Klacid sr 500 mg 14 pcs. extended-release film-coated tablets

Release form and composition

The drug is available in the form of prolonged-release, film-coated tablets: oval, yellow (5, 7, 10 or 14 pcs. in blisters made of polyvinyl chloride and aluminum foil, in a cardboard package 1 or 2 blisters together and instructions for use of Klacida SR ).

Composition per tablet:

active ingredient: clarithromycin – 500 mg;
auxiliary components of the tablet core: lactose monohydrate, magnesium stearate, anhydrous citric acid, povidone K30, stearic acid, sodium alginate, talc, sodium calcium alginate;
film coating: titanium dioxide, sorbic acid, macrogol 8000, macrogol 400, hypromellose, quinoline yellow dye.

Analogues of the drug according to ATC codes:

CLARBACT CLAREXIDE CLARITHROMYCIN CLARITROSINE CLAROMINE CLACID CLACID CLERIMED FROMILIDE FROMILIDE FROMILIDE UNO All

Before using KLACID SR you should consult your doctor. These instructions for use are for informational purposes only. For more complete information, please refer to the manufacturer's instructions.

Pharmacological properties

Pharmacodynamics

Clarithromycin is a semisynthetic antibiotic from the macrolide group. It interacts with the 50S subunit of ribosomes and inhibits protein synthesis of bacteria that are sensitive to this antibiotic (has an antibacterial effect).

Under in vitro conditions, clarithromycin is highly active against both laboratory strains and bacterial strains that were isolated from patients during clinical studies. The drug demonstrates significant pharmacological effectiveness against many anaerobic and aerobic gram-negative and gram-positive microorganisms. It should be noted that for most pathogenic microbes, the MIC (minimum inhibitory concentration) of clarithromycin is lower than similar concentrations of erythromycin (by approximately one log2 dilution).

In vitro, clarithromycin demonstrated high activity against Mycoplasma pneumoniae and Legionella pneumophila. The drug has a bactericidal effect on Helicobacter pylori, and it is more active at neutral pH than at acidic pH.

According to in vivo and in vitro data, Klacid SR affects clinically significant types of mycobacteria. Pseudomonas spp., Enterobacteriaceae and other gram-negative bacteria that do not ferment lactose are not sensitive to the drug.

The activity of clarithromycin in vitro and in clinical practice has been proven against most strains of the following microorganisms:

aerobic gram-negative bacteria: Moraxella catarrhalis, Legionella pneumophila, Haemophilus influenzae, Neisseria gonorrhoeae, Haemophilus parainfluenzae;
aerobic gram-positive bacteria: Streptococcus pneumoniae, Staphylococcus aureus, Listeria monocytogenes, Streptococcus pyogenes;
mycobacteria: Mycobacterium kansasii, Mycobacterium fortuitum, Mycobacterium leprae, Mycobacterium chelonae, Mycobacterium avium complex (includes Mycobacterium intracellulare and Mycobacterium avium);
other microorganisms: Chlamydia pneumoniae (TWAR pathogen), Mycoplasma pneumoniae.

The activity of clarithromycin does not depend on the production of beta-lactamase. Staphylococcal strains resistant to oxacillin and methicillin are also resistant to clarithromycin.

Klacid SR is active against Helicobacter pylori, however, some strains of this bacterium (about 10%) are resistant to clarithromycin or have moderate resistance to the drug.

In vitro, clarithromycin was effective against most strains of the following microorganisms (the effectiveness of the drug against the listed bacteria in clinical practice has not been confirmed by relevant studies and the practical significance of clarithromycin in these cases remains unclear):

aerobic gram-negative bacteria: Pasteurella multocida, Bordetella pertussis;
aerobic gram-positive bacteria: VGS (Viridans group streptococci), Streptococci (groups C, F, G), Streptococcus agalactiae;
anaerobic gram-negative bacteria: Bacteroides melaninogenicus;
anaerobic gram-positive bacteria: Peptococcus niger, Clostridium perfringens, Propionibacterium acnes;
Campylobacter: Campylobacter jejuni;
spirochetes: Treponema pallidum, Borrelia burgdorferi.

The main metabolite of clarithromycin in the human body is 14-OH-clarithromycin (14-hydroxyclarithromycin). Its microbiological activity is similar to the original substance or 2 times weaker. This situation is observed for most microorganisms, with the exception of Haemophilus influenzae. The effectiveness of the metabolite against Haemophilus influenzae is 2 times higher than the activity of clarithromycin. The parent substance and metabolite exhibit additive synergism against Haemophilus influenzae.

Pharmacokinetics

The absorption of clarithromycin when administered in the form of extended-release tablets and regular-release tablets is the same (if the doses are equivalent). Metabolism is carried out by the liver enzyme system CYP3A. The bioavailability of clarithromycin is about 50%. The drug does not accumulate with repeated use.

After taking Klacid SR in therapeutic doses, binding to plasma proteins is 70%. The maximum plasma concentration of clarithromycin and 14-OH-clarithromycin (after taking 500 mg of the drug) is 1.3 μg/ml and 0.48 μg/ml, respectively. The half-life of clarithromycin was 5.3 hours, and that of its active metabolite was 7.7 hours. After taking a single dose of 1000 mg (2 tablets of the drug), the maximum plasma concentrations and half-life were: 2.4 μg/ml and 5.8 hours for clarithromycin; 0.67 μg/ml and 8.9 hours for 14-OH-clarithromycin. The time to peak concentration was the same for both the 500 mg dose and the 1000 mg dose and was about 6 hours.

The pharmacokinetics of the drug is nonlinear: the maximum concentration of the active metabolite in plasma does not increase in proportion to the dose of the drug, but the half-life of both clarithromycin and 14-OH-clarithromycin lengthens with increasing doses of Klacid SR.

About 40% of the drug entering the body is excreted by the kidneys and approximately 30% by the intestines.

Clarithromycin and its active metabolite are rapidly distributed into various tissues and fluids. The concentration of the drug in tissues is usually several times higher than the serum concentration. A small amount of clarithromycin (approximately 1–2% of serum concentration) penetrates into the cerebral fluid.

In case of moderate and severe liver dysfunction (if kidney function is preserved), no dose adjustment of Klacid SR is required. The systemic clearance of clarithromycin and its equilibrium concentration in plasma in patients of this group are similar to those in healthy volunteers, but the equilibrium concentration of the active metabolite in liver dysfunction decreases when compared with healthy people.

In patients with impaired renal function, the maximum and minimum plasma concentrations of clarithromycin, the half-life, and the AUC (area under the concentration-time curve) of clarithromycin and its active metabolite are increased. Excretion of the drug by the kidneys and the elimination constant are reduced. The degree of change in these parameters correlates with the degree of renal dysfunction.

In elderly patients, plasma levels of the drug and the active metabolite are higher and the rate of elimination is slower than in younger patients. After dose adjustment taking into account renal impairment, these differences disappear, that is, the main influence on the pharmacokinetics of clarithromycin is the degree of renal impairment, and not the age of the patient.

Klacid sr 500 mg 14 pcs. extended-release film-coated tablets

pharmachologic effect

Antibiotic macrolide.

Composition and release form Klacid sr 500 mg 14 pcs. extended-release film-coated tablets

Tablets - 1 tablet:

Active ingredient: clarithromycin - 500.0 mg;
Excipients: anhydrous citric acid - 128.00 mg, sodium alginate - 120.00 mg, sodium calcium alginate - 15.00 mg, lactose monohydrate - 115.0 mg, povidone-K-30 - 30.00 mg, talc - 30.0 mg, stearic acid - 21.00 mg, magnesium stearate - 10.00 mg.
Film coating: hypromellose - 9.81 mg, macrogol 400 - 3.27 mg, macrogol 8000 - 3.27 mg, titanium dioxide - 1.64 mg, yellow dye (quinoline yellow) - 1.23 mg, sorbic acid-0 .16 mg.

5, 7, 14 tablets in a blister made of PVC/PVDC/Al foil.

1 or 2 blisters along with instructions for use in a cardboard pack.

Description of the dosage form

Yellow oval film-coated tablets.

Directions for use and doses

Inside, without breaking, without chewing, swallowing whole, during meals. Usually adults are prescribed 1 tablet. clarithromycin 500 mg once daily. For more severe infections, the dose is increased to 2 tablets. (1000 mg) 1 time per day.

The usual duration of treatment is 5–14 days; The exception is patients with community-acquired pneumonia and sinusitis, the duration of treatment of which is 6–14 days.

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.

Extended-release tablets have a homogeneous base, which provides prolonged release of the active substance as it passes through the gastrointestinal tract.

Clarithromycin is highly effective in vitro against both standard laboratory strains of bacteria and those isolated from patients during clinical practice. It exhibits high activity against a wide range of aerobic and anaerobic, gram-positive and gram-negative microorganisms. The MIC of clarithromycin for most pathogens is less than the MIC of erythromycin.

In vitro studies have shown that clarithromycin is highly active against Legionella pneumophila, Mycoplasma pneumoniae, but Enterobacteriaceae, Pseudomonas spp. and other non-lactose-fermenting gram-negative microorganisms are immune to the action of clarithromycin.

The activity of clarithromycin against most strains of the microorganisms listed below has been proven both in vitro and in clinical practice for diseases.

Aerobic gram-positive microorganisms - Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes; aerobic gram-negative microorganisms - Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, Legionella pneumophila; other microorganisms - Mycoplasma pneumoniae, Chlamydia pneumoniae; mycobacteria - Mycobacterium avium complex (MAC) - a complex including Mycobacterium avium, Mycobacterium intracellulare.

Beta-lactamases do not affect the activity of clarithromycin.

Clarithromycin is active in vitro against most strains of the following microorganisms:

aerobic gram-positive microorganisms - Streptococcus agalactiae; Streptococcus spp. groups C, F, G; Streptococcus spp. Viridans groups; Listeria monocytogenes;
aerobic gram-negative microorganisms - Bordetella pertussis; Pasteurella multocida; Neisseria gonorrhoeae;
anaerobic gram-positive microorganisms - Clostridium perfringens; Peptococcus niger; Propionibacterium acnes;
anaerobic gram-negative microorganisms - Bacteroides melaninogenicus;
spirochetes - Borrelia burgdorferi; Treponema pallidum;
mycobacteria - Mycobacterium leprae, Mycobacterium kansasii, Mycobacterium chelonae, Mycobacterium fortuitum;
campylobacter - Campylobacter jejuni.

The main metabolite of clarithromycin in the human body is the microbiologically active metabolite 14(R)-hydroxy-clarithromycin (14-OH-clarithromycin), which is twice as active against Haemophilus influenzae (H. influenzae) as the parent compound. The parent compound (clarithromycin) and its metabolite, when combined, may have either additive or synergistic effects on H. influenzae in vitro and in vivo, depending on the strain of the bacterium.

Pharmacokinetics

Clarithromycin is metabolized by the cytochrome P450 3A (CYP3A) system of the liver. Absolute bioavailability is about 50%. With repeated administration of the drug, no accumulation was detected; the nature of metabolism in the human body did not change.

In vitro

In vitro studies have shown that, on average, about 70% of clarithromycin is bound to human serum proteins at drug concentrations of 0.45–4.5 μg/ml. When the concentration was increased to 45.0 μg/ml, clarithromycin binding decreased to 41%, which may indicate saturation of binding sites. This phenomenon was observed only at drug concentrations significantly higher than therapeutic levels.

Healthy Volunteers

In patients taking 500 mg of the drug Klacid® SR 1 time per day, the Cmax of clarithromycin and 14-OH-clarithromycin in the blood plasma was 1.3 and 0.48 μg/ml, respectively. T1/2 of the parent drug and metabolite were 5.3 and 7.7 hours, respectively. When taking a single dose of Klacid®SR 1000 mg (2 times 500 mg), the Cmax of clarithromycin and its hydroxylated metabolite reached 2.4 and 0.67 μg/ml, respectively. T1/2 of clarithromycin when taken at a dose of 1000 mg was 5.8 hours, while the same figure for 14-OH-clarithromycin was 8.9 hours. Tmax when taking both 500 mg and 1000 mg was approximately 6 hours. Cmax 14 -OH-clarithromycin did not increase proportionally to the dose of clarithromycin, while T1/2 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 dosages, indicates a nonlinear metabolism of clarithromycin, which becomes more pronounced at high dosages.

Approximately 40% of ingested clarithromycin is excreted by the kidneys. Approximately 30% is excreted by the intestines.

Patients taking clarithromycin for indications

Clarithromycin and its 14-OH metabolite quickly penetrate into body tissues and fluids. Limited data from trials involving small numbers of patients suggest that oral cerebrospinal fluid concentrations of clarithromycin are negligible. Concentrations in tissues are usually several times higher than in serum.

Liver diseases

A comparative study showed that if renal function was preserved in patients with moderate to severe impairment of hepatic function, no dosage adjustment was required.

Kidney diseases

In people with kidney disease, plasma concentrations, T1/2, Cmax and Cmin of clarithromycin and its 14-OH metabolite were higher than in people with normal renal function. In patients with impaired renal function, the AUC was higher, and the elimination constant and renal excretion were lower. The extent of these differences correlated with the severity of kidney disease: the more severe the renal dysfunction, the greater the differences.

Aged people

In elderly people, plasma levels of clarithromycin and its 14-OH metabolite are higher and elimination is slower compared to young people. However, the main influence on the pharmacokinetic parameters of clarithromycin is renal function, not age.

Indications for use Klacid sr 500 mg 14 pcs. extended-release film-coated tablets

Infectious and inflammatory diseases caused by microorganisms sensitive to the drug:

lower respiratory tract infections (such as bronchitis, pneumonia);
infections of the upper respiratory tract and ENT organs (such as pharyngitis, sinusitis);
infections of the skin and soft tissues (such as folliculitis, inflammation of the subcutaneous tissue, erysipelas).

Contraindications

hypersensitivity to the components of the drug and other macrolides;
severe renal failure (creatinine Cl less than 30 ml/min);
simultaneous use of clarithromycin with the following drugs: astemizole, cisapride, pimozide, terfenadine, ergotamine, dihydroergotamine;
simultaneous use with the following drugs: alprazolam, midazolam, triazolam (oral dosage forms);
children under 18 years of age (efficacy and safety have not been established);
porphyria;
lactose intolerance, lactase deficiency, glucose-galactose malabsorption.

With caution: impaired liver and kidney function; myasthenia gravis (possibly increased symptoms); simultaneous use with drugs that are metabolized by the liver.

Application Klacid sr 500 mg 14 pcs. extended-release film-coated tablets during pregnancy and lactation

The safety of clarithromycin in pregnant and lactating women has not been studied.

Use during pregnancy (especially in the first trimester) is possible only if the potential benefit to the mother outweighs the potential risk to the fetus and/or there is no safer therapy with alternative drugs.

If pregnancy occurs while using the drug, the patient should be warned about the possible risks to the fetus.

Clarithromycin is known to be excreted in breast milk. During lactation, the issue of stopping breastfeeding should be decided.

special instructions

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

Long-term use of clarithromycin, like other antibiotics, can provoke colonization with an increase in the number of resistant bacteria and fungi. If a secondary infection occurs, adequate therapy should be prescribed.

When treated with almost all antibacterial agents, cases of pseudomembranous colitis have been described, the severity of which can vary from mild to life-threatening. One of the symptoms of pseudomembranous colitis is diarrhea caused by Clostridium difficile. Therefore, when diarrhea occurs after prescribing antibacterial agents, the possibility of such a disease should be taken into account.

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.

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

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

In case of co-administration with warfarin or other indirect anticoagulants, PT must be monitored.

Overdose

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

Treatment: in case of overdose, symptomatic therapy should be carried out, including gastric lavage, aimed at maintaining the vital functions of the body. Hemodialysis and peritoneal dialysis do not have a significant effect on clarithromycin serum levels, which is also typical for other macrolide drugs.

Side effects Klacid sr 500 mg 14 pcs. extended-release film-coated tablets

Side effects are presented depending on the effect on organs and organ systems. For cases indicating frequency, consider: often >1%,

From the cardiovascular system: rarely - ventricular tachycardia, incl. pirouette type, ventricular flutter and fibrillation, increased QT interval on the ECG.

From the digestive system: often - dyspepsia, nausea, abdominal pain, vomiting, diarrhea, gastralgia, acute pancreatitis, glossitis, stomatitis, candidiasis of the oral mucosa, discoloration of the tongue and teeth, pseudomembranous enterocolitis. Liver dysfunction, incl. often - increased activity of liver enzymes, hepatocellular and cholestatic hepatitis, cholestatic jaundice. In very rare cases, fatal liver failure has been reported, mainly due to severe concomitant diseases and/or concomitant drug therapy.

From the nervous system: headaches (often); dizziness, anxiety, insomnia, dream disturbances (“nightmare” dreams), ringing in the ears, depersonalization, hallucinations, convulsions, psychotic disorders, confusion, disorientation, depression.

From the musculoskeletal system: myalgia.

From the urinary system: interstitial nephritis.

From the senses: often - distortion or loss of taste; deafness, cases of changes in sense of smell.

Allergic reactions: anaphylactic reactions, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria, skin flushing, itching, rash.

Changes in laboratory parameters: leukopenia, thrombocytopenia, increased creatinine in the blood, hypoglycemia - rarely (including when taking hypoglycemic drugs simultaneously).

Drug interactions

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

Cisapride and pimozide

When used together, it is possible to increase the concentration of cisapride, increase the QT interval, and the appearance of cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation, and torsade de pointes.

Terfenadine and astemizole

When used together, it is possible to increase the concentration of terfenadine/astemizole in the blood, increase the QT interval, cause cardiac arrhythmias, ventricular tachycardia, ventricular fibrillation and pirouette-type tachycardia.

Ergotamine/dihydroergotamine

When used together, 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.

Effect of other drugs on clarithromycin

The following drugs have a proven or suspected effect on clarithromycin concentrations; if they are co-administered 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 plasma level of clarithromycin, weaken the therapeutic effect, and at the same time increase the level of 14-OH-clarithromycin, a metabolite, also being microbiologically active.

Fluconazole

Coadministration of fluconazole 200 mg daily and clarithromycin 500 mg twice daily in 21 healthy volunteers resulted in clarithromycin trough mean Css and AUC increases of 33% and 18%, respectively.

However, co-administration did not significantly affect the average Css 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 coadministered with ritonavir, clarithromycin Cmax increased by 31%, Cmin increased by 182%, and AUC increased by 77%. Complete inhibition of 14-OH-clarithromycin formation was noted. Due to the wide therapeutic index, dosage 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: if creatinine Cl is 30–60 ml/min, the dose of clarithromycin should be reduced by 50% (no more than one Klacid® SR tablet per day). Patients with severe renal failure (Cl creatinine

Effect of clarithromycin on other drugs

Antiarrhythmic drugs (quinidine and disopyramide)

Torsade de pointes may occur when clarithromycin is co-administered with quinidine or disopyramide. When clarithromycin is coadministered with these drugs, ECG monitoring should be performed regularly to monitor for QT interval prolongation, and serum concentrations of these drugs should also be monitored.

CYP3A-mediated interactions

Co-administration of clarithromycin, which is known to inhibit CYP3A isoenzymes, and drugs primarily metabolized by CYP3A isoenzymes, may be associated with a mutual increase in their concentrations, which may increase or prolong both therapeutic and side effects. Clarithromycin should be administered with caution to patients receiving drugs that are substrates of the CYP3A enzyme, especially if the CYP3A substrate has a narrow therapeutic range (eg, carbamazepine) and/or is extensively metabolized by this enzyme. If necessary, the dose of the drug taken together with Klacid® SR should be adjusted, and the joint use of certain drugs should be excluded. Also, whenever possible, serum levels of drugs primarily metabolized by CYP3A should be monitored. The following drugs/classes are metabolized by the same CYP3A isoenzyme as clarithromycin: alprazolam, astemizole, carbamazepine, cilostazol, cisapride, cyclosporine, disopyramide, ergot alkaloids, lovastatin, methylprednisolone, midazolam, omeprazole, oral anticoagulants (e.g. warfarin), pimozide, quinidine, rifabutin, sildenafil, simvastatin, tacrolimus, terfenadine, triazolam and vinblastine. Drugs that interact similarly through other isoenzymes within the cytochrome P450 system include phenytoin, theophylline, and valproic acid.

HMG-CoA reductase inhibitors

Like other macrolides, clarithromycin increases concentrations of HMG-CoA reductase inhibitors (eg lovastatin and simvastatin). Rare cases of rhabdomyolysis have been reported in patients taking these drugs together.

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, plasma Css of omeprazole were increased (Cmax, AUC0–24 and T1/2 increased by 30, 89 and 34%, respectively). The average pH value in the stomach over 24 hours was 5.2 when taking omeprazole alone and 5.7 when taking omeprazole together with clarithromycin.

Oral anticoagulants

The effect of oral anticoagulants may be enhanced. If patients are receiving clarithromycin and oral anticoagulants concomitantly, the PT should be carefully monitored.

Sildenafil, tadalafil and vardenafil

Each of these phosphodiesterase inhibitors is metabolized, at least in part, by CYP3A. However, CYP3A may be inhibited in the presence of clarithromycin. Co-administration of clarithromycin with sildenafil, tadalafil or vardenafil may lead to increased phosphodiesterase inhibitory effects. When prescribing these drugs together, consider reducing the dose of sildenafil, tadalafil and vardenafil.

Theophylline, carbamazepine

It is possible to increase the concentration of theophylline or carbamazepine in the systemic circulation.

Tolterodine

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

Triazolobenzodiazepines (eg alprazolam, midazolam, triazolam)

When midazolam and clarithromycin (500 mg 2 times a day) were co-administered, an increase in midazolam AUC was observed: 2.7 times after intravenous administration of midazolam and 7 times after oral administration. Concomitant oral administration of midazolam and clarithromycin should be avoided. If clarithromycin is co-administered with intravenous midazolam, the patient's condition should be carefully monitored for possible dose adjustment. The same precautions should be applied to other benzodiazepines that are metabolized by CYP3A, including triazolam and alprazolam. For benzodiazepines whose elimination is not dependent on CYP3A (temazepam, nitrazepam, lorazepam), a clinically significant interaction with clarithromycin is unlikely.

When clarithromycin and triazolam are used together, CNS effects such as drowsiness and confusion are possible.

Interaction with other drugs

Colchicine

Colchicine is a substrate of both CYP3A and the drug efflux transport protein P-glycoprotein (P-gp). Clarithromycin and other macrolides are known to inhibit CYP3A and P-gp. When clarithromycin and colchicine are co-administered, inhibition of P-gp and/or CYP3A may result in an increased effect of colchicine. There have been post-marketing reports of cases of colchicine poisoning when taken concomitantly with clarithromycin, most often in elderly patients. Some of the reported cases occurred in patients suffering from kidney failure. Some cases were reported to be fatal.

Digoxin

Digoxin is thought to be a substrate for P-gp. Clarithromycin is known to inhibit P-gp. When clarithromycin and digoxin are co-administered, inhibition of P-gp by clarithromycin may result in increased effects of digoxin. Coadministration of digoxin and clarithromycin may also result in increased serum digoxin concentrations in patients, developing 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 regular-release oral tablets and zidovudine in adult HIV-infected patients may result in a decrease in the Css of zidovudine. Because clarithromycin interferes with the oral absorption of zidovudine, interactions can be largely avoided by titrating the dosage of clarithromycin and zidovudine. This type of interaction does not occur in HIV-infected children receiving clarithromycin suspension with zidovudine. Interaction studies between Klacid® SR and zidovudine have not been conducted.

Bidirectional drug interactions

Atazanavir

Clarithromycin and atazanavir are substrates and inhibitors of CYP3A. There is evidence of a bidirectional interaction between these drugs. Coadministration of clarithromycin (500 mg twice daily) and atazanavir (400 mg once daily, daily) may result in a 28% increase in atazanavir AUC, a twofold increase in clarithromycin AUC, and a 70% decrease in 14-OH-clarithromycin AUC. Due to the wide therapeutic range of clarithromycin, no dose reduction is required in patients with normal renal function. In patients with moderate renal impairment (Cl creatinine 30–60 ml/min), the dose of clarithromycin should be reduced by 50%. Clarithromycin in doses exceeding 1000 mg/day should not be co-administered with protease inhibitors.

Itraconazole

Clarithromycin and itraconazole are substrates and inhibitors of CYP3A. Clarithromycin may increase plasma levels of itraconazole, while itraconazole may increase clarithromycin levels. 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 CYP3A. Coadministration of clarithromycin (500 mg twice daily) and saquinavir (soft gelatin capsules, 1200 mg three times daily) may increase 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. When these two drugs are administered together for a limited time at the doses/formulations indicated above, no dose adjustment is required. The results of drug interaction studies using saquinavir soft gelatin capsules may not be consistent with the effects observed with saquinavir hard gelatin capsules. The results of drug interaction studies with saquinavir alone may not correspond to the effects observed with saquinavir/ritonavir therapy. When taking saquinavir with ritonavir, consider the potential effect of ritonavir on clarithromycin.

Verapamil

When taken together with clarithromycin, arterial hypotension, bradyarrhythmia and lactic acidosis are possible.

Contraindications

Absolute:

severe renal failure (creatinine clearance value less than 30 ml/min);
severe liver failure in the presence of renal failure;
a history of hepatitis or cholestatic jaundice developing as a result of the use of clarithromycin;
porphyria;
hypokalemia (due to increased risk of QT prolongation);
ventricular arrhythmia or ventricular tachycardia of the “pirouette” type;
indications in the anamnesis of prolongation of the QT interval;
children under 12 years of age;
lactation period;
lactase deficiency, galactose intolerance, glucose-galactose malabsorption;
simultaneous use with ergot alkaloids, cisapride, terfenadine, astemizole, pimozide, midazolam (oral), statins (largely metabolized by the CYP3A4 isoenzyme), colchicine, ranolazine and ticagrelor;
hypersensitivity to the main or auxiliary substances of the drug, as well as other macrolide antibiotics.

Relative (Klacid SR is used with caution):

mild to moderate renal and/or liver dysfunction;
severe heart failure;
cardiac ischemia;
severe bradycardia (less than 50 beats per minute);
hypomagnesemia;
simultaneous use with class IA and III antiarrhythmic drugs, benzodiazepines, ototoxic drugs, statins (the metabolism of which does not depend on the CYP3A isoenzyme), slow calcium channel blockers (metabolized by the CYP3A4 isoenzyme); drugs metabolized by the CYP3A isoenzyme (cyclosporine, carbamazepine, omeprazole, tacrolimus, warfarin, etc.); drugs that induce the CYP3A4 isoenzyme (phenytoin, rifampicin, phenobarbital, etc.);
pregnancy period.

Pregnancy and lactation

The safety of clarithromycin in pregnant and lactating women has not been studied. Use during pregnancy (especially in the first trimester) is possible only if the potential benefit to the mother outweighs the potential risk to the fetus and/or there is no safer therapy with alternative drugs.

If pregnancy occurs while using the drug, the patient should be warned about the possible risks to the fetus.

Clarithromycin is known to be excreted in breast milk. During lactation, the issue of stopping breastfeeding should be decided.

Klacid SR: instructions for use (dosage and method)

Klacid SR 500 mg tablets are taken orally during meals, without chewing or breaking, but swallowing them whole.

As a rule, for children over 12 years of age and adults, the daily dose of Klacid SR is 500 mg (1 tablet).

In case of severe infection, the daily dose of the drug is increased to 1000 mg (2 tablets), taken once, with meals. The average course of treatment is 5–14 days; for sinusitis and community-acquired pneumonia, the duration of therapy is 6–14 days.

In case of impaired renal function (creatinine clearance 30–60 ml/min), the dose of clarithromycin should be reduced by 2 times, and the maximum daily dose should not exceed 500 mg. Klacid SR is contraindicated in patients with severe renal impairment.

Side effects

gastrointestinal tract: often - nausea, vomiting, abdominal pain, diarrhea, dyspepsia; uncommon – glossitis, stomatitis, gastritis, dry mouth, gastroesophageal reflux disease, belching, pain in the rectum, constipation, flatulence; with unknown frequency - discoloration of teeth and tongue, cholestatic jaundice, acute pancreatitis, liver failure;
respiratory system: infrequently – nosebleeds;
cardiovascular system: uncommon – atrial flutter, prolongation of the QT interval on the ECG; with an unknown frequency - ventricular tachycardia (including tachycardia of the “pirouette” type);
nervous system: often – insomnia, headache; uncommon – drowsiness, anxiety, dizziness, tremor; with unknown frequency - disorientation, psychotic disorders, convulsions, hallucinations, mania, confusion, depression, nightmares, depersonalization, paresthesia;
sense organs: often – taste perversion, taste disorders; uncommon – ringing in the ears, hearing loss, vertigo; with unknown frequency – loss of smell, loss of taste, deafness, olfactory hallucinations;
musculoskeletal system: infrequently – myalgia; with unknown frequency – myopathy, rhabdomyolysis;
urinary system: with unknown frequency - interstitial nephritis, renal failure;
metabolism and nutrition: infrequently – decreased appetite, anorexia;
skin: often – increased sweating; with unknown frequency - hemorrhages, acne;
allergic reactions: often - skin rash; uncommon – itching, nettle rash, hypersensitivity; with unknown frequency - Quincke's edema, toxic epidermal necrolysis, anaphylactic reaction, DRESS syndrome;
parasitic and infectious diseases: infrequently – gastroenteritis, candidiasis; with unknown frequency - erysipelas, pseudomembranous colitis;
laboratory test indicators: often - abnormal liver tests; uncommon – leukopenia, increased activity of liver enzymes; with unknown frequency - thrombocytopenia, agranulocytosis, increased bilirubin levels in the blood, change in urine color, prolongation of prothrombin time and increase in INR (international normalized ratio);
general disorders: infrequently – asthenia.

In patients with immunodeficiency conditions (including AIDS) receiving Klacid SR for a long time and in higher doses for the treatment of mycobacterial infections, it is often very difficult to distinguish the side effects of clarithromycin from signs of HIV infection or symptoms of concomitant illness.

Most often, patients taking Klacid SR at a daily dose of 1000 mg experienced the following adverse events: taste disturbance, nausea, abdominal pain, vomiting, flatulence, diarrhea/constipation, increased activity of liver enzymes, headache, hearing loss, rash. Dry mouth, shortness of breath and insomnia were less common.

When should you take the drug?

It is necessary to use medicine to treat inflammatory processes only if the causative agents of the disease show sensitivity to the active substance. Klacid is sometimes combined with other drugs of similar action for more effective therapy.

The drug Klacid is used to treat the following pathologies:

Infectious processes in the lower respiratory tract (bronchopneumonia, obstructive bronchitis, pneumonia)
Infectious processes in the upper parts of the respiratory system (tonsillitis, sinusitis, pharyngitis, scarlet fever, laryngitis)
Infectious inflammation of the skin (erysipelas, leprosy, folliculitis, impetigo, cellulite)
Acute otitis media
Peptic ulcer caused by Helicobacter pylori
Localized mycobacterial infectious processes caused by rapidly growing mycobacteria
Odontogenic inflammatory processes
Infectious pathologies sexually transmitted
Inflammatory processes of the eye caused by gonococci and chlamydia

The listed diseases can provoke the development of severe complications. Timely treatment will help prevent unwanted consequences for the body.

You can replace the drug with another antibiotic that also contains an active substance or belongs to the group of macrolides. After studying the patient's medical history, the specialist can select an effective analogue.

Popular drugs in this category based on the same active ingredient are Fromilid, Clarimax, Clarithromycin. Sumamed, Hemomycin, Azithromycin, Rovamycin have a similar therapeutic effect.

The drug Klacid can be used to treat ailments caused by a bacterial pathogen.

Overdose

When taking a large dose of Klacid SR, disorders of the digestive system are possible.

Treatment consists of removing remnants of unabsorbed clarithromycin from the gastrointestinal tract (by gastric lavage and taking activated charcoal or other intestinal sorbents) and carrying out other necessary symptomatic therapy. Peritoneal dialysis and hemodialysis do not significantly change the serum concentration of the drug, which is also typical for other macrolide antibiotics.

special instructions

Long-term treatment with antibacterial drugs can lead to the appearance of colonies with a large number of bacteria or fungi that are insensitive to the antibiotic. In such cases (with superinfection), appropriate therapy is required.

Liver dysfunction that occurs during drug treatment may be severe, but is usually reversible. If symptoms of hepatitis appear (itching, jaundice, abdominal tenderness during examination, anorexia, dark urine), Klacid SR should be stopped immediately.

In patients with chronic liver diseases, regular monitoring of serum enzyme concentrations is required.

Treatment with clarithromycin, like other antibacterial agents, can lead to the development of pseudomembranous colitis (from mild to life-threatening). Antibiotics can alter the natural intestinal microflora and promote the unrestricted growth of Clostridium difficile colonies. If diarrhea occurs during therapy with Klacid SR, pseudomembranous colitis must be excluded. Monitoring the patient is required for some time after completion of the course, as isolated cases of pseudomembranous colitis that occurred 2 months after taking antibacterial agents have been described.

In patients with severe heart failure, coronary heart disease, severe bradycardia, hypomagnesemia, and taking class IA and class III antiarrhythmic drugs simultaneously with clarithromycin, it is necessary to regularly monitor the ECG for prolongation of the QT interval.

Cross-resistance is possible between clarithromycin and other macrolide antibiotics, as well as clindamycin and lincomycin.

Before prescribing Klacid SR to patients with community-acquired pneumonia, given the growing resistance of the pathogen to macrolides, the sensitivity of Streptococcus pneumoniae to clarithromycin should be determined. Treatment of hospital-acquired pneumonia must be carried out in combination with appropriate antibiotics.

Susceptibility testing is also required before using clarithromycin for mild to moderate skin and soft tissue infections caused by Streptococcus pyogenes and Staphylococcus aureus.

Immediate discontinuation of Klacid SR is necessary in the event of anaphylactic reactions, DRESS syndrome, toxic epidermal necrolysis and Stevens-Johnson syndrome.

When used simultaneously with indirect anticoagulants, it is important to monitor prothrombin time and INR.

Impact on the ability to drive vehicles and complex mechanisms

Klacid SR can cause dizziness, disorientation, vertigo and confusion, therefore, until the patient’s individual sensitivity to the drug is determined, caution should be exercised when driving cars and other vehicles, and working with complex machines and mechanisms.

Drug interactions

Due to the possible risk of serious adverse reactions, Klacid SR is contraindicated for use simultaneously with the following drugs and substances:

terfenadine, pimozide, astemizole and cisapride: possible increase in plasma concentrations of these drugs and further prolongation of the QT interval, as well as the appearance of cardiac arrhythmias, including ventricular fibrillation and ventricular tachycardia (including torsade de pointes);
statins (lovastatin, simvastatin): serum concentrations of statins increase and the risk of myopathy (up to rhabdomyolysis) increases;
ergot alkaloids (ergotamine, dihydroergotamine): acute poisoning with ergot alkaloids is possible, manifested by vascular spasm, tissue ischemia, including the central nervous system;
colchicine: the effect of colchicine may be enhanced and clinical symptoms of poisoning with this drug may develop (especially in elderly patients), therefore this combination is contraindicated.

Klacid SR should be used with caution in combination with drugs that are inducers of the CYP3A isoenzyme (phenytoin, phenobarbital, carbamazepine, St. John's wort, rifampicin), since these drugs can accelerate the metabolism of clarithromycin and reduce its effectiveness. In turn, clarithromycin may increase plasma concentrations of inducers of the CYP3A isoenzyme (for example, rifabutin, with increasing concentrations of which the risk of uveitis increases).

Combinations to consider (dose adjustments or substitution of alternative therapy may be required):

nevirapine, rifabutin, rifampicin, efavirenz, rifapentine: the metabolism of clarithromycin may be accelerated and its effectiveness may be reduced;
etravirine: the concentration of clarithromycin decreases, but the concentration of its active metabolite increases, and since 14-OH-clarithromycin has low activity against Mycobacterium avium complex, alternative drugs must be considered for its treatment;
fluconazole: the average minimum equilibrium concentration (by 33%) and AUC (by 18%) of clarithromycin increases, while the equilibrium concentration of the active metabolite does not change significantly;
ritonavir: there is a noticeable suppression of the metabolism of clarithromycin (in patients with impaired renal function, a reduction in the dose of Klacid SR is required).

Drug interactions due to the influence of clarithromycin on other drugs or substances:

antiarrhythmic drugs (disopyramide, quinidine): the risk of ventricular tachycardia of the “pirouette” type increases (it is necessary to regularly monitor the ECG and serum concentrations of disopyramide or quinidine);
insulin and oral hypoglycemic drugs: severe hypoglycemia may develop (careful monitoring of blood glucose levels is required);
indirect anticoagulants: bleeding may occur, as well as a significant prolongation of prothrombin time and INR (it is necessary to monitor these indicators);
omeprazole: the equilibrium plasma concentration of omeprazole, its AUC and half-life increases;
phosphodiesterase inhibitors (vardenafil, tadalafil, sildenafil): it is possible to increase the inhibitory effect of the listed drugs on phosphodiesterase (a reduction in their doses may be required);
carbamazepine, theophylline: it is possible to increase the concentrations of carbamazepine and theophylline in the systemic circulation;
benzodiazepines (midazolam, alprazolam, triazolam): the AUC of midazolam increases (7 times after oral administration and 2.7 times after intravenous injection); administration with the oral form of midazolam is contraindicated; the intravenous form is used with caution; the combination of clarithromycin and triazolam may cause drowsiness and confusion.

Other types of drug interactions that must be taken into account when used together with Klacid SR:

ototoxic drugs (especially aminoglycosides): it is necessary to monitor the functions of the auditory and vestibular apparatus (during treatment and after completion of therapy);
digoxin: it is possible to increase the serum concentration of digoxin and enhance its effect (it is necessary to carefully monitor the level of digoxin in the blood serum);
zidovudine: a decrease in the equilibrium concentration of the oral form of zidovudine is possible (to avoid such an interaction, it is necessary to observe a 4-hour interval between taking these drugs);
valproic acid and phenytoin: possible increase in serum concentrations of phenytoin and valproic acid (it is recommended to monitor the concentrations of these drugs during treatment with clarithromycin);
slow calcium channel blockers: there is a risk of arterial hypotension, lactic acidosis and bradyarrhythmia;
itraconazole: plasma concentrations of both itraconazole and clarithromycin may increase (it is necessary to monitor the severity of the pharmacological effects of both drugs).

Pharmacokinetics

Clarithromycin is metabolized in the liver with the participation of isoenzymes of the cytochrome P450 3A system. The main metabolite of clarithromycin is 14-OH-clarithromycin. Absolute bioavailability is about 50%. With repeated administration of the drug, no accumulation was detected; the nature of metabolism in the human body did not change.

In vitro studies have shown that the binding of clarithromycin to plasma proteins averages about 70% at drug concentrations of 0.45-4.5 μg/ml. When the concentration was increased to 45 μg/ml, clarithromycin binding decreased to 41%, which may indicate saturation of binding sites. This phenomenon was observed only at drug concentrations significantly higher than therapeutic levels.

Healthy Volunteers

When taking the drug Klacid® SR at a dose of 500 mg 1 time / day, Cmax of clarithromycin and 14-OH-clarithromycin in blood plasma was 1.3 μg/ml and 0.48 μg/ml, respectively; T1/2 was 5.3 hours and 7.7 hours, respectively. With a single dose of Klacid® SR at a dose of 1000 mg (500 mg 2 times a day), the Cmax of clarithromycin and its hydroxylated metabolite reached 2.4 μg/ml and 0.67 μg/ml, respectively; T1/2 was 5.8 hours and 8.9 hours, respectively. The time to reach Cmax when taking both 500 mg and 1000 mg was approximately 6 hours. Cmax of 14-OH-clarithromycin did not increase in proportion to the dose of clarithromycin, while T1/2 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, which becomes more pronounced at high doses.

Approximately 40% of ingested clarithromycin is excreted by the kidneys; through the intestines - approximately 30%.

Patients

Pharmacokinetics in special clinical situations

A comparative study showed that if renal function was preserved in patients with moderate to severe liver dysfunction, no dose adjustment was required.

In elderly people, plasma concentrations of clarithromycin and its 14-OH metabolite are higher, and elimination is slower compared to young people. However, the main influence on the pharmacokinetic parameters of clarithromycin is renal function, not age.

Reviews of Klacida SR

Patients leave very conflicting reviews about Klacida SR. Some note its high effectiveness (even with severe infections), good tolerability, quick results, ease of administration, and the presence of detailed instructions. Others describe the insufficiently strong therapeutic effect of clarithromycin or the complete lack of effect of treatment, a large number of contraindications, the unpleasant taste of the tablets, serious side effects (bitterness in the mouth, nausea, headache, panic attacks, etc.) and the high cost of the drug.