Clacid, 500 mg 14 pcs

Pharmacotherapeutic group

Antibiotic, macrolide

ATX code: J01FA09

Pharmacodynamics:

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

Clarithromycin has shown high in-vitro activity against both standard laboratory strains of bacteria and those isolated from patients in clinical practice. It shows high activity against many aerobic and anaerobic gram-positive and gram-negative microorganisms. Minimum inhibitory concentrations (MIC) of clarithromycin for most pathogens are lower than MIC of erythromycin on average by one log2 dilution.

Clarithromycin is highly active against LegionellapneumophilaMycoplasmapneumoniae. It has a bactericidal effect against Helicobacterpylori this activity of clarithromycin is higher at neutral pH than at acidic pH.

In addition, in-vitro and in-vivo data indicate that clarithromycin is active against clinically relevant mycobacterial species. Enterobacteriaceae and Pseudomonasspp. 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 demonstrated both in vitro and in clinical practice for the conditions listed under “Indications for use”.

Aerobic Gram-positive microorganisms

Staphylococcusaureus

Streptococcus pneumoniae

Streptococcus pyogenes

Listeria monocytogenes

Aerobic Gram-negative microorganisms

p> Haemophilusinfluenzae

Haemophilus parainfluenzae

Moraxella catarrhalis

Neisseria gonorrhoeae

Legionella pneumophila

Other microorganisms/p>

Mycoplasma pneumoniae

Chlamydia pneumoniae (TWAR)

Mycobacteria

/p>

Mycobacterium leprae

Mycobacterium kansasii

Mycobacterium chelonae

/p>

Mycobacterium fortuitum

Mycobacterium avium complex (MAC) – a complex including: Mycobacterium avium

MycobacteriumintracellulareThe production of beta-lactamase has no effect on clarithromycin activity. Most staphylococcal strains that are resistant to methicillin and oxacillin are also resistant to clarithromycin.

Helicobacter pylori

Sensitivity of H.pylori to clarithromycin was studied in H.pylori isolates isolated from 104 patients before initiation of therapy with the drug. Clarithromycin-resistant H.pylori strains were isolated in 4 patients, 2 patients had moderate resistance strains, and the remaining 98 patients had clarithromycin-sensitive H.pylori isolates.

Clarithromycin also has activity against most strains of the following microorganisms (but the safety and efficacy of clarithromycin in clinical practice has not been confirmed by clinical studies and the practical value remains unclear):

Aerobic Gram-positive microorganisms

Streptococcusagalactiae

Streptococci (Group C FG)

Viridansgroupstreptococci

Aerobic gram-negative microorganisms

/p>

Bordetellapertussis

Pasteurellamultocida

Anaerobic gram-positive microorganisms

/p>

Clostridim perfringens

Peptococcus niger

Propionibacterium acnes

/p>

Anaerobic Gram-negative microorganisms

Bacteroides melaninogenicus

p> Spirochetes

Borrelia burgdorferi

Treponema pallidum

Campylobacter

/p>

Campilobacterjejuni

The main metabolite of clarithromycin in humans is the microbiologically active metabolite 14-hydroxyclarithromycin (14-OH-clarithromycin). The microbiological activity of the metabolite is the same as that of the parent substance or 1-2 times weaker against most microorganisms. The exception is H.influenzae against which the effectiveness of the metabolite is twice as high. The parent substance and its main metabolite have either additive or synergistic effect against H.influenzae under in-vitro and in-vivo conditions depending on the bacterial strain.

Sensitivity test

Quantitative methods requiring measurement of the diameter of the growth suppression zone provide the most accurate estimates of bacterial sensitivity to antimicrobials. One recommended technique for sensitivity testing uses 15-µg clarithromycin-impregnated disks (Kirby-Bauer disco-diffusion method); in interpreting the test, zona diameters of growth suppression correlate with the IPC values of clarithromycin. IPC values are determined by dilution in broth or agar. Using these techniques, a report from the laboratory that the strain is “sensitive” indicates that the infectious agent is likely to respond to treatment. A “resistant” response indicates that the pathogen will probably not respond to treatment. An “intermediate sensitivity” response suggests that the therapeutic effect of the drug may be ambiguous or that the microorganism may be sensitive with higher doses of the drug. (Intermediate sensitivity is also called “moderate sensitivity.)

Pharmacokinetics:

Intake

The drug is easily and quickly absorbed in the gastrointestinal tract. Absolute bioavailability is about 50%. No cumulation was found when multiple doses of the drug were administered and the metabolism did not change in the human body. Eating immediately before taking the drug increased the bioavailability of the drug by 25% on average. Overall, this increase is insignificant and should have little clinical significance with the recommended dosing regimens. Therefore, clarithromycin can be used regardless of food intake.

Distribution metabolism and excretion

Invitro studies have shown that clarithromycin binds to plasma proteins by 70% at concentrations from 045 to 45 µg/ml. At a concentration of 450 µg/ml, the binding decreases to 41% probably as a result of saturation of the binding sites. This is observed only at concentrations many times greater than the therapeutic concentration.

Invivo studies on animals have shown that clarithromycin is present in all tissues except the central nervous system at concentrations several times greater than plasma concentrations. The highest concentrations (10-20 times higher than plasma concentrations) were found in the liver and lungs.

Health

When clarithromycin was administered at a dose of 250 mg twice daily, the maximum equilibrium concentration (Cmax) of clarithromycin and 14-OH-clarithromycin in plasma was reached after 2-3 days and was 1 µg/ml and 06 µg/ml, respectively. The half-life (T1/2) of clarithromycin and its main metabolite were 3-4 hours and 5-6 hours, respectively.

When clarithromycin was administered at a dose of 500 mg twice daily, the Cmax of clarithromycin and 14-OH clarithromycin in plasma was reached after the 5th dose. After the 5th and 7th dose, the Cmax of clarithromycin and 14-OH-clarithromycin in plasma averaged 27 to 29 mcg/mL and 088 to 083 mcg/mL, respectively. The T1/2 of clarithromycin and its main metabolite were 45 – 48 hours and 69 – 87 hours, respectively.

The cmax of 14-OH clarithromycin did not increase in proportion to the clarithromycin dose, whereas the elimination half-life of both clarithromycin and its hydroxylated metabolite tended to increase with increasing dose. This nonlinear pharmacokinetics of clarithromycin combined with decreased formation of 14-hydroxylated and N-demethylated products at high doses indicates a nonlinear metabolism of clarithromycin that becomes more pronounced at higher doses.

The urinary excretion is about 379% after oral clarithromycin doses of 250 mg and 460% after clarithromycin doses of 1200 mg; the intestinal excretion is about 402% and 291% (including subjects with only one stool sample containing 141%), respectively.

Patients

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

The table shows examples of tissue and serum concentrations:

Liver function disorders

/p>

In patients with moderate to severe hepatic impairment but with preserved renal function, clarithromycin dose adjustment is not necessary. Equilibrium plasma concentration and systemic clearance of clarithromycin do not differ between patients in this group and healthy patients. The equilibrium concentration of 14-OH clarithromycin is lower in people with hepatic impairment than in healthy patients.

In impaired renal function, the Cmax and minimum plasma concentration (Cmin) of clarithromycin and its metabolite 14-OH clarithromycin increase in the elimination half-life. The elimination constant and renal excretion decreases. The degree of change in these parameters depends on the degree of renal impairment.

Elderly patients

Elderly patients had higher blood concentrations of clarithromycin and its metabolite 14-OH clarithromycin and slower excretion than the younger group. However, after adjustment for renal creatinine clearance there were no differences in the two groups. Thus, the main influence on the pharmacokinetic parameters of clarithromycin is renal function and not age.

Patients with mycobacterial infections

The equilibrium concentrations of clarithromycin and 14-OH clarithromycin in patients with HIV infection receiving clarithromycin at conventional doses (500 mg twice daily) were similar to those in healthy subjects. However, when clarithromycin is used in higher doses that may be necessary to treat mycobacterial infections, concentrations of the antibiotic may be significantly higher than usual. In HIV-infected patients taking clarithromycin at a dose of 1000 mg/day or 2000 mg/day in two doses, equilibrium Cmax values were typically 2-4 mcg/ml and 5 – 10 mcg/ml, respectively. Longer half-life was observed at higher doses than in healthy subjects receiving clarithromycin at normal doses. The increased plasma concentrations and prolonged half-life when using clarithromycin at higher doses are due to the non-linear pharmacokinetics of the drug.

Combination therapy with omeprazole

Clarithromycin 500 mg 3 times daily in combination with omeprazole at a dose of 40 mg/day helps to increase T1/2 and AUC0-24 of omeprazole. In all patients receiving combined therapy compared to those receiving omeprazole alone there was an 89% increase in AUC0-24 and 34% increase in T1/2 of omeprazole. In clarithromycin Cmax Cminn AUC0-8 were increased by 10% 27% and 15% respectively compared to data when clarithromycin alone was used without omeprazole. At equilibrium concentrations of clarithromycin in gastric mucosa 6 hours after administration were 25 times higher in the group receiving the combination compared to those receiving clarithromycin alone. Concentrations of clarithromycin in gastric tissue 6 hours after the administration of 2 drugs were twice as high as in the group of patients receiving clarithromycin alone.

Indications

Infectious and inflammatory diseases caused by microorganisms sensitive to clarithromycin in adults and children over 12 years of age:

– lower respiratory tract infections (such as bronchitis and pneumonia);

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

– infections of the skin and soft tissues (such as folliculitis, inflammation of the subcutaneous tissue of the erysipelas);

– disseminated or localized mycobacterial infections caused by Mycobacterium avium and Mycobacterium intracellulare; localized infections caused by Mycobacterium chelonae Mycobacterium fortuitum and Mycobacterium kansasii;

-prevention of the spread of infection caused by the Mycobacterium avium complex (MAC) in HIV-infected patients with a CD4 lymphocyte (T-helper lymphocyte) content of no more than 100 per 1 mm3.

– eradication of H. pylori and reduction in the frequency of relapses of duodenal ulcers.

Pharmacological effect

Pharmacotherapeutic group

Antibiotic, macrolide

ATX code: J01FA09

Pharmacodynamics:

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

Clarithromycin demonstrated high in vitro activity against both standard laboratory strains of bacteria and those isolated from patients during clinical practice. Shows high activity against many aerobic and anaerobic gram-positive and gram-negative microorganisms. The minimum inhibitory concentrations (MICs) of clarithromycin for most pathogens are less than the MICs of erythromycin by an average of one log2 dilution.

Clarithromycin is highly active in vitro against Legionellapneumophila Mycoplasma pneumoniae. It has a bactericidal effect against Helicobacter pylori; this activity of clarithromycin is higher at neutral pH than at acidic pH.

In addition, in vitro and in vivo data indicate that clarithromycin acts against clinically relevant mycobacterial species. Enterobacteriaceae and Pseudomonaspp. 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 both in vitro and in clinical practice for the diseases listed in the “Indications for Use” section.

Aerobic gram-positive microorganisms

Staphylococcus aureus

Streptococcus pneumoniae

Streptococcus pyogenes

Listeria monocytogenes

Aerobic gram-negative microorganisms

Haemophilusinfluenzae

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) – a complex including: Mycobacterium avium

Mycobacterium intracellulareBeta-lactamase production does not affect the activity of clarithromycin. Most strains of staphylococci resistant to methicillin and oxacillin are also resistant to clarithromycin.

Helicobacter pylori

The sensitivity of H. pylori to clarithromycin was studied on H. pylori isolates isolated from 104 patients before starting drug therapy. In 4 patients, strains of H.pylori resistant to clarithromycin were isolated; in 2, strains with moderate resistance were isolated; in the remaining 98 patients, H.pylori isolates were sensitive to clarithromycin.

Clarithromycin has an in vitro effect against most strains of the following microorganisms (however, the safety and effectiveness of the use of clarithromycin in clinical practice has not been confirmed by clinical studies and the practical significance remains unclear):

Aerobic gram-positive microorganisms

Streptococcusagalactiae

Streptococci (group C FG)

Viridansgroupstreptococci

Aerobic gram-negative microorganisms

Bordetella pertussis

Pasteurellamultocida

Anaerobic gram-positive microorganisms

Clostridium perfringens

Peptococcus niger

Propionibacterium acnes

Anaerobic gram-negative microorganisms

Bacteroides melaninogenicus

Spirochetes

Borrelia burgdorferi

Treponema pallidum

Campylobacter

Campilobacter 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 parent substance or 1-2 times weaker against most microorganisms. The exception is H. influenzae, for which the effectiveness of the metabolite is twice as high. The parent substance and its main metabolite have either an additive or synergistic effect against H. influenzae in vitro and in vivo, depending on the bacterial strain.

Sensitivity test

Quantitative methods requiring measurement of the diameter of the zone of growth inhibition provide the most accurate estimates of the sensitivity of bacteria to antimicrobial drugs. One of the recommended methods for determining sensitivity uses disks impregnated with 15 μg of clarithromycin (Kirby-Bauer disk diffusion method); when interpreting the test, the diameters of the zones of growth inhibition correlate with the MIC values ​​of clarithromycin. MIC values ​​are determined by broth or agar dilution method. With these techniques, a laboratory report that a strain is “sensitive” indicates that the infectious agent is likely to respond to treatment. The response “resistant” indicates that the pathogen may not respond to treatment. An “intermediate sensitivity” response suggests that the therapeutic effect of the drug may be ambiguous or that the organism may be sensitive when using higher doses of the drug. (Intermediate sensitivity is also called “moderate sensitivity”).

Pharmacokinetics:

Suction

The drug is easily and quickly absorbed from the gastrointestinal tract. Absolute bioavailability is about 50%. With repeated doses of the drug, practically no accumulation was detected and the nature of metabolism in the human body did not change. Eating immediately before taking the drug increased the bioavailability of the drug by an average of 25%. Overall, this increase is small and should be of little clinical significance at recommended dosing regimens. Therefore, clarithromycin can be used regardless of food intake.

Distribution metabolism and excretion

Invitro

In vitro studies have shown that clarithromycin binds to plasma proteins by 70% at concentrations from 045 to 45 mcg/ml. At a concentration of 450 μg/ml, binding decreases to 41%, probably as a result of saturation of binding sites. This is observed only at concentrations many times higher than the therapeutic one.

Invivo

In vivo animal studies have shown that clarithromycin is present in all tissues except the central nervous system at concentrations several times higher than plasma concentrations. The highest concentrations (10-20 times higher than plasma levels) were found in the liver and lungs.

Healthy

When clarithromycin was prescribed at a dose of 250 mg 2 times a day, the maximum equilibrium concentration (Cmax) of clarithromycin and 14-OH-clarithromycin in plasma was reached after 2-3 days and was 1 μg/ml and 06 μg/ml, respectively. The half-life (T1/2) of clarithromycin and its main metabolite was 3-4 hours and 5-6 hours, respectively.

When clarithromycin was prescribed at a dose of 500 mg 2 times a day, Cmax of clarithromycin and 14-OH-clarithromycin in plasma was achieved after taking the 5th dose. After taking the 5th and 7th doses, the Cmax of clarithromycin and 14-OH-clarithromycin in plasma averaged 27 – 29 mcg/ml and 088 – 083 mcg/ml, respectively. T1/2 of clarithromycin and its main metabolite was 45-48 hours and 69-87 hours, respectively.

The Cmax of 14-OH-clarithromycin did not increase proportionally with the dose of clarithromycin, while the half-life of both clarithromycin and its hydroxylated metabolite tended to increase with increasing dose. This nonlinear pharmacokinetics of clarithromycin, coupled with a decrease in the formation of 14-hydroxylated and N-demethylated products at high doses, indicates a nonlinear metabolism of clarithromycin that becomes more pronounced at high doses.

Renal excretion is approximately 379% after oral administration of clarithromycin at a dose of 250 mg and 460% after oral administration of clarithromycin at a dose of 1200 mg; the intestines excreted about 402% and 291% (including the subject with only one stool sample containing 141%), respectively.

Patients

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

The table provides examples of tissue and serum concentrations:

Concentrations (250 mg every 12 hours)

Type of fabric

Tissue (µg/g)

Serum (µg/ml)

Tonsils

16

08

Lungs

88

17

Liver dysfunction

In patients with moderate to severe hepatic impairment but with preserved renal function, no dose adjustment of clarithromycin is required. The equilibrium plasma concentration and systemic clearance of clarithromycin do not differ between patients in this group and healthy patients. The steady-state concentration of 14-OH-clarithromycin in people with impaired liver function is lower than in healthy people.

Renal dysfunction

If renal function is impaired, the Cmax and minimum concentration (Cmin) of clarithromycin in the blood plasma increase, the half-life of the area under the pharmacokinetic concentration-time curve (AUC) of clarithromycin and its metabolite 14-OH-clarithromycin. The elimination constant and renal excretion decrease. The degree of changes in these parameters depends on the degree of renal dysfunction.

Elderly patients

In elderly patients, the concentration of clarithromycin and its metabolite 14-OH-clarithromycin in the blood was higher and elimination was slower than in the group of young people. However, after adjustment for renal creatinine clearance, there was no difference in both groups. Thus, the main influence on the pharmacokinetic parameters of clarithromycin is exerted by renal function and not age.

Patients with mycobacterial infections

Steady-state concentrations of clarithromycin and 14-OH-clarithromycin in patients with HIV infection receiving clarithromycin at usual doses (500 mg twice daily) were similar to those in healthy people. However, when clarithromycin is used in higher doses, which may be required to treat mycobacterial infections, antibiotic concentrations may be significantly higher than usual. In patients with HIV infection taking clarithromycin at a dose of 1000 mg/day or 2000 mg/day in two doses, the equilibrium Cmax values ​​were usually 2-4 µg/ml and 5-10 µg/ml, respectively. When using the drug in higher doses, a prolongation of the half-life was observed compared with that in healthy people receiving clarithromycin in usual doses. Increased plasma concentrations and prolongation of the half-life when using clarithromycin at higher doses are associated with the nonlinear pharmacokinetics of the drug.

Combination treatment with omeprazole

Clarithromycin 500 mg 3 times a day in combination with omeprazole at a dose of 40 mg/day increases T1/2 and AUC0-24 of omeprazole. In all patients receiving combination therapy compared with those receiving omeprazole alone, an increase of 89% in AUC0-24 and a 34% increase in T1/2 of omeprazole was observed. For clarithromycin, Cmax Cminn AUC0-8 increased by 10%, 27% and 15%, respectively, compared to the data when only clarithromycin was used without omeprazole. At steady state, clarithromycin concentrations in the gastric mucosa 6 hours after dosing in the group receiving the combination were 25 times higher than those in those receiving clarithromycin alone. Concentrations of clarithromycin in gastric tissue 6 hours after taking 2 drugs were 2 times higher than the data obtained in the group of patients receiving clarithromycin alone.

Special instructions

Long-term use of antibiotics can lead to the formation of colonies with an increased number of insensitive bacteria and fungi. In case of superinfection, appropriate therapy must be prescribed.

Prescription of clarithromycin to pregnant women should be carried out with a careful assessment of the risk-benefit ratio, especially during the first three months of pregnancy.

Liver dysfunction (increased activity of liver enzymes in the blood, hepatocellular and/or cholestatic hepatitis with or without jaundice) has been reported with the use of clarithromycin. Liver dysfunction can be severe but is usually reversible. There are cases of fatal liver failure, mainly associated with the presence of serious concomitant diseases and/or concomitant use of other drugs. If signs and symptoms of hepatitis such as anorexia, jaundice, dark urine, itching, abdominal tenderness on palpation appear, clarithromycin therapy should be stopped immediately.

In the presence of chronic liver diseases, it is necessary to regularly monitor serum enzymes.

When treated with almost all antibacterial agents, including clarithromycin, cases of pseudomembranous colitis have been described, the severity of which can vary from mild to life-threatening. When treated with almost all antibacterial drugs, including clarithromycin, cases of Clostridium difficile-associated diarrhea have been described, the severity of which can vary from mild diarrhea to life-threatening colitis.

Antibacterial drugs can change the normal intestinal microflora, which can lead to the growth of C. difficile. Pseudomembranous colitis caused by Clostridium difficile should be suspected in all patients who develop diarrhea after using antibacterial agents. After a course of antibiotic therapy, careful medical monitoring of the patient is necessary. Cases of the development of pseudomembranous colitis 2 months after taking antibiotics have been described.

When treated with macrolides, including clarithromycin, prolongation of cardiac repolarization and the QT interval was observed, causing the risk of developing cardiac arrhythmia and torsade de pointes (TdP) (see section “Side effects”). Since the following situations may lead to an increased risk of developing ventricular arrhythmias (including torsade de pointes), clarithromycin should not be used in the following categories of patients:

– in patients with hypokalemia (see section “Contraindications”);

– simultaneous administration of clarithromycin with astemizole, cisapride, pimozide and terfenadine is contraindicated (see section “Contraindications”);

– in patients with congenital or acquired registered prolongation of the QT interval or a history of ventricular arrhythmia (see section “Contraindications”).

– Clarithromycin should be used with caution in the following categories of patients:

– in patients with coronary heart disease (CHD), severe heart failure, conduction disturbances or clinically significant bradycardia;

– in patients with electrolyte disturbances such as hypomagnesemia;

– in patients simultaneously taking other drugs associated with prolongation of the QT interval (see section “Interaction with other drugs”).

Epidemiological studies examining the risk of adverse cardiovascular outcomes with macrolide use have reported mixed results. Some observational studies have established a short-term risk of arrhythmia, myocardial infarction, and cardiovascular death associated with the use of macrolides including clarithromycin. When prescribing clarithromycin, the expected benefits of taking the drug should be weighed against these risks.

It is possible to develop cross-resistance to clarithromycin and other macrolide antibiotics, as well as lincomycin and clindamycin.

Given the increasing resistance of Streptococcus pneumoniae to macrolides, it is important to conduct sensitivity testing when prescribing clarithromycin to patients with community-acquired pneumonia. For hospital-acquired pneumonia, clarithromycin should be used in combination with appropriate antibiotics. Mild to moderate skin and soft tissue infections are most often caused by Staphylococcus aureus and Streptococcus pyogenes. Moreover, both pathogens can be resistant to macrolides. Therefore, it is important to conduct a sensitivity test. Macrolides can be used for infections caused by Corynebacterium minutissimum, acne vulgaris and erysipelas, as well as in situations where penicillin cannot be used.

In the event of acute hypersensitivity reactions such as anaphylactic reaction, severe skin drug reactions (for example, acute generalized exanthematous pustulosis), Stevens-Johnson syndrome, toxic epidermal necrolysis and drug rash with eosinophilia and systemic symptoms (DRESS syndrome), immediately stop taking clarithromycin and begin appropriate therapy.

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

Impact on the ability to drive vehicles. Wed and fur.:

There are no data regarding the effect of clarithromycin on the ability to drive a car or use machinery.

Caution should be exercised when operating vehicles and machinery, given the potential for dizziness, vertigo, confusion and disorientation that may occur when using this drug.

Active ingredient

Clarithromycin

Composition

1 film-coated tablet contains:

Active ingredient: clarithromycin – 500.00 mg.

Excipients: core: croscarmellose sodium – 65.60 mg; microcrystalline cellulose – 183.90 mg; silicon dioxide – 12.00 mg; povidone (K 29 – 32) – 25.50 mg; stearic acid – 21.00 mg; magnesium stearate – 12.60 mg; talc – 29.40 mg;

film coating: hypromellose (hydroxypropyl methylcellulose) – 22.10 mg; hyprolose – 1.70 mg; propylene glycol – 14.62 mg; sorbitan oleate – 1.70 mg; titanium dioxide – 5.10 mg; sorbic acid -0.94 mg; vanillin – 0.94 mg; quinoline yellow dye E-104 – 0.07 mg.

Pregnancy

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

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

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

Contraindications

For oral administration. Regardless of food intake.

The usual recommended dose of clarithromycin in adults and children over 12 years of age is 250 mg 2 times a day (in this case, it is possible to use the drug Klacid® film-coated tablets 250 mg).

Clarithromycin 500 mg twice daily is used for more severe infections.

The usual duration of treatment is from 5 to 14 days.

The exceptions are community-acquired pneumonia and sinusitis, which require treatment from 6 to 14 days.

Doses for the treatment of mycobacterial infections other than tuberculosis:

For mycobacterial infections, the recommended dose of clarithromycin is 500 mg 2 times a day.

Treatment of disseminated MAC infections in patients with AIDS should be continued as long as there is clinical and microbiological effectiveness. Clarithromycin should be prescribed in combination with other antimicrobial drugs active against these pathogens.

The duration of treatment for other non-tuberculous mycobacterial infections is determined by the doctor.

To prevent infections caused by MAS:

The recommended dose of clarithromycin for adults is 500 mg 2 times a day.

For eradication of H. pylori.

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

Patients with renal failure

Patients with creatinine clearance less than 30 ml/min are prescribed half the usual dose of clarithromycin (in this case, a dose of 250 mg is used). Treatment of such patients continues for no more than 14 days.

Use in children under 12 years of age

Clarithromycin tablets have not been studied in children under 12 years of age.

With caution:

– Moderate to severe renal failure.

– Moderate to severe liver failure.

– Concomitant use of clarithromycin with benzodiazepines such as alprazolam triazolam midazolam for intravenous use or for application to the oral mucosa (see “Interaction with other drugs”).

– Concomitant use with drugs that are metabolized by the CYP3A isoenzyme, for example carbamazepine cilostazol cyclosporine disopyramide methylprednisolone omeprazole indirect anticoagulants (for example warfarin) quinidine rifabutin sildenafil tacrolimus vinblastine (see section “Interaction with other drugs”).

– Simultaneous use with drugs that induce the CYP3A4 isoenzyme, for example rifampicin phenytoin carbamazepine phenobarbital St. John’s wort (see section “Interaction with other drugs”).

– Simultaneous use of clarithromycin with statins that do not depend on the metabolism of the CYP3A isoenzyme (for example, fluvastatin) (see section “Interaction with other drugs”).

– Simultaneous use with blockers of “slow” calcium channels that are metabolized by the CYP3A4 isoenzyme (for example, verapamil amlodipine diltiazem).

– Patients with coronary heart disease (CHD), severe heart failure, hypomagnesemia, conduction disturbances or clinically significant bradycardia, as well as patients simultaneously taking class 1A (quinidine procainamide) and class III antiarrhythmic drugs (dofetilide amiodarone sotalol).

Pregnancy.

Side Effects

Classification of adverse reactions by frequency (number of reported cases/number of patients): very common (≥1/10) common (≥1/100 < 1/10) uncommon (≥1/1000 < 1/100) frequency unknown (side effects from post-marketing experience; frequency cannot be estimated based on available data).

Allergic reactions

Common: rash.

Uncommon: anaphylactoid reaction1 hypersensitivity bullous dermatitis1 itching urticaria macular papular rash3.

Not known: anaphylactic reaction angioedema serious cutaneous adverse reactions (eg acute generalized exanthematous pustulosis) Stevens-Johnson syndrome toxic epidermal necrolysis drug rash with eosinophilia and systemic symptoms (DRESS syndrome).

From the nervous system

Common: headache, insomnia.

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

Frequency unknown: seizures psychotic disorders confusion depersonalization depression disorientation hallucinations dream disturbances (nightmare dreams) paresthesia mania.

From the skin

Common: intense sweating.

Frequency unknown: acne.

From the urinary system

Frequency unknown: renal failure, interstitial nephritis.

Metabolism and nutrition

Uncommon: anorexia, decreased appetite.

From the musculoskeletal system

Uncommon: muscle spasm3 musculoskeletal stiffness1 myalgia2.

Frequency unknown: rhabdomyolysis2* myopathy.

From the digestive system

Common: diarrhea, vomiting, dyspepsia, nausea, abdominal pain.

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

Frequency unknown: acute pancreatitis, discoloration of the tongue and teeth, liver failure, cholestatic jaundice.

From the respiratory system

Uncommon: asthma1 epistaxis2 pulmonary embolism1.

From the senses

Common: dysgeusia.

Uncommon: vertigo, hearing loss, tinnitus.

Frequency unknown: deafness ageusia (loss of taste) parosmia anosmia.

From the cardiovascular system

Common: vasodilation1.

Uncommon: cardiac arrest1 atrial fibrillation1 prolongation of the QT interval on the electrocardiogram extrasystole1 palpitations.

Frequency unknown: ventricular tachycardia, including pirouette type, ventricular fibrillation, bleeding.

Laboratory indicators

Common: abnormal liver function test.

Uncommon: increased creatinine concentration1 increased urea concentration1 change in albumin-globulin ratio1 leukopenia neutropenia4 eosinophilia4 thrombocythemia3 increased activity of: alanine aminotransferase (ALT) aspartate aminotransferase (ACT) gammaglutamyltransferase (GGTP)4 alkaline phosphatase4 lactate dehydrogenase (LDH)4.

Frequency unknown: agranulocytosis thrombocytopenia increased international normalized ratio (INR) prolongation of prothrombin time change in urine color increased bilirubin concentration in the blood.

General disorders

Very common: phlebitis at the injection site1.

Common: pain at the injection site1 inflammation at the injection site1.

Uncommon: malaise4 hyperthermia3 asthenia, chest pain4 chills4 fatigue4.

Infectious and parasitic diseases

Uncommon: cellulitis1 candidiasis gastroenteritis2 secondary infections3 (including vaginal).

Frequency unknown: pseudomembranous colitis erysipelas.

It is assumed that the frequency, type and severity of adverse reactions in children is the same as in adults.

Immunosuppressed patients

In patients with AIDS and other immunodeficiencies receiving clarithromycin in higher doses over a long period of time to treat mycobacterial infections, it is often difficult to distinguish unwanted effects of the drug from symptoms of HIV infection or concomitant disease.

The most common adverse events in patients taking a daily dose of clarithromycin of 1000 mg were: nausea, vomiting, taste disturbance, abdominal pain, diarrhea, rash, flatulence, headache, constipation, hearing impairment, increased activity of AST and ALT in the blood. There were also cases of adverse events with a low incidence. Such as shortness of breath, insomnia and dry mouth.

In patients with suppressed immunity, laboratory parameters were assessed by analyzing their significant deviations from the norm (sharp increase or decrease). Based on this criterion, 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, was recorded in 2 – 3% of patients receiving clarithromycin at a dose of 1000 mg daily. Increases in residual urea nitrogen concentrations have also been reported in a small number of patients.

* In some reports of rhabdomyolysis, clarithromycin was taken together with other drugs known to be associated with rhabdomyolysis (statin fibrates colchicine or allopurinol).

1 Reports of these adverse reactions were received only when using the drug Klacid® lyophilisate for the preparation of a solution for infusion.

2 Reports of these adverse reactions were received only with the use of the drug Klacid® SR extended-release film-coated tablets.

3 Reports of these adverse reactions were received only when using the drug Klacid® granules for the preparation of an oral suspension.

4 Reports of these adverse reactions were received only when using the drug Klacid® film-coated tablets.

Interaction

The use of the following drugs with clarithromycin is contraindicated due to the potential for serious side effects:

Cisapride pimozide terfenadine and astemizole

When clarithromycin was co-administered with cisapride, pimozide, terfenadine or astemizole, an increase in the concentration of the latter in the blood plasma was reported, which could lead to prolongation of the QT interval and the appearance of cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation and torsade de pointes (see section “Contraindications”).

Ergot alkaloids

Post-marketing studies show that when clarithromycin is used together with ergotamine or dihydroergotamine, the following effects associated with acute poisoning with drugs of the ergotamine group are possible: vascular spasm, ischemia of the limbs and other tissues, including the central nervous system. Concomitant use of clarithromycin with ergot alkaloids is contraindicated (see section “Contra-indications”).

Midazolam for oral use

When midazolam was coadministered with clarithromycin tablets (500 mg twice daily), midazolam AUC increased 7-fold after oral administration. Concomitant use of clarithromycin with oral midazolam is contraindicated (see section “Contraindications”).

HMG-CoA reductase inhibitors (statins)

Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated (see section “Contraindications”) due to the fact that these statins are largely metabolized by the CYP3A4 isoenzyme and combined use with clarithromycin increases their serum concentrations, which leads to an increased risk of developing myopathy including rhabdomyolysis. Cases of rhabdomyolysis have been reported in patients taking clarithromycin in conjunction with these drugs. If clarithromycin is necessary, lovastatin or simvastatin should be discontinued during therapy.

Clarithromycin should be used with caution in combination therapy with other statins. If coadministration is necessary, it is recommended to take the lowest dose of statin. It is recommended to use statins that do not depend on the metabolism of the CYP3A isoenzyme (for example, fluvastatin). The development of signs and symptoms of myopathy should be monitored.

Effect of other drugs on clarithromycin

Drugs that are inducers of the CYP3A isoenzyme (for example, rifampicin, phenytoin, carbamazepine, phenobarbital, St. John’s wort) can induce the metabolism of clarithromycin. This may result in subtherapeutic concentrations of clarithromycin, resulting in reduced effectiveness. In addition, it is necessary to monitor the concentration of the CYP3A inducer in the blood plasma, which may increase due to inhibition of the CYP3A isoenzyme by clarithromycin. When rifabutin and clarithromycin were used together, an increase in plasma concentrations of rifabutin and a decrease in serum concentrations of clarithromycin were observed with an increased risk of developing uveitis.

The following drugs have a proven or suspected effect on clarithromycin plasma concentrations; if used concomitantly with clarithromycin, dosage adjustments or switching to alternative treatment may be required.

Efavirenz nevirapine rifampicin rifabutin and rifapentine

Strong inducers of the cytochrome P450 system such as efavirenz nevirapine rifampicin rifabutin and rifapentine can accelerate the metabolism of clarithromycin and thus reduce the concentration of clarithromycin in plasma and at the same time increase the concentration of 14-OH-clarithromycin, a metabolite that is also microbiologically active. Since the microbiological activity of clarithromycin and 14-OH-clarithromycin differs against different bacteria, the therapeutic effect may be reduced when clarithromycin and enzyme inducers are used together.

Etravirine

The concentration of clarithromycin decreases with the use of etravirine, but the concentration of the active metabolite 14-OH-clarithromycin increases. Because 14-OH-clarithromycin has low activity against Mycobacterium avium complex (MAC) infections, overall activity against these pathogens may be altered, so alternative treatments should be considered for the treatment of MAC.

Fluconazole

Coadministration of fluconazole 200 mg daily and clarithromycin 500 mg twice daily in 21 healthy volunteers resulted in an increase in mean clarithromycin minimum steady-state concentration (Cmin) and AUC by 33% and 18%, respectively. However, co-administration did not significantly affect the average steady-state concentration of the active metabolite 14-OH-clarithromycin. No dose adjustment of clarithromycin is required when taking fluconazole concomitantly.

Ritonavir

A pharmacokinetic study showed that co-administration of ritonavir 200 mg every eight hours and clarithromycin 500 mg every 12 hours resulted in a marked suppression of the metabolism of clarithromycin. When co-administered with ritonavir, clarithromycin Cmax increased by 31%, Cmin increased by 182% and AUC increased by 77%. Almost complete suppression of the formation of 14-OH-clarithromycin was noted. Due to the wide therapeutic range of clarithromycin, dose reduction is not required in patients with normal renal function. In patients with renal failure, it is advisable to consider the following dose adjustment options: with CC 30 – 60 ml/min, the dose of clarithromycin should be reduced by 50%; with CC less than 30 ml/min, the dose of clarithromycin should be reduced by 75%. Ritonavir should not be co-administered with clarithromycin in doses exceeding 1 g/day.

Similar dosage adjustments should be considered in patients with reduced renal function if ritonavir is used as a pharmacokinetic enhancer when using other HIV protease inhibitors including atazanavir and saquinavir (see section “Bidirectional Drug Interactions”).

Effect of clarithromycin on other drugs

Antiarrhythmic drugs (quinidine and disopyramide)

Torsade de pointes-type ventricular tachycardia may occur with the combined use of clarithromycin and quinidine or disopyramide. When clarithromycin is taken concomitantly with these drugs, the electrocardiogram should be regularly monitored for prolongation of the QT interval and serum concentrations of these drugs should also be monitored.

During post-marketing use, cases of hypoglycemia have been reported during co-administration of clarithromycin and disopyramide. It is necessary to monitor the concentration of glucose in the blood while using clarithromycin and disopyramide.

Oral hypoglycemic agents/insulin

When clarithromycin is used together with oral hypoglycemic agents (for example, sulfonylureas) and/or insulin, severe hypoglycemia may occur. Concomitant use of clarithromycin with certain hypoglycemic drugs (for example, nateglinide, pioglitazone, repaglinide and rosiglitazone) may lead to inhibition of the CYP3A isoenzyme by clarithromycin, which may result in hypoglycemia. Careful monitoring of glucose concentrations is recommended.

Interactions due to CYP3A isoenzyme

Co-administration of clarithromycin, which is known to inhibit the CYP3A isoenzyme, and drugs primarily metabolized by the CYP3A isoenzyme may be associated with a mutual increase in their concentrations, which may enhance or prolong both therapeutic and side effects. Clarithromycin should be used with caution in patients receiving drugs that are substrates of the CYP3A isoenzyme, especially if these drugs have a narrow therapeutic index (for example, carbamazepine) and/or are extensively metabolized by this enzyme. If necessary, the dose of the drug taken together with clarithromycin should be adjusted. Also, whenever possible, serum concentrations of drugs primarily metabolized by the CYP3A isoenzyme should be monitored.

The following drugs/classes are metabolized by the same CYP3A isoenzyme as clarithromycin, e.g. alprozolam carbamazepine cilostazol cyclosporine disopyramide methylprednisolone midazolam omeprazole indirect anticoagulants (e.g. warfarin) atypical antipsychotics (e.g. quetiapine) quinidine rifabutin sildenafil tacrolimus triazolam and vinblastine.

Also, agonists of the CYP3A isoenzyme include the following drugs that are contraindicated for combined use with clarithromycin: astemizole cisapride pimozide terfenadine lovastatin simvastatin and ergot alkaloids (see section “Contraindications”). Drugs that interact in this way through other isoenzymes within the cytochrome P450 system include phenytoin theophylline and valproic acid.

Indirect anticoagulants

When taking warfarin and clarithromycin together, bleeding is possible and a marked increase in INR and prothrombin time is possible. In case of combined use with warfarin or other indirect anticoagulants, it is necessary to monitor the INR and prothrombin time.

Omeprazole

Clarithromycin (500 mg every 8 hours) was studied in healthy adult volunteers in combination with omeprazole (40 mg daily). When clarithromycin and omeprazole were co-administered, steady-state plasma concentrations of omeprazole were increased (Cmax AUCo-24 and T1/2 increased by 30%, 89% and 34%, respectively). The mean 24-hour gastric pH was 52 when omeprazole was taken alone and 57 when omeprazole was taken with clarithromycin.

Sildenafil tadalafil and vardenafil

Each of these phosphodiesterase inhibitors is metabolized at least in part by the CYP3A isoenzyme. At the same time, the CYP3A isoenzyme can be inhibited in the presence of clarithromycin. Concomitant use of clarithromycin with sildenafil, tadalafil or vardenafil may result in increased phosphodiesterase inhibitory effects. When using these drugs together with clarithromycin, consider reducing the dose of sildenafil, tadalafil and vardenafil.

Theophylline carbamazepine

When clarithromycin and theophylline or carbamazepine are used together, the concentration of these drugs in the systemic circulation may increase.

Tolterodine

The primary metabolism of tolterodine occurs through the 2D6 isoform of cytochrome P450 (CYP2D6). However, in part of the population lacking the CYP2D6 isoenzyme, metabolism occurs through the CYP3A isoenzyme. In this population, inhibition of CYP3A results in significantly higher serum tolterodine concentrations. In populations that are poor metabolizers of CYP2D6, a dose reduction of tolterodine may be required in the presence of CYP3A inhibitors such as clarithromycin.

Benzodiazepines (eg alprazolam midazolam triazolam)

When midazolam was co-administered with clarithromycin tablets (500 mg twice daily), midazolam AUC increased by 27 times after intravenous midazolam administration. If an intravenous form of midazolam is used together with clarithromycin, the patient’s condition should be carefully monitored for possible dose adjustment. Administration of a drug through the oral mucosa, which bypasses presystemic drug elimination, is likely to result in an interaction similar to that observed with intravenous midazolam rather than with oral administration.

The same precautions should be applied to other benzodiazepines that are metabolized by the CYP3A isoenzyme including triazolam and alprazolam. For benzodiazepines whose elimination is not dependent on the CYP3A isoenzyme (temazepam nitrazepam lorazepam), a clinically significant interaction with clarithromycin is unlikely.

When clarithromycin and triazolam are used together, effects on the central nervous system (CNS) such as drowsiness and confusion are possible. Therefore, it is advisable to monitor for symptoms of CNS impairment if coadministration occurs.

Interactions with other drugs

Colchicine

Colchicine is a substrate of both CYP3A and the P-glycoprotein (Pgp) transporter protein. It is known that clarithromycin and other macrolides are inhibitors of the CYP3A and Pgp isoenzymes. When clarithromycin and colchicine are taken together, inhibition of Pgp and/or CYP3A may result in increased effects of colchicine. There have been post-marketing reports of cases of colchicine poisoning when taken concomitantly with clarithromycin, more often in elderly patients. Some of the reported cases occurred in patients suffering from kidney failure. Some cases were reported to be fatal. The simultaneous use of clarithromycin and colchicine is contraindicated (see section “Contraindications”).

Digoxin

Digoxin is suspected to be a Pgp substrate. Clarithromycin is known to inhibit Pgp. When clarithromycin and digoxin are co-administered, inhibition of Pgp by clarithromycin may result in increased effects of digoxin. Post-marketing studies have shown that coadministration of digoxin and clarithromycin may also lead to increased serum concentrations of digoxin. Some patients experienced clinical symptoms of digoxin toxicity including potentially fatal arrhythmias. Serum digoxin concentrations should be carefully monitored when clarithromycin and digoxin are coadministered.

Zidovudine

Concomitant use of clarithromycin tablets and oral zidovudine by adult HIV-infected patients may result in decreased steady-state zidovudine concentrations.

Because clarithromycin interferes with the oral absorption of zidovudine, the interaction can be largely avoided by taking clarithromycin and zidovudine 4 hours apart.

A similar interaction was not observed in HIV-infected children taking clarithromycin pediatric suspension with zidovudine or dideoxyinosine. Since clarithromycin may interfere with the absorption of zidovudine when taken orally in adult patients, such an interaction is unlikely to occur when clarithromycin is used intravenously.

Phenytoin and valproic acid

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

Bidirectional drug interactions

Ltazanavir

Clarithromycin and atazanavir are both substrates and inhibitors of the CYP3A isoenzyme. There is evidence of a bidirectional interaction between these drugs. Coadministration of clarithromycin (500 mg twice daily) and atazanavir (400 mg once daily) may result in a twofold increase in clarithromycin exposure and a 70% decrease in 14-OH-clarithromycin exposure, with a 28% increase in atazanavirane AUC.

Due to the wide therapeutic range of clarithromycin, dose reduction is not required in patients with normal renal function. In patients with moderate renal failure (creatinine clearance 30 – 60 ml/min), the dose of clarithromycin should be reduced by 50%. In patients with CC 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 should not be used in conjunction with protease inhibitors.

Blockers of “slow” calcium channels

When using clarithromycin simultaneously with blockers of “slow” calcium channels that are metabolized by the CYP3A4 isoenzyme (for example, verapamil amlodipine diltiazem), caution should be exercised since there is a risk of arterial hypotension. Plasma concentrations of clarithromycin, as well as slow calcium channel blockers, may increase with simultaneous use. Arterial hypotension, bradyarrhythmia and lactic acidosis are possible when taking clarithromycin and verapamil simultaneously.

Itraconazole

Clarithromycin and itraconazole are substrates and inhibitors of the CYP3A isoenzyme, which determines the bidirectional interaction of the drugs. Clarithromycin may increase plasma concentrations of itraconazole while itraconazole may increase plasma concentrations of clarithromycin. Patients taking itraconazole and clarithromycin concomitantly should be closely monitored for symptoms of increased or prolonged pharmacological effects of these drugs.

Saquinavir

Clarithromycin and saquinavir are substrates and inhibitors of the CYP3A isoenzyme, which determines the bidirectional interaction of the drugs. Coadministration of clarithromycin (500 mg twice daily) and saquinavir (soft gelatin capsule 1200 mg three times daily) in 12 healthy volunteers increased the AUC and Cmax of saquinavir by 177% and 187%, respectively, compared with saquinavir alone. The AUC and Cmax values ​​of clarithromycin were approximately 40% higher than with clarithromycin monotherapy. When these two drugs are used together for a limited time in the doses/compositions indicated above, no dose adjustment is required. The results of drug interaction studies using saquinavir soft gelatin capsules may not correspond to the effects observed with saquinavir hard gelatin capsules. The results of drug interaction studies with saquinavir monotherapy may not correspond to the effects observed with saquinarine/ritonavir therapy. When taking saquinavir with ritonavir, the potential effect of ritonavir on clarithromycin should be considered.

Overdose

Symptoms: Taking a large dose of clarithromycin may cause gastrointestinal symptoms.

In one patient with a history of bipolar disorder, changes in mental status, paranoid behavior, hypokalemia, and hypoxemia were described after taking 8 g of clarithromycin.

Storage conditions

In a place protected from light, at a temperature not exceeding 30 °C

Shelf life

1 year

Manufacturer

EbbVee S.r.L., Italy