacies:On prescription

Registration number:П N012722 / 01

Date of registration:20.03.2008

The owner of the registration certificate:Abbott SpAAbbott SpA Italy

Manufacturer: & nbsp

ABBOTT, S.P.A. Italy

Representation: & nbspABBOTT LABORATORIES LLC ABBOTT LABORATORIES LLC Russia

Information update date: & nbsp12.05.2015

Illustrated instructions

Instructions

Clacid® (Klacid®)