Clacid, 125 mg/5 ml 70.7 g

Name: Clacid, 125 mg/5 ml 70.7 g
SKU: 321280
Availability: InStock

€16.90

EAN: 8002660028372 SKU: 321280 Categories: Antibiotics, Medicine

Description

Pharmacotherapeutic group: Antibiotic, macrolide

Pharmacological action

Semi-synthetic antibiotic of macrolide group. It has antibacterial action, interacting with 50S ribosomal subunit of bacteria 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 per log₂ dilution.

Clarithromycin in vitro is highly active against Legionella pneumophila and 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 on clinically relevant mycobacterial species. 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 demonstrated both in vitro and in clinical practice for the diseases listed under “Indications”.

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 β-lactamase has no effect on clarithromycin activity.

Most strains of staphylococci resistant to methicillin and oxacillin are also resistant to clarithromycin.

Helicobacter pylori

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

Clarithromycin has action in vitro against most strains of the microorganisms listed below, 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: Streptococcus agalactiae, Streptococci (groups C, F, G), Streptococci group Viridans; aerobic Gram-negative microorganisms: Bordetella pertussis, Pasteurella multocida; anaerobic gram-positive microorganisms: Clostridium perfringens, Peptococcus niger, Propionibacterium acnes; anaerobic gram-negative microorganisms: Bacteroides melaninogenicus; spirochetes: Borrelia burgdorferi, Treponema pallidum; Campylobacter: Campylobacter jejuni.

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 Haemophilus influenzae, against which the effectiveness of the metabolite is 2 times higher. The parent compound and its main metabolite have either additive or synergistic effect against Naemophilus influenzae under in vitro and in vivo conditions depending on the bacterial strain.

Sensitivity test

Quantitative methods that require measurement of the diameter of the growth suppression zone provide the most accurate estimates of bacterial sensitivity to antimicrobial agents. One recommended technique for sensitivity testing uses discs impregnated with 15 µg of clarithromycin (Kirby-Bauer disc-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.

When 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. A response of “intermediate resistance” suggests that the therapeutic effect of the drug may be ambiguous or the microorganism may be sensitive when higher doses of the drug are used (“intermediate resistance” is also called “moderate resistance”).

Pharmacokinetics

Intake

The first pharmacokinetic data were obtained when clarithromycin tablets were studied. The drug is rapidly absorbed from the gastrointestinal tract. The absolute bioavailability of clarithromycin tablets of 250 mg is approximately 50%. Food slightly delayed the onset of absorption and formation of the active metabolite 14-OH clarithromycin, but did not affect the bioavailability of the drug.

Distribution, metabolism and excretion

In in vitro studies, the plasma protein binding of clarithromycin averaged about 70% at clinically relevant concentrations of 0.45 to 4.5 µg/mL.

Healthy. The bioavailability and pharmacokinetics of clarithromycin suspension were studied in healthy adults and children. When administered as a single dose in adults, the overall bioavailability of the suspension was equivalent to that of the tablets (in both cases the dose was 250 mg) or slightly higher. As with tablets, food slightly delayed absorption of clarithromycin suspension, but had no effect on the overall bioavailability of the drug. The maximum concentration (C_max), area under the concentration-time curve (AUC) and elimination half-life (T_1/2) of clarithromycin when taking the infant suspension (after meals) were 0.95 µg/mL, 6.5 µg×h/mL, and 3.7 h, respectively, and 1.10 µg/mL, 6.3 µg×h/mL, and 3.3 h, respectively, when the 250 mg tablet (fasting) was taken.

When clarithromycin suspension was administered at a dose of 250 mg every 12 h in adults, equilibrium concentrations (C_ss) in the blood were reached by the fifth dose. The pharmacokinetic parameters were as follows: C_max was 1.98 μg/mL, AUC was 11.5 μg×h/mL, time to reach maximum concentration (T_max) was 2.8 h and T_1/2 – 3.2 h for clarithromycin and, respectively, 0.67, 5.33, 2.9 and 4.9 for 14-OH clarithromycin.

In healthy subjects, serum concentrations peaked within 2 h after ingestion on an empty stomach. When the drug is taken in tablet form at a dose of 250 mg every 12 h, the peak equilibrium serum concentrations of clarithromycin were reached within 2-3 days and were approximately 1 mcg/ml. Corresponding peak concentrations for the 500 mg dose every 12 h ranged from 2 µg/ml to 3 µg/ml.

The T_1/2 of clarithromycin was 3-4 h when tablets were taken 250 mg every 12 h, but increased to 5-7 h after 500 mg every 12 h. The equilibrium C_max of the main metabolite, 14-OH-clarithromycin, is about 0.6 µg/mL, and the T_1/2 when the drug is taken at a dose of 250 mg every 12 h is 5-6 h. When clarithromycin is taken at a dose of 500 mg every 12 h, the equilibrium C_max of 14-OH-clarithromycin is slightly higher (up to 1 µg/mL), and the T_1/2 is about 7 h. With both doses, equilibrium concentrations of the metabolite are usually reached within 2-3 days.

When using clarithromycin at a dose of 250 mg every 12 h, approximately 20% of the dose is excreted unchanged by the kidneys. When using clarithromycin in a dose of 500 mg every 12 hours approximately 30% of the dose is excreted unchanged by the kidneys. Renal clearance of clarithromycin is not significantly dose-dependent and is approximately equal to normal glomerular filtration rate. The main metabolite detected in the urine is 14-OH clarithromycin, the proportion of which is 10-15% of the dose (250 or 500 mg every 12 hours).

Patients. Clarithromycin and its metabolite 14-OH-clarithromycin penetrate rapidly into tissues and body fluids. Tissue concentrations are usually several times higher than serum concentrations.

The table shows examples of tissue and serum concentrations:

Concentrations (250 mg every 12 h)
Tissue type		Tissue (µg/g)	Serum (µg/mL)
Mindalids	1.6	0.8
Lungs	8.8	1.7

In children who required oral antibiotic treatment, clarithromycin demonstrated high bioavailability, with a pharmacokinetic profile similar to that of adults taking the same dosage form. The drug is quickly and well absorbed in children. Food slightly delays absorption of clarithromycin, but has no significant effect on its bioavailability or pharmacokinetic properties. Equilibrium parameters of clarithromycin pharmacokinetics achieved after 5 days (ninth dose) were as follows: C_max was 4.60 μg/mL, AUC was 15.7 μg×h/mL, and T_max was 2.8 h; corresponding values for the 14-OH metabolite clarithromycin were 1.64 μg/mL, 6.69 μg×h/mL, and 2.7 h, respectively. The calculated T_1/2 of clarithromycin and its metabolite were 2.2 and 4.3 h, respectively.

In patients with otitis media, 2.5 h after the fifth dose (7.5 mg/kg 2 times/day), the mean concentrations of clarithromycin and its metabolite in 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.

Pharmacokinetics in special clinical cases

Hepatic impairment. C_ss of clarithromycin in patients with impaired liver function do not differ from those in healthy subjects, while 14-OH-clarithromycin concentrations were lower. The decrease in 14-OH-clarithromycin formation in patients with hepatic impairment was at least partially offset by increased renal clearance of clarithromycin compared to that in healthy subjects.

Renal dysfunction. The pharmacokinetics of clarithromycin were also altered in patients with impaired renal function who received the drug in repeated doses of 500 mg. In such patients, plasma concentrations, T_1/2, C_max, C_min and AUC of clarithromycin and its metabolite were higher than in healthy subjects. Deviations of these parameters correlated with the degree of renal impairment: the differences were greater with more severe renal impairment.

Patients in the elderly. Elderly patients had higher blood concentrations of clarithromycin and its metabolite 14-OH-clarithromycin and slower excretion than the younger group (when clarithromycin was given in repeated doses of 500 mg). However, after adjusting the results for renal creatinine clearance (KK), there were no differences in the two groups. Thus, the main influence on the pharmacokinetic parameters of clarithromycin is renal function, not age.

Patients with mycobacterial infections. C_ss clarithromycin and 14-OH clarithromycin in patients with HIV infection who received clarithromycin at conventional doses (adult tablets, pediatric suspension) were similar to those in healthy subjects. However, when clarithromycin is given in higher doses, which may be necessary to treat mycobacterial infections, concentrations of the antibiotic may be significantly higher than usual.

In children with HIV infection who took clarithromycin at a dose of 15 to 30 mg/kg/day in two doses, equilibrium C_max values were typically 8 to 20 µg/mL. However, in children with HIV infection who received clarithromycin suspension at a dose of 30 mg/kg/day in two doses, C_max reached 23 µg/ml. When the drug was taken at higher doses, there was a prolongation of T_1/2 compared to that in healthy subjects receiving clarithromycin at normal doses. Increased plasma concentrations and prolongation of T_1/2 when using clarithromycin at higher doses are due to the non-linear pharmacokinetics of the drug.

Indications

Infectious and inflammatory diseases caused by microorganisms sensitive to clarithromycin:

lower respiratory tract infections (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.

Pharmacological effect

Pharmacotherapeutic group: Antibiotic, macrolide

Pharmacological action

Semi-synthetic antibiotic of the macrolide group. It has an antibacterial effect by interacting with the 50S ribosomal subunit of bacteria and inhibiting protein synthesis in bacteria sensitive to it.

Clarithromycin demonstrated high activity in vitro 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 on average by one log2 dilution.

Clarithromycin is highly active in vitro against Legionella pneumophila and Mycoplasma pneumoniae. 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 is active against clinically relevant mycobacterial species. 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 both in vitro and in clinical practice for the diseases listed in the “Indications” section.

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) – a complex including Mycobacterium avium, Mycobacterium intracellulare.

The production of β-lactamase 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 Helicobacter pylori to clarithromycin was studied on Helicobacter pylori isolates isolated from 104 patients before starting drug therapy. Helicobacter pylori strains resistant to clarithromycin were isolated in 4 patients, moderately resistant strains were isolated in 2 patients, and Helicobacter pylori isolates were sensitive to clarithromycin in the remaining 98 patients.

Clarithromycin is effective in vitro against most strains of the microorganisms listed below, but the safety and effectiveness of 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), streptococci of the Viridans group; aerobic gram-negative microorganisms: Bordetella pertussis, Pasteurella multocida; anaerobic gram-positive microorganisms: Clostridium perfringens, Peptococcus niger, Propionibacterium acnes; anaerobic gram-negative microorganisms: Bacteroides melaninogenicus; spirochetes: Borrelia burgdorferi, Treponema pallidum; Campylobacter: 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 parent substance, or 1-2 times weaker against most microorganisms. The exception is Haemophilus influenzae, for which the effectiveness of the metabolite is 2 times higher. The parent compound and its major metabolite have either additive or synergistic effects against Haemophilus influenzae in vitro and in vivo, depending on the bacterial strain.

Sensitivity test

Quantitative methods that require measuring the diameter of the zone of growth inhibition provide the most accurate estimates of bacterial sensitivity to antimicrobial drugs. One recommended technique 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 report from the laboratory that the strain is “susceptible” indicates that the infectious agent is likely to respond to treatment. A “resistant” response indicates that the pathogen may not respond to treatment. The answer “intermediate resistance” suggests that the therapeutic effect of the drug may be ambiguous or the organism may be sensitive when using higher doses of the drug (“intermediate resistance” is also called “moderate resistance”).

Pharmacokinetics

Suction

The first data on pharmacokinetics were obtained from the study of clarithromycin tablets. The drug is quickly absorbed from the gastrointestinal tract. The absolute bioavailability of clarithromycin 250 mg tablets is approximately 50%. Food slightly 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 in vitro studies, the binding of clarithromycin to plasma proteins averaged about 70% at clinically relevant concentrations from 0.45 to 4.5 μg/ml.

Healthy. The bioavailability and pharmacokinetics of clarithromycin suspension were studied in healthy adults and children. When administered as a single dose in adults, the overall bioavailability of the suspension was equivalent to or slightly greater than that of the tablets (both 250 mg doses). As with tablets, food slightly delayed the absorption of clarithromycin suspension but did not affect the overall bioavailability of the drug. The maximum concentration (Cmax), area under the concentration-time curve (AUC) and half-life (T1/2) of clarithromycin when taking the pediatric suspension (after meals) were 0.95 μg/ml, 6.5 μg × h/ml and 3.7 hours, respectively, and when taking a 250 mg tablet (on an empty stomach) – 1.10 μg/ml, 6.3 µg×h/ml and 3.3 h, respectively.

When clarithromycin suspension was administered at a dose of 250 mg every 12 hours in adults, steady-state blood concentrations (Css) were reached by the fifth dose. The pharmacokinetic parameters were as follows: Cmax – 1.98 µg/ml, AUC – 11.5 µg×h/ml, time to reach maximum concentration (Tmax) – 2.8 hours and T1/2 – 3.2 hours for clarithromycin and, respectively, 0.67, 5.33, 2.9 and 4.9 for 14-OH-clarithromycin.

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

T1/2 of clarithromycin was 3-4 hours when taking 250 mg tablets every 12 hours, but increased to 5-7 hours after taking 500 mg every 12 hours. The steady-state Cmax of the main metabolite, 14-OH-clarithromycin, is about 0.6 μg/ml, and T1/2 when taking the drug at a dose of 250 mg every 12 hours is 5-6 h. When taking clarithromycin at a dose of 500 mg every 12 hours, the equilibrium Cmax of 14-OH-clarithromycin is slightly higher (up to 1 μg/ml), and T1/2 is about 7 hours. When using both doses, equilibrium concentrations of the metabolite are usually achieved within 2-3 days.

When clarithromycin is used at a dose of 250 mg every 12 hours, approximately 20% of the dose is excreted unchanged by the kidneys. When clarithromycin is taken at a dose of 500 mg every 12 hours, approximately 30% of the dose is excreted unchanged by the kidneys. The renal clearance of clarithromycin is not significantly dose dependent and is approximately equal to the normal glomerular filtration rate. The main metabolite detected in urine is 14-OH-clarithromycin, which accounts for 10-15% of the dose (250 or 500 mg every 12 hours).

Patients. Clarithromycin and its metabolite 14-OH-clarithromycin quickly penetrate into body tissues and fluids. Tissue concentrations are usually several times higher than serum concentrations.

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
1.6
0.8
Lungs
8.8
1.7

In children requiring oral antibiotic treatment, clarithromycin showed high bioavailability, with a pharmacokinetic profile similar to that in adults taking the same dosage form. The drug is quickly and well absorbed in children. Food slightly 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: Cmax – 4.60 μg/ml, AUC – 15.7 μg×h/ml and Tmax – 2.8 h; the corresponding values for the 14-OH-clarithromycin metabolite were 1.64 μg/ml, 6.69 μg×h/ml and 2.7 h, respectively. The calculated T1/2 of clarithromycin and its metabolite are 2.2 and 4.3 hours, respectively.

In patients with otitis media, 2.5 hours after taking the fifth dose (7.5 mg/kg 2 times/day), the average concentrations of clarithromycin and its metabolite in the middle ear fluid were 2.53 and 1.27 mcg/g. Concentrations of the drug and its metabolite were 2 times higher than serum concentrations.

Pharmacokinetics in special clinical situations

Liver dysfunction. Css of clarithromycin in patients with impaired liver function did not differ from those in healthy subjects, while concentrations of 14-OH-clarithromycin were lower. The decreased formation of 14-OH-clarithromycin in patients with hepatic impairment was at least partially offset by the increased renal clearance of clarithromycin compared with that in healthy subjects.

Renal dysfunction. 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, T1/2, Cmax, Cmin and AUC of clarithromycin and its metabolite were higher than in healthy people. Deviations in these parameters correlated with the degree of renal failure: with more severe renal dysfunction, the differences were more significant.

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 a group of young people (when taking clarithromycin in repeated doses of 500 mg). However, after adjusting the results for renal creatinine clearance (CK), there were no differences in both groups. Thus, the main influence on the pharmacokinetic parameters of clarithromycin is renal function, and not age.

Patients with mycobacterial infections. Css 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 clarithromycin is taken in higher doses, which may be required to treat mycobacterial infections, concentrations of the antibiotic may be significantly higher than usual.

In children with HIV infection receiving clarithromycin at a dose of 15-30 mg/kg/day in two doses, steady-state Cmax values typically ranged from 8 to 20 mcg/ml. However, in children with HIV infection who received a clarithromycin suspension at a dose of 30 mg/kg/day in two doses, Cmax reached 23 mcg/ml. When taking the drug in higher doses, a prolongation of T1/2 was observed compared with that in healthy people receiving clarithromycin in usual doses. Increased plasma concentrations and prolongation of T1/2 when using clarithromycin in higher doses are associated with the nonlinear pharmacokinetics of the drug.

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.

Cases of hepatic dysfunction (increased activity of liver enzymes in the blood, hepatocellular and/or cholestatic hepatitis with or without jaundice) have been reported with the use of clarithromycin. Liver dysfunction can be severe but is usually reversible. There have been 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 appear, such as anorexia, jaundice, dark urine, itching, abdominal tenderness on palpation, 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 drugs, incl. clarithromycin, cases of Clostridium difficile-associated diarrhea have been described, the severity of which can range from mild diarrhea to life-threatening colitis. Antibacterial drugs can change the normal intestinal microflora, which can lead to the growth of Clostridium difficile. Pseudomembranous colitis caused by Clostridium difficile should be suspected in any patient who develops diarrhea after taking 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.

Prolongation of cardiac repolarization and QT interval has been observed during treatment with macrolides, including clarithromycin, causing a risk of cardiac arrhythmia and torsade de pointes (TdP). Because the following situations may lead to an increased risk of developing ventricular arrhythmias (including ventricular tachycardia of the “pirouette” type), then

Clarithromycin should not be used in the following categories of patients:
in patients with hypokalemia;
simultaneous administration of clarithromycin with astemizole, cisapride, pimozide and terfenadine is contraindicated;
in patients with congenital or acquired documented prolongation of the QT interval or a history of ventricular arrhythmia.
Clarithromycin should be used with caution in the following categories of patients:
in patients with coronary artery disease, severe heart failure, conduction disorders or clinically significant bradycardia;
in patients with electrolyte disturbances such as hypomagnesemia;
in patients concomitantly taking other drugs associated with prolongation of the QT interval.

Epidemiological studies examining the risk of adverse cardiovascular outcomes with macrolide use have reported mixed results. Some observational studies have identified 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 perform susceptibility 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.

If acute hypersensitivity reactions occur, such as anaphylactic reaction, severe cutaneous drug reactions (eg, acute generalized exanthematous pustulosis), Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS syndrome), immediately stop taking clarithromycin and initiate appropriate therapy.

In case of combined use with warfarin or other indirect anticoagulants, it is necessary to monitor the INR and prothrombin time.

When prescribing the drug to patients with diabetes, it is necessary to take into account that the drug contains sucrose: Klacid®, granules for the preparation of a suspension for oral administration 125 mg/5 ml, in 1 ml of suspension – 0.055 XE or 0.55 g of sucrose; Klacid®, granules for the preparation of a suspension for oral administration 250 mg/5 ml, in 1 ml of suspension – 0.046 XE or 0.46 g of sucrose.

Impact on the ability to drive vehicles and machinery

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 or machinery, given the potential for dizziness, vertigo, confusion and disorientation that may occur while taking this drug.

Active ingredient

Clarithromycin

Composition

5 ml of ready-made suspension:

Active substances:

clarithromycin 250 mg

Excipients:

carbomer (carbopol 974P) – 150 mg,

povidone K90 – 35 mg,

hypromellose phthalate – 304.2 mg,

castor oil – 32.1 mg,

silicon dioxide – 10 mg,

maltodextrin – 238.7 mg,

sucrose – 2276.2 mg,

titanium dioxide – 35.7 mg,

xanthan gum – 3.8 mg,

fruit flavoring – 35.7 mg,

potassium sorbate – 20 mg,

citric acid – 4.24 mg.

Contraindications

simultaneous use of clarithromycin with the following drugs: astemizole, cisapride, pimozide, terfenadine;
simultaneous use of clarithromycin with ergot alkaloids, for example, ergotamine, dihydroergotamine;
simultaneous use of clarithromycin with midazolam for oral administration;
simultaneous use of clarithromycin with HMG-CoA reductase inhibitors (statins), which are largely metabolized by the CYP3A4 isoenzyme (lovastatin or simvastatin), due to an increased risk of myopathy, including rhabdomyolysis;
simultaneous use of clarithromycin with colchicine;
simultaneous use of clarithromycin with ticagrelor or ranolazine;
history of QT prolongation (congenital or acquired recorded QT prolongation) or ventricular arrhythmia, including torsade de pointes (TdP);
hypokalemia (risk of QT interval prolongation);
severe liver failure occurring simultaneously with renal failure;
history of cholestatic jaundice/hepatitis that developed while using clarithromycin;
congenital fructose intolerance, sucrase-isomaltase deficiency, glucose-galactose malabsorption syndrome;
porphyria;
breastfeeding period;
hypersensitivity to clarithromycin, macrolides and other components of the drug.

With caution:

moderate to severe renal failure;
moderate to severe liver failure;
simultaneous use of clarithromycin with benzodiazepines, such as alprazolam, triazolam, midazolam for intravenous use or for application to the oral mucosa;
simultaneous 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;
simultaneous use with drugs that induce the CYP3A4 isoenzyme, for example, rifampicin, phenytoin, carbamazepine, phenobarbital, St. John’s wort;
simultaneous use of clarithromycin with statins that do not depend on the metabolism of the CYP3A isoenzyme (for example, fluvastatin);
simultaneous use with slow calcium channel blockers that are metabolized by the CYP3A4 isoenzyme (for example, verapamil, amlodipine, diltiazem);
coronary heart disease (CHD), severe heart failure, hypomagnesemia, conduction disturbances or clinically significant bradycardia, as well as simultaneous use of class IA (quinidine, procainamide) and class III antiarrhythmic drugs (dofetilide, amiodarone, sotalol);
pregnancy;
diabetes mellitus (the drug contains sucrose).

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: often – rash; uncommon – anaphylactoid reaction1, hypersensitivity, bullous dermatitis1, itching, urticaria, maculopapular rash3; frequency unknown – anaphylactic reaction, angioedema, serious cutaneous adverse reactions (for example, acute generalized exanthematous pustulosis), Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS syndrome).

From the nervous system: often – headache, insomnia; uncommon – loss of consciousness1, dyskinesia1, dizziness, drowsiness, tremor, anxiety, increased excitability3; frequency unknown – convulsions, psychotic disorders, confusion, depersonalization, depression, disorientation, hallucinations, dream disturbances (nightmares), paresthesia, mania.

From the skin: often – intense sweating; frequency unknown – acne.

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

From the side of metabolism and nutrition: infrequently – anorexia, loss of appetite.

From the musculoskeletal system: infrequently – muscle spasm3, musculoskeletal stiffness1, myalgia2; frequency unknown – rhabdomyolysis2*, myopathy.

From the digestive system: often – 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 and hepatocellular4; frequency unknown – acute pancreatitis, discoloration of the tongue and teeth, liver failure, cholestatic jaundice.

From the respiratory system: infrequently – asthma1, nosebleeds2, pulmonary embolism1.

From the senses: often – dysgeusia; infrequently – vertigo, hearing loss, ringing in the ears; frequency unknown – deafness, ageusia (loss of taste), parosmia, anosmia.

From the cardiovascular system: often – vasodilation1; uncommon – cardiac arrest1, atrial fibrillation1, prolongation of the QT interval on the ECG, extrasystole1, palpitations; frequency unknown – ventricular tachycardia, incl. pirouette type, ventricular fibrillation, bleeding.

From the laboratory parameters: often – deviation in the liver test; infrequently – increased creatinine concentration1, increased urea concentration1, change in albumin-globulin ratio1, leukopenia, neutropenia4, eosinophilia4, thrombocythemia3, increased activity of ALT, AST, GGTP4, ALP4, LDH4; frequency unknown – agranulocytosis, thrombocytopenia, increased MHO value, prolongation of prothrombin time, change in urine color, increased bilirubin concentration in the blood.

General disorders: very often – phlebitis at the injection site1, often – pain at the injection site1, inflammation at the injection site1; uncommon – malaise4, hyperthermia3, asthenia, chest pain4, chills4, fatigue4.

Infectious and parasitic diseases: infrequently – cellulitis1, candidiasis, gastroenteritis2, secondary infections (including vaginal)3; 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 for the treatment of mycobacterial infections, it is often difficult to distinguish adverse 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 equal to 1000 mg were: nausea, vomiting, taste disturbance, abdominal pain, diarrhea, rash, flatulence, headache, constipation, hearing loss, increased concentrations of AST and ALT in the blood. Low incidence adverse events such as shortness of breath, insomnia and dry mouth were also reported.

In patients with suppressed immunity, laboratory parameters were assessed, analyzing their significant deviations from standard values (sharp increase or decrease). Based on this criterion, 2-3% of patients receiving clarithromycin at a dose of 1000 mg daily had significant increases in AST and ALT concentrations in the blood, as well as a decrease in the number of leukocytes and platelets. Increases in residual urea nitrogen concentrations have also been reported in a small number of patients.

*In some reports of rhabdomyolysis, clarithromycin was co-administered with other drugs known to be associated with rhabdomyolysis (statins, fibrates, colchicine or allopurinol).

1 Reports of these adverse reactions were received during clinical trials, as well as post-marketing use of the drug Klacid®, lyophilisate for solution for infusion.

2 Reports of these adverse reactions have been received during clinical trials and post-marketing use of Klacid® SR, extended-release film-coated tablets.

3 Reports of these adverse reactions have been received during clinical trials, as well as post-marketing use of Klacid®, granules for oral suspension.

4 Reports of these adverse reactions were received during the use of the drug Klacid®, film-coated tablets. Classification of adverse reactions by frequency of development (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 experience post-marketing use; frequency cannot be estimated based on available data).