Pharmacological properties of the drug Lecoclar
Semi-synthetic antibiotic of the macrolide group. The antimicrobial effect is due to inhibition of protein synthesis in the bacterial cell, leading to disruption of the normal functioning of microorganisms. May have a bacteriostatic or bactericidal effect. Clarithromycin is active against the following microorganisms: gram-positive - streptococci and staphylococci, Listeria monocytogenes , Corynebacterium spp .; gram-negative - Haemophilus influenzae, H. ducreyi, Moraxella catarrhalis, Bordetella pertussis, Neisseria gonorrhoeae and N. meningitidis, Borrelia burgdorferi, Pasteurella multocida, Campylobacter spp . and Helicobacter pylori; anaerobes - Eubacterium spp., Peptococcus spp., Propionibacterium spp ., Clostridium perfringens and Bacteroides melaninogenicus ; intracellular microorganisms - Mycoplasma pneumoniae, Legionella pneumophila, Chlamydia trachomatis, C. pneumoniae and Ureaplasma urealyticum , Toxoplasma gondii and all mycobacteria except M. tuberculosis . The spectrum of antibacterial action of clarithromycin is similar to that of erythromycin; in addition, it is active against atypical mycobacteria. There is a high degree of cross-resistance of microorganisms to erythromycin and clarithromycin. Clarithromycin remains stable in the presence of gastric acid and is well absorbed after oral administration. Food intake does not affect the degree of absorption of clarithromycin, however, in its presence, the absorption of the drug may slow down. Approximately 20% of clarithromycin is immediately converted to 14-hydroxyclarithromycin, which acts similarly to clarithromycin. Quickly penetrates into body fluids and tissues. Typically, the concentration of clarithromycin in tissues is 10 times higher than in serum. Clarithromycin is actively metabolized in the liver with the participation of cytochrome P450. 7 metabolites are known. The drug is excreted in the form of metabolites or unchanged (approximately 20–30%) in the urine, and to a lesser extent in the feces. The half-life of clarithromycin is 3–4 hours when administered at a dose of 250 mg every 12 hours and 5–7 hours when administered at a dose of 500 mg every 12 hours.
Lekoklar granules for the preparation of suspension for oral administration 250 mg/5 ml in a 60 ml bottle No. 1
Name
Lecoclare gran. d/prig. susp. d/pr. ext. 250mg/5ml in vial. about. 60ml per pack. No. 1
Description
Granules from white to beige. The prepared suspension is white to beige in color.
Main active ingredient
clarithromycin
Release form
Granules
Dosage
250mg/5ml
special instructions
Long-term or repeated use of an antibiotic may cause overgrowth of non-susceptible bacteria and fungi. If superinfection occurs, appropriate therapy should be initiated. Cases of liver dysfunction, including elevated liver enzymes, and hepatocellular or cholestatic hepatitis, with or without jaundice, have been reported with the use of clarithromycin. This type of liver dysfunction can be severe and is usually reversible. There have also been cases of fatal liver failure that have been associated with serious underlying medical conditions or concomitant medications. If you experience symptoms of hepatitis, such as anorexia, jaundice, dark urine, itching, or a tender abdomen, you should stop using clarithromycin immediately. Most of clarithromycin is eliminated through the liver, so patients with impaired liver function should prescribe this antibiotic with caution. Cases of pseudomembranous colitis, the severity of which varies from moderate to life-threatening, have been reported with most antibacterial drugs, including macrolides. Clostridium difficile-associated diarrhea (CDAD), ranging from mild to fatal colitis, has been reported with most antibacterial drugs, including clarithromycin. Taking antibacterial drugs alters the normal intestinal flora, leading to increased growth of C. difficile. Colchicine. Post-marketing reports have reported toxicity of colchicine when coadministered with clarithromycin, especially in elderly patients who have renal impairment. Deaths have been reported in some patients. Concomitant use of clarithromycin and colchicine is contraindicated. Caution should be used when clarithromycin is administered concomitantly with triazolobenzodiazepines such as intravenous triazolam and intravenous midazolam. Caution should be exercised when co-administering clarithromycin and other ototoxic drugs, especially aminoglycosides. Vestibular and auditory functions should be monitored during and after treatment. Due to the risk of QT prolongation, clarithromycin should be used with caution in patients with coronary artery disease, severe heart failure, hypomagnesemia, bradycardia (
Pharmacological properties
Pharmacodynamics
Clarithromycin is the active ingredient of Lecoclar, a semi-synthetic antibiotic of the macrolide group. The antibacterial effect of Lecoclar is determined by its binding to the 5OS ribosomal subunit of sensitive bacteria and inhibition of protein biosynthesis. The drug Lekoklar is effective against a wide range of aerobic and anaerobic gram-positive and gram-negative microorganisms, including hospital strains. The minimum inhibitory concentrations (MICs) of clarithromycin are usually 2 times lower than the MICs of erythromycin. Clarithromycin is bactericidal against Helicobacter pylori; the activity of clarithromycin at neutral pH is higher than at acidic pH. In vitro studies have shown that strains of Enterobacteriaceae and Pseudomonas, as well as gram-negative bacteria that do not ferment lactose, are insensitive to clarithromycin. Clarithromycin is active against most strains of the following microorganisms: 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), which includes Mycobacterium avium, Mycobacterium intracellulare. Beta-lactamases of microorganisms do not affect the effectiveness of clarithromycin. Most methicillin- and oxacillin-resistant strains of staphylococci are resistant to clarithromycin. Helicobacter: H. pylori Clarithromycin is active in vitro against most strains of such microorganisms, but its clinical effectiveness against these microorganisms and the safety of its use in the treatment of infections have not been confirmed in controlled clinical studies. Aerobic gram-positive microorganisms: Streptococcus agalactiae, Streptococci (groups C,F,G), Viridans group streptococci. Aerobic gram-negative microorganisms: Bordetella pertussis, Pasteurella multocida. Anaerobic gram-positive microorganisms: Clostridium perfringens, Peptococcus niger, Propionibacterium acnes. Anaerobic gram-negative microorganisms: Bacteriodes melaninogenicus. Spirochetes: Borrelia burgdorferi, Treponema pallidum. Campylobacter: Campylobacter jejuni.
Pharmacokinetics
Clarithromycin is quickly and well absorbed from the digestive tract. Microbiologically active 14-OH-clarithromycin is formed during the first passage through the liver. When taking the drug with food, the onset of absorption and formation of 14-OH-clarithromycin is slightly delayed, but the overall bioavailability does not change. Although the pharmacokinetics of clarithromycin is nonlinear, stable concentrations are established over 2 consecutive days of dosing. Pharmacokinetic parameters after taking the fifth dose (250 mg clarithromycin suspension) were: Cmax – 1.98 µg/ml, AUC – 11.5 µg•h/ml, Tmax – 2.8 hours and T½ – 3.2 hours for clarithromycin and 0.67 µg/ml, 5.33 µg•h/ml, 2.9 hours and 4.9 hours for 14-OH-clarithromycin, respectively. Concentrations of clarithromycin in body tissues are several times higher than in blood serum. Increased concentrations of clarithromycin are observed in tonsillar and pulmonary tissues. Concentrations of clarithromycin in middle ear fluid exceed concentrations in serum. According to in vitro data, clarithromycin binds to human plasma proteins by an average of approximately 70% at clinically relevant concentrations from 0.45 to 4.5 μg/ml. 14-OH-clarithromycin is the main metabolite excreted by the kidneys and accounts for approximately 10-15% of the administered dose. Most of the remainder of the dose is excreted in the feces, mainly bile. 5–10% of the original substance is excreted in feces. Steady-state clarithromycin concentrations do not differ between patients with hepatic impairment and healthy volunteers, except for lower concentrations of 14-OH-clarithromycin in hepatic dysfunction. In patients with impaired renal function who took 500 mg of clarithromycin, the values of pharmacokinetic parameters increased in accordance with the severity of renal failure. The age of patients does not affect the pharmacokinetic parameters of clarithromycin. In HIV-infected children, higher clarithromycin plasma concentrations and a longer half-life were observed when clarithromycin was administered at doses of 15–30 mg/kg/day (in two divided doses).
Indications for use
Treatment of infectious diseases caused by microorganisms sensitive to clarithromycin: - upper respiratory tract infections, in particular tonsillitis, pharyngitis - sinusitis and acute otitis media in children - lower respiratory tract infections (community-acquired pneumonia and bronchitis) - mild to moderate skin and soft tissue infections gravity
Directions for use and doses
Children aged 6 months to 12 years The duration of treatment is usually 5-10 days, depending on the type of pathogen and the severity of the disease. The suspension is used regardless of food intake (can be taken with milk). For children weighing up to 8 kg, the dose should be calculated per 1 kg of body weight (7.5 mg/kg 2 times a day). Treatment is continued until clinical effectiveness of the drug is observed (the addition of other antimycobacterial drugs may be necessary). For infections with Streptococcus pyogenes (for example, beta-hemolytic streptococcus), the minimum duration of treatment is 10 days. The duration of treatment with Lecoclar depends on the patient’s condition and is determined by the doctor. Adults and children over 12 years of age (with a body weight of more than 30 kg) For children, Lecoclar can be prescribed in the form of a suspension or tablets. Typically, the suspension is not prescribed to children weighing more than 30 kg; this group of patients is recommended to prescribe the drug in tablets. Dosage for renal failure In children with creatinine clearance less than 30 ml/min, the dose of Lecoclar should be reduced by 50%. Treatment should last no more than 14 days. The drug Lekoklar, granules for the preparation of a suspension for oral administration 125 mg/5 ml: shake the bottle with granules, add 59 ml of water in two doses (first 2/3 and then to the mark) and shake until a white to beige suspension is formed. The drug Lekoklar, granules for the preparation of an oral suspension 250 mg/5 ml: shake the bottle with granules, add 57 ml of water in two doses (first 2/3 and then to the mark) and shake until a white to beige suspension is formed. Directions for use: Shake before use. The prepared suspension is intended for oral administration using a measuring syringe located in the package, regardless of food intake. Immediately after taking the suspension, you should drink a few sips of water to eliminate the slightly bitter taste of the suspension. Children Clinical studies of the use of clarithromycin in the form of a suspension were conducted with the participation of children aged 6 months to 12 years, therefore clarithromycin in the form of a suspension is prescribed to children aged 6 months to 12 years.
Interaction with other drugs
Concomitant use of the following medications with clarithromycin is strictly contraindicated as their combination may cause severe interaction effects. Cisapride, pimozide, astemizole and terfenadine. When these drugs are used concomitantly with clarithromycin, QT interval prolongation and arrhythmias, including ventricular tachycardia, ventricular fibrillation, and torsade de pointes, may occur. Ergot alkaloids. Post-marketing studies show that co-administration of clarithromycin and ergotamine or dihydroergotamine results in ergot toxicity manifested as vasospasm, ischemia of the limbs and other tissues, including the central nervous system. HMG-CoA reductase inhibitors (statins). Co-administration of clarithromycin with lovastatin or simvostatin is contraindicated, since they are significantly metabolized by CYP3A4, and the presence of clarithromycin causes an increase in their plasma concentrations, which increases the risk of developing myopathy and rhabdomyolysis. There are reports of cases of rhabdomyolysis in patients who simultaneously took clarithromycin with these statins. If the use of clarithromycin is mandatory, then lovastatin or simvastatin should be discontinued while clarithromycin is being used. Caution should be exercised when concomitantly using clarithromycin with statins. If concomitant use of clarithromycin and statins is unavoidable, a statin that is not dependent on CYP3A metabolism, such as fluvastatin, should be considered. It is recommended to prescribe the lowest possible dose of statin. Patients should be monitored for signs and symptoms of myopathy. Drugs that induce CYP3A4 (eg, rifampicin, rifabutin, phenytoin, carbamazepine, phenobarbital, St. John's wort) accelerate the metabolism of clarithromycin. This may result in decreased clarithromycin concentrations and decreased effectiveness. When taking etravirine, the concentration of the active metabolite of clarithromycin increases, and when taking ritonavir simultaneously, the formation of the active metabolite-14-OH is completely inhibited. Antiarrhythmic drugs. In post-marketing practice, cases of bidirectional tachycardia have been reported with the simultaneous use of clarithromycin with quinidine or disopyramide. When taking clarithromycin concomitantly with these drugs, it is recommended to perform ECG monitoring for timely detection of QT interval prolongation. Serum concentrations of these drugs should be monitored during clarithromycin therapy. There are also reports of cases of hypoglycemia when taking clarithromycin and disopyramide simultaneously. Oral hypoglycemic agents and insulin. When used concomitantly with certain hypoglycemic agents such as nateglinide and repaglinide and clarithromycin, inhibition of the CYP3A enzyme may occur, which can cause hypoglycemia. Close monitoring of glucose levels is recommended. CYP3A-related interactions. Concomitant use of clarithromycin, a known inhibitor of the CYP3A enzyme, and any other drug primarily metabolized by CYP3A may lead to an increase in the concentration of the latter in the blood plasma, which, in turn, may enhance or prolong its therapeutic effect and adverse reactions. The following drugs or groups of drugs are known to be metabolized by the same CYP3A isoenzyme: alprazolam, astemizole, carbamazepine, cilostazol, cisapride, cyclosporine, disopyramide, horn alkaloids, lovastatin, methylprednisolone, midazolam, omeprazole, oral anticoagulants (eg, warfarin), pimozide, quinidine, rifabutin, sildenafil, simvastatin, tacrolimus, terfenadine, triazolam and vinblastine, but this list is not complete. A similar mechanism of interaction was noted with the use of phenytoin, theophylline and valproate, which are metabolized by another isoenzyme of the cytochrome P450 system. Omeprazole. When taken simultaneously with clarithromycin, an increase in the equilibrium concentration of omeprazole in plasma was noted (increase in Cmax, AUC0-24 and t1/2 by 30%, 89% and 34%, respectively). The average gastric pH was 5.2 when omeprazole was taken alone and 5.7 when omeprazole was taken with clarithromycin. Sildenafil, tadalafil and vardenafil. There is a possibility of increased plasma concentrations of phosphodiesterase inhibitors (sildenafil, tadalafil and vardenafil) when used together with clarithromycin, which may require a reduction in the dose of phosphodiesterase inhibitors. Theophylline, carbamazepine. The results of clinical studies show that there is a small but statistically significant (p≤0.05) increase in the circulating concentrations of theophylline and carbamazepine when taken together with clarithromycin. An increase in the concentration of a number of drugs in plasma has been established when taken simultaneously with clarithromycin: omeprazole, sildenafil, vardenafil, theophylline and carbamazepine, digoxin, colchicine, phenytoin, valproate. Triazolobenzodiazepines (eg, alprazolam, midazolam, triazolam). Concomitant use of oral midazolam and clarithromycin is contraindicated. The same precautions should be taken when using other benzodiazepines that are metabolized by CYP3A, including triazolam and alprazolam. For benzodiazepines whose elimination does not depend on CYP3A (temazepam, nitrazepam, lorazepam), the development of a clinically significant interaction with clarithromycin is unlikely. There are post-marketing reports of drug interactions and central nervous system side effects (such as drowsiness and confusion) when clarithromycin and triazolam are used together. Patients should be monitored for the possibility of increased pharmacological effects on the central nervous system. Interactions with other drugs Aminoglycosides: Caution should be exercised when co-administering clarithromycin and other ototoxic drugs, especially aminoglycosides. Colchicine is a substrate for both CYP3A and the p-glycoprotein efflux transporter. Clarithromycin and other macrolides are known to be inhibitors of CYP3A and p-glycoprotein. If clarithromycin is used concomitantly with colchicine, inhibition of p-glycoprotein and CYP3A by clarithromycin may result in increased colchicine exposure. Patients should be monitored for clinical manifestations of colchicine intoxication. Patients with normal liver and kidney function should reduce the dose of colchicine when taken concomitantly with clarithromycin. Concomitant use of clarithromycin and colchicine is contraindicated in patients with hepatic or renal insufficiency. Zidovudine. Concomitant oral administration of clarithromycin tablets and zidovudine in adult HIV-infected patients may result in a decrease in the steady-state concentration of zidovudine. Clarithromycin interferes with the absorption of zidovudine when administered concomitantly orally, which can largely be avoided by maintaining a 4-hour interval between doses of clarithromycin and zidovudine. This interaction does not occur in pediatric patients infected with HIV when taking clarithromycin suspension concomitantly with zidovudine and dideoxyinosine. Phenytoin and valproate. Spontaneous reports indicate interactions between CYP3A inhibitors, such as clarithromycin, and drugs that are theoretically not metabolized by CYP3A (eg, phenytoin and valproate). When co-prescribing such drugs with clarithromycin, it is recommended to analyze their serum levels. There is evidence of increased serum concentrations of these drugs. Bidirectional drug interactions Atazanavir and clarithromycin are substrates and inhibitors of CYP3A. There is evidence of a bidirectional interaction between these drugs. Co-administration of clarithromycin (500 mg twice daily) with atazanavir (400 mg once daily) resulted in a 2-fold increase in clarithromycin exposure, a 70% decrease in 14-OH-clarithromycin exposure, and a 28% increase in atazanavir AUC. Since clarithromycin has a large therapeutic window, no dose reduction of clarithromycin is required in patients with normal renal function. For patients with moderate renal impairment (creatinine clearance from 30 to 60 ml/min), the dose of clarithromycin should be reduced by 50%. For patients with CC less than 30 ml/min, the dose of clarithromycin should be reduced by 75% by using the appropriate dosage form. When co-administered with protease inhibitors, the dose of clarithromycin should not exceed 1000 mg per day. Calcium channel blockers. Due to the risk of arterial hypotension, clarithromycin should be used with caution concomitantly with calcium channel blockers metabolized by CYP 3A4 (for example, verapamil, amlodipine, diltiazem). When they interact, plasma concentrations of both clarithromycin and calcium channel blockers may increase. Hypotension, bradyarrhythmias and lactic acidosis have been observed in patients receiving clarithromycin with verapamil. Itraconazole and clarithromycin are substrates and inhibitors of CYP3A, and therefore clarithromycin may increase plasma levels of itraconazole and vice versa. When using itraconazole with clarithromycin, patients should be closely monitored by a physician for signs and symptoms of enhanced or prolonged pharmacological effects. Saquinavir and clarithromycin are substrates and inhibitors of CYP3A. There is evidence of a bidirectional interaction between these drugs.
Contraindications
- Hypersensitivity to antibiotics from the macrolide group or to one of the excipients. - Co-administration with the following drugs: astemizole, cisapride, pimozide, terfenadine ergot alkaloids (for example, ergotamine or dihydroergotamine) oral midazolam HMG-CoA reductase inhibitors (statins) that are widely metabolized by CYP3A4 (lovastatin or simvastatin) colchicine ticagrelor or ranolazine - History of QT interval prolongation, ventricular cardiac arrhythmia (including bidirectional tachycardia). — Hypokalemia (risk of QT interval prolongation). - Severe liver failure and/or renal failure (creatinine clearance less than 30 ml/min).
Compound
5 ml of the prepared suspension contains: active substance - clarithromycin 125 mg or 250 mg, excipients pellets: poloxamer 188, povidone K-30, hypromellose, macrogol 6000, titanium dioxide (E 171), methacrylic acid - ethyl acrylate copolymer (1:1) (Eudragit L30D-55), triethyl citrate, glycerol monostearate, polysorbate 80, granules: powdered sucrose, maltodextrin, powdered potassium sorbate, anhydrous colloidal silicon dioxide, xanthan gum, powdered fruit punch flavor, titanium dioxide (E 171).
Overdose
Side effect
The following are adverse reactions that occurred during clinical trials and post-marketing use of various dosage forms and dosages of clarithromycin. Adverse reactions associated or possibly associated with clarithromycin are distributed according to the frequency of occurrence: ≥1/10 – very common, ≥1/100 to
Storage conditions
Store at a temperature not exceeding 25 °C. Keep out of the reach of children!
Buy Lecoclar gran. d/prig. susp. d/pr. ext. 250mg/5ml in vial. about. 60ml per pack. No. 1 in pharmacy
Price for Lecoclar gran. d/prig. susp. d/pr. ext. 250mg/5ml in vial. about. 60ml per pack. No. 1
Instructions for use for Lecoclar gran. d/prig. susp. d/pr. ext. 250mg/5ml in vial. about. 60ml per pack. No. 1
Indications for use of the drug Lecoclar
Infections of the upper respiratory tract and ENT organs (streptococcal tonsillopharyngitis, acute otitis media, acute sinusitis), lower respiratory tract infections (acute bacterial bronchitis, chronic bacterial bronchitis in the acute phase, community-acquired and atypical pneumonia, skin and soft tissue infections, mycobacterial infections, caused by M. avium complex , M. kansassi, M. marinum and M. Leprae, peptic ulcer of the stomach or duodenum associated with Helicobacter pylori (as part of combined eradication regimens).
Use of the drug Lecoclar
Inside, without breaking the tablet, with water. Adults and children over 12 years of age are usually prescribed a dose of 250–500 mg 2 times a day for 7–14 days; Clinical trials have established the clinical effectiveness of a shorter course of treatment for acute bronchitis and otitis media (5–6 days). HIV-infected patients, as well as patients with infection caused by M. avium complex, are prescribed a dose of 1–2 g of clarithromycin per day. The maximum daily dose for adults is 2 g. The table shows standard regimens recommended for the treatment of adults.
Indication | Dose (every 12 hours), mg | Duration of treatment, days |
| Tonsillopharyngitis | 250 | 10 |
| Acute sinusitis | 500 | 14 |
Chronic bronchitis in the acute phase or community-acquired pneumonia caused by:
| 250 250 500 250 | 7–14 7–14 7–14 7–14 |
| Infections of the skin and its appendages | 250 | 7–14 |
| Eradication of Helicobacter pylori (as part of complex regimens) | From 250 (2 times a day) to 500 (3 times a day) | 14 |
No dose adjustment is required in patients with impaired liver function with unchanged renal function. For patients with severe renal impairment (creatinine clearance less than 30 ml/min), the dose of the drug should be halved or the intervals between doses should be doubled. For elderly patients, no dose adjustment is required, except in cases of severe renal impairment.
Instructions for use LEKOKLAR® (LEKOKLAR)
The use of the following drugs together with clarithromycin is strictly contraindicated due to the possibility of severe reactions
Cisapride, pimozide, astemizole and terfenadine
When clarithromycin and cisapride are taken simultaneously, increases in the levels of the latter are described, which can lead to prolongation of the QT interval and cardiac arrhythmias, incl. ventricular tachycardia, ventricular fibrillation and ari. Similar effects are observed with the simultaneous use of clarithromycin and pimozide.
There are reports of macrolides interfering with the metabolism of terfenadine, which leads to an increase in plasma levels of the latter, which may result in prolongation of the QT interval and cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation and arrhythmias. In a study of 14 volunteers, coadministration of clarithromycin and terfenadine resulted in a 2- to 3-fold increase in serum levels of the acid metabolite terfenadine and prolongation of the QT interval without any clinical manifestations. Similar effects were observed with the simultaneous use of astemizole and other macrolides.
Ergotamine/dihydroergotamine
Post-marketing reports indicate that coadministration of clarithromycin with ergotamine or dihydroergotamine is associated with acute ergot derivative toxicity characterized by vasospasm and ischemia of the extremities and other tissues, including the central nervous system. The simultaneous administration of Lecoclair and these medications is contraindicated.
HMG-CoA reductase inhibitors
Concomitant use of clarithromycin and lovastatin or simvastatin is contraindicated.
Effect of other drugs on clarithromycin
Drugs that are CYP3A4 inducers (eg, rifampicin, phenytoin, carbamazepine, phenobarbital, St. John's wort) may increase the metabolism of clarithromycin, resulting in subtherapeutic clarithromycin plasma levels and reduced efficacy. In addition, it may be necessary to monitor plasma levels of the CYP3A4 inducer, as it may increase due to the inhibition of CYP3A4 by clarithromycin. Co-administration of rifabutin and clarithromycin resulted in increased rifabutin levels and decreased clarithromycin serum levels, which was associated with an increased risk of uveitis.
The following drugs are known or suspected to have an effect on clarithromycin blood concentrations; A dose adjustment of clarithromycin or alternative treatment may be necessary.
Efavirenz, nevirapine, rifampicin, rifabutin and rifapentine
Potent inducers of the cytochrome P450 metabolic system, such as efavirenz, nevirapine, rifampicin, rifabutin and rifapentine, can accelerate the metabolism of clarithromycin and thus reduce its plasma levels, while increasing the level of 14-hydroxyclarithromycin, a metabolite that also has antimicrobial activity . Since the antimicrobial activity of clarithromycin and 14-hydroxyclarithromycin is different for different bacteria, the expected therapeutic effect may be reduced by the simultaneous administration of Lecoclair and enzyme inducers.
Fluconazole
Co-administration of fluconazole 200 mg/day and clarithromycin 500 mg 2 times/day to 21 healthy volunteers resulted in an increase in mean Cssmin and AUC by 33% and 18%, respectively. Css of the active metabolite 14-hydroxyclarithromycin did not change significantly when taking fluconazole simultaneously. No dose adjustment of Lecoclair is required.
Ritonavir
A pharmacokinetic study showed that co-administration of ritonavir (200 mg every 8 hours) and clarithromycin (500 mg 2 times a day) significantly inhibits the metabolism of the latter. When co-administered with ritonavir, clarithromycin Cmax increases by 31%, Cmin by 182% and AUC by 77%. The formation of the active 14-hydroxy metabolite is almost completely suppressed. Due to the large therapeutic window for clarithromycin, dose reductions are not required in patients with normal renal function. However, patients with impaired renal function require dose adjustment:
- with CC 30-60 ml/min, the dose of Lecoclair should be reduced by 50%, and with CC <30 ml/min - by 75%. When taken together with ritonavir, the dose of Lecoclair should not exceed 1 g/day.
Similar dose adjustments should be made in patients with impaired renal function when ritonavir is prescribed as a pharmacokinetic enhancer with other HIV protease inhibitors, including atazanavir and saquinavir.
Interactions during Helicobacter pylori eradication
Although plasma concentrations of clarithromycin and omeprazole may increase when administered concomitantly, no dosage adjustment is necessary. When taken in recommended doses, there is no clinically significant interaction between clarithromycin and lansoprazole. An increase in clarithromycin concentrations may also occur when the drug is taken concomitantly with antacids and ranitidine. There is also no need for dose adjustment. There are no pharmacokinetic interactions between the antibiotics included in the Helicobacter pylori eradication regimen.
Effect of clarithromycin on other drugs
CYP3A-related interactions
Co-administration of clarithromycin (an inhibitor of the CYP3A metabolizing enzyme) and a drug primarily metabolized by CYP3A may be associated with increased drug concentrations, which in turn may increase or prolong both the therapeutic and adverse effects of the latter. Lecoclar should be administered with caution to patients receiving treatment with other drugs that are CYP3A substrates, especially drugs with a narrow safety profile, such as carbamazepine, and/or a substrate actively metabolized by this enzyme.
In such patients, the possibility of changing the dose of Lecoclair should be considered, and, if possible, carefully monitor the serum concentrations of drugs metabolized primarily by CYP3A.
The following drugs or classes of drugs are (or are thought to be) metabolized by the same isoenzyme CYP3A:
- alprazolam, astemizole, carbamazepine, cilostazol, cisapride, cyclosporine, disopyramide, ergot alkaloids, lovastatin, methylprednisolone, midazolam, omeprazole, oral anticoagulants (eg, warfarin), pimozide, quinidine, rifabutin, sildenafil, simvastatin, sirolimus, tacroli mus, terfenadine, triazolam and vinblastine. Drugs whose mechanism of interaction is similar to that described above (via other isoenzymes of the cytochrome P450 system) include phenytoin, theophylline and valproic acid.
Antiarrhythmic drugs
Cases of cardiac dysfunction have been reported in patients taking clarithromycin concomitantly with quinidine or disopyramide.
Monitor the QT interval when these drugs are administered together.
During treatment with Lecoclair, it is necessary to monitor the concentrations of quinidine and disopyramide in the blood serum.
Cyclosporine, tacrolimus and sirolimus
Concomitant use of oral clarithromycin and cyclosporine or tacrolimus results in a more than twofold increase in the minimum concentration of cyclosporine and tacrolimus. A similar effect is also expected for sirolimus. When clarithromycin is co-administered with cyclosporine, tacrolimus or sirolimus, serum concentrations of immunosuppressive drugs should be carefully monitored and their dosage reduced if necessary. When clarithromycin treatment is discontinued in these patients, the dose of cyclosporine, tacrolimus, or sirolimus may need to be adjusted again.
Warfarin
Concomitant use of clarithromycin and warfarin may potentiate the effect of warfarin. Prothrombin time should be monitored frequently in this group of patients.
Omeprazole
Clarithromycin (500 mg every 8 hours) was administered in combination with omeprazole (40 mg/day) to healthy adults. When co-administered with clarithromycin, steady-state plasma concentrations of omeprazole increased (Cmax, AUC0-24 and T1/2 increased by 30%, 89% and 34%, respectively). The average gastric pH value during 24-hour monitoring was 5.2 with omeprazole monotherapy and 5.7 with the combination of omeprazole and clarithromycin.
Sildenafil, tadalafil and vardenafil
Each of these phosphodiesterase inhibitors is metabolized (at least in part) by CYP3A, and CYP3A may be inhibited by concomitant administration of clarithromycin. Therefore, when clarithromycin is co-administered with sildenafil, tadalafil and vardenafil, there is a possibility of increased exposure to phosphodiesterase inhibitors. When taking Lecoclair simultaneously with these drugs, you should consider reducing their dose.
Theophylline, carbamazepine
The results of clinical studies indicate a moderate but statistically significant (p < 0.05) increase in blood levels of theophylline or carbamazepine when any of these drugs are prescribed together with clarithromycin. A dose reduction may be necessary.
Tolterodine
Tolterodine is primarily metabolized by cytochrome P450 isoenzyme 2D6 (CYP2D6). However, in a subset of the CYP2D6-deficient population, metabolism is mediated by CYP3A. In this subgroup, inhibition of CYP3A results in significantly higher serum concentrations of tolterodine, which requires a reduction in the tolterodine dose when using CYP3A inhibitors such as clarithromycin.
Triazolobenzodiazepines (eg, alprazolam, midazolam, triazolam)
When midazolam was co-administered with clarithromycin (500 mg 2 times a day), the AUC of midazolam increased 2.7 times after intravenous administration and 7 times after oral administration. The simultaneous administration of midazolam and Lecoclair by mouth should be avoided. When administering midazolam intravenously in combination with Lecoclair, the patient should be closely monitored to allow for dose adjustment. The same precautions should be observed for other benzodiazepines that are metabolized by CYP3A, incl. triazolam and alprazolam. For benzodiazepines not metabolized by CYP3A (temazepam, nitrazepam, lorazepam), interaction with clarithromycin is unlikely.
There are post-marketing reports of drug interactions and effects (drowsiness and confusion) on the central nervous system when clarithromycin and triazolam are taken together. The patient should be monitored for the possibility of increased pharmacological effects on the central nervous system.
Other drug interactions
Colchicine
Colchicine is a substrate for both CYP3A and the transport protein P glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. When Lecoclair and colchicine are co-administered, inhibition of Pgp and/or CYP3A by clarithromycin may lead to increased colchicine exposure. Patients should be monitored for clinical symptoms of colchicine toxicity.
Digoxin and other substrates for the transport protein - glycoprotein P
Digoxin is thought to be a substrate for the efflux transporter P glycoprotein (Pgp). Clarithromycin is known to inhibit Pgp. When Lecoclair is co-administered with digoxin, inhibition of Pgp by clarithromycin may lead to increased digoxin exposure. In post-marketing surveillance, an increase in the concentration of digoxin was noted when it was co-administered with clarithromycin. Some patients experienced symptoms of digoxin toxicity, including potentially fatal arrhythmias. During co-administration of digoxin and Lecoclair, serum concentrations of digoxin should be carefully monitored.
Zidovudine
Concomitant administration of oral clarithromycin and zidovudine to HIV-infected adult patients may result in decreased steady-state zidovudine concentrations. Because when zidovudine and clarithromycin are administered orally simultaneously, they compete with each other for absorption; they should be taken separately with an interval of 4 hours. Such interaction is absent in HIV-infected children who take a suspension of clarithromycin with zidovudine or dideoxyinosine. Such an interaction is unlikely with intravenous administration of clarithromycin.
Phenytoin and valproate
There are isolated reports or publications of the interaction of CYP3A inhibitors (including clarithromycin) with drugs that are not believed to be metabolized by CYP3A (for example, phenytoin and valproate). When co-administered with Lecoclair, it is recommended to determine serum levels of these drugs. There are reports of their levels increasing.
Bidirectional drug interactions
Both clarithromycin and atazanavir, itraconazole and saquinavir are substrates and inhibitors of CYP3A, and their drug interactions are bidirectional.
Atazanavir
Clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and their drug interactions are bidirectional. Co-administration of clarithromycin (500 mg 2 times / day) and atazanavir (400 mg 1 time / day) leads to a twofold increase in clarithromycin exposure and a 70% decrease in 14-hydroxyclarithromycin exposure with a 28% increase in atazanavir AUC. Due to the large therapeutic window of clarithromycin, no dose adjustment is required in patients with normal renal function. With a moderate decrease in the functional state of the kidneys (creatinine clearance 30-60 ml/min), the dose of Lecoclair should be reduced by 50%. In patients with CC less than 30 ml/min, the dose of Lecoclair should be reduced by 75% by prescribing a suitable dosage form of clarithromycin. When taken together with protease inhibitors, the dose of Lecoclair should not exceed 1000 mg/day.
Itraconazole
Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A, leading to bidirectional drug interactions. Co-administration of clarithromycin and itraconazole leads to a mutual increase in their plasma concentrations. Patients taking itraconazole and Lecoclar concomitantly should be closely monitored for symptoms of enhanced or prolonged pharmacological action.
Saquinavir
Both clarithromycin and saquinavir are CYP3A substrates and inhibitors and their drug interactions are bidirectional. Coadministration of clarithromycin (500 mg twice daily) and saquinavir (soft gelatin capsules 1200 mg three times daily) in 12 healthy volunteers increased the steady-state AUC and Cmax of saquinavir by 177% and 187%, respectively, compared with monotherapy with saquinavir. The AUC and Cmax values for clarithromycin were approximately 40% higher than with monotherapy with this drug. When taking drugs together for a limited time in the studied doses and dosage forms, no dose adjustment is required. Drug interaction information obtained with saquinavir soft gelatin capsules may not be consistent with that obtained with saquinavir hard gelatin capsules. Drug interaction data obtained with saquinavir monotherapy may not be consistent with those obtained with saquinavir/ritonavir coadministration. When co-administering saquinavir with ritonavir, the possible effect of the latter on Lecoclar should be taken into account.
Verapamil
Hypotension, bradyarrhythmia and lactic acidosis were observed when clarithromycin and verapamil were taken concomitantly.
Side effects of the drug Lecoclar
Most side effects are mild and transient. Gastrointestinal disorders (diarrhea, nausea, dyspepsia, gastralgia), headache are more common; possible stomatitis, glossitis, changes in taste, hypersensitivity reactions (skin rash, anaphylaxis, very rarely - Stevens-Johnson syndrome). There have been isolated reports of reactions from the central nervous system (dizziness, confusion, anxiety, insomnia, nightmares). In exceptional cases, increased activity of liver enzymes and cholestatic jaundice were noted. Clarithromycin, like erythromycin, has been associated with the occurrence of ventricular arrhythmias, including ventricular tachycardia and torsades de pointes in some patients with a prolonged QT on the ECG.
Lekoclar
Contraindicated combinations
Concomitant use with astemizole, cisapride, pimozide, terfenadine is contraindicated.
With the simultaneous use of clarithromycin and the above drugs metabolized by CYP3A isoenzymes, a mutual increase in their concentrations is possible, which can enhance and prolong both therapeutic and side effects (prolongation of the QT interval, arrhythmias, including ventricular tachycardia, ventricular fibrillation, tachycardia of the “pirouette” type).
Concomitant use with ergotamine and dihydroergotamine is contraindicated, because Possible acute poisoning with drugs of the ergotamine group (vascular spasm, ischemia of the limbs and other tissues, including the central nervous system).
Colchicine is a substrate of both the CYP3A4 isoenzyme and the transport protein responsible for drug excretion, P-glycoprotein (Pgp).
Clarithromycin, like other macrolides, inhibits the isoenzyme CYP3A4 and Pgp. When clarithromycin and colchicine are used together, inhibition of Pgp and/or CYP3A4 may result in increased effects of colchicine. The development of clinical symptoms of colchicine poisoning should be monitored.
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 with renal failure. Some cases were reported to be fatal. The simultaneous use of clarithromycin and colchicine is contraindicated (see also section “Contraindications”).
Clarithromycin increases the concentration of HMG-CoA reductase inhibitors (lovastatin, simvastatin) in the blood serum, which is associated with the risk of developing rhabdomyolysis. The combined use of these drugs with clarithromycin is contraindicated.
Patients receiving statins should be monitored for signs and symptoms of myopathy. In situations where concomitant use of clarithromycin and statins cannot be avoided, use of the statin at the lowest registered dose is recommended. The use of statins whose metabolism is not dependent on CYP3A isoenzymes (for example, fluvastatin) should be considered.
Concomitant use of clarithromycin and oral midazolam is contraindicated.
Effect of other drugs on clarithromycin
Drugs that induce the CYP3A4 isoenzyme (for example, rifampicin, phenytoin, carbamazepine, phenobarbital, St. John's wort) may induce the metabolism of clarithromycin, which may lead to a decrease in clarithromycin concentrations to subtherapeutic levels and a decrease in its effectiveness. Plasma concentrations of inducers of the CYP3A4 isoenzyme, which may increase due to inhibition of the CYP3A4 isoenzyme by clarithromycin, should be monitored.
Efavirenz, nevirapine, rifampicin, rifabutin and rifapentine (cytochrome P450 inducers) reduce the concentration of clarithromycin in the blood plasma and weaken its therapeutic effect, while at the same time increasing the concentration of 14-OH-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 concentration of clarithromycin in the blood plasma decreases with the use of etravirine, but the concentration of its active metabolite, 14-OH-clarithromycin, increases. Because 14-OH-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be reduced and alternatives to clarithromycin should be considered in the treatment of MAC.
When taking fluconazole at a dose of 200 mg daily and clarithromycin at a dose of 1 g/day, the steady-state concentration (Css) and AUC of clarithromycin may increase by 33% and 18%, respectively. No dose adjustment of clarithromycin is required.
With simultaneous use of ritonavir 600 mg/day and clarithromycin 1 g/day, a decrease in the metabolism of clarithromycin is possible (increase in Cmax by 31%, Css by 182% and AUC by 77%), complete suppression of the formation of 14-OH-clarithromycin. No dose adjustment is required in patients with normal renal function. In patients with chronic renal failure, a dose adjustment of the drug is necessary: with a CC of 30-60 ml/min, the dose of clarithromycin should be reduced by 50%, with a CC of <30 ml/min - by 75%. Ritonavir should not be taken concomitantly with clarithromycin at a dose exceeding 1 g/day.
Effect of clarithromycin on other drugs
The following drugs or groups of drugs are known or suspected to be metabolized by the same CYP3A isoenzyme: alprazolam, carbamazepine, cilostazol, cyclosporine, disopyramide, lovastatin, methylprednisolone, omeprazole, oral anticoagulants (e.g., warfarin), atypical antipsychotics (e.g., quetiapine), quinidine, rifabutin, sildenafil, sirolimus, tacrolimus, triazolam and vinblastine.
There are post-registration reports of the occurrence of ventricular tachycardia of the “pirouette” type (Torsade de pointes) with the simultaneous use of clarithromycin and quinidine or disopyramide. When clarithromycin and these drugs are used concomitantly, ECG monitoring should be performed for prolongation of the QT interval. Serum concentrations of quinidine and disopyramide should be monitored during clarithromycin therapy.
There are post-registration reports of the development of hypoglycemia during concomitant use of clarithromycin and disopyramide. Accordingly, during the simultaneous use of clarithromycin and disopyramide, the concentration of glucose in the blood should be monitored.
When using clarithromycin and omeprazole, it is possible to increase Cmax, AUC and T1/2 omeprazole by 30%, 89% and 34%, respectively. The average pH value in the stomach over 24 hours is 5.2 when taking omeprazole alone and 5.7 when taking omeprazole with clarithromycin.
When using clarithromycin and indirect anticoagulants, the effect of the latter may be enhanced with the development of bleeding, a pronounced increase in INR and PT. If simultaneous use with warfarin or other indirect anticoagulants is necessary, it is necessary to monitor PT and INR.
When clarithromycin is used with sildenafil, tadalafil and vardenalafil (phosphodiesterase-5 (PDE-5) inhibitors), an increase in the inhibitory effect on PDE is possible. A dose reduction of PDE5 inhibitors may be required.
When used simultaneously with theophylline and carbamazepine, the concentration of the latter in the systemic circulation may increase. When using clarithromycin with tolterodine in patients with low CYP2D6 activity, a reduction in the dose of tolterodine may be required.
Caution is recommended when using clarithromycin concomitantly with triazolobeisodiazepines that are metabolized by CYP3A isoenzymes (midazolam, triazolam and alprazolam).
With simultaneous use of clarithromycin (1 g/day) with midazolam, the AUC of midazolam may increase by 2.7 times after intravenous administration and by 7 times after oral administration of midazolam. When midazolam is used for intravenous administration, it is recommended to carefully monitor the patient's condition in order to adjust the dose.
The same precautions should be applied to other benzodiazepines, including triazolas and alprazolams, which are metabolized by CYP3A isoenzymes.
In post-marketing studies, CNS adverse reactions (eg, drowsiness and confusion) have been reported with concomitant use of clarithromycin and triazolam. If coadministration occurs, monitoring for CNS symptoms is recommended. It is recommended to monitor the occurrence of adverse reactions from the central nervous system.
For benzodiazepines whose elimination is not dependent on CYP3A isoenzymes (temazepam, nitrazepam, lorazepam), a clinically significant interaction is unlikely.
Other drug interactions
Caution should be exercised when used concomitantly with other ototoxic drugs, especially aminoglycosides, and the functions of the vestibular apparatus and hearing organs should be monitored both during and after therapy.
Digoxin is believed to be a substrate for the efflux transporter, Pgp. Clarithromycin is known to inhibit Pgp. When used simultaneously
Clarithromycin and Digoxin Inhibition of Pgp by clarithromycin may result in increased exposure to digoxin. In addition, during post-registration studies, an increase in the concentration of digoxin in the blood plasma was detected in patients simultaneously receiving digoxin and clarithromycin. Some patients experienced clinical signs of digoxin toxicity, including potentially fatal arrhythmias. When clarithromycin and digoxin are used simultaneously, the concentration of digoxin in the blood serum should be carefully monitored (increased concentrations and the development of potentially fatal arrhythmias are possible).
Concomitant use of clarithromycin 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, the interaction can be largely avoided by taking clarithromycin and zidovudine 4 hours apart. This type of interaction does not occur in HIV-infected children receiving clarithromycin suspension concomitantly with zidovudine or didanosine (dideoxyinosine). Since this interaction is due to the fact that clarithromycin may interfere with the absorption of zidovudine in adult patients, it is unlikely to occur when clarithromycin is used intravenously.
Clarithromycin and atazanavir are both substrates and inhibitors of the CYP3A4 isoenzyme. There is evidence of a bidirectional interaction between these drugs. Concomitant use of clarithromycin (500 mg twice daily) and atazanavir (400 mg/day) may result in a twofold increase in clarithromycin exposure and a 70% decrease in 14-OH-clarithromycin exposure, with a 28% increase in atazanavir AUC. Due to the wide therapeutic range of clarithromycin, dose reduction is not required in patients with normal renal function. In patients with CC 30-60 ml/min, the dose of clarithromycin should be reduced by 50%, with CC <30 ml/min - by 75%.
Clarithromycin in doses exceeding 1 g/day should not be administered concomitantly with protease inhibitors.
Clarithromycin and itraconazole are substrates and inhibitors of the CYP3A4 isoenzyme, which determines the bidirectional interaction of the drugs. When used simultaneously with itraconazole, a mutual increase in the concentration of drugs in the blood plasma is possible. Patients taking clarithromycin and itraconazole concomitantly should be closely monitored for symptoms of increased or prolonged pharmacological effects of these drugs.
Clarithromycin and saquinavir are substrates and inhibitors of the CYP3A4 isoenzyme, which determines the bidirectional interaction of the drugs.
Concomitant administration of clarithromycin (500 mg twice daily) and saquinavir (soft gelatin capsules, 1200 mg three times daily) in 12 healthy volunteers increased the AUC and Cmax of saquinavir by 177% and 187%, respectively, compared with saquinavir administration alone. separately. The AUC and Cmax values of clarithromycin were approximately 40% higher than with clarithromycin monotherapy. When clarithromycin and saquinavir are used together for a limited time at the doses/formulations indicated above, no dose adjustment is required. The results of drug interaction studies with saquinavir monotherapy may not be consistent with the effects observed with saquinavir hard gelatin capsules. The results of drug interaction studies with saquinavir monotherapy may not be consistent with the effects observed with saquinavir/ritonavir therapy. When taking saquinavir with ritonavir, consider the potential effect of ritonavir on clarithromycin.
When simultaneous use of clarithromycin with blockers of “slow” calcium channels metabolized by the CYP3A4 isoenzyme (for example, amlodipine, diltiazem, verapamil), caution should be exercised due to the possible risk of arterial hypotension, bradyarrhythmia and lactic acidosis. Plasma concentrations of clarithromycin, as well as blockers of “slow” calcium channels, may increase with simultaneous use.
Concomitant use of clarithromycin and oral hypoglycemic drugs (for example, sulfonylureas) and/or insulin can lead to significant hypoglycemia. When clarithromycin is used concomitantly with certain oral hypoglycemic drugs, such as nateglinide, pioglitazone, repaglinide, rosiglitazone, hypoglycemia may occur due to inhibition of the CYP3A4 isoenzyme by clarithromycin. Careful monitoring of blood glucose concentrations is recommended.
There are spontaneous and published reports of interactions between CYP3A inhibitors, such as clarithromycin, and drugs not metabolized by CYP3A (eg, phenytoin and valproic acid). With simultaneous use, their concentrations may increase, so it is recommended to determine the concentrations of these drugs in the blood serum. Phenytoin and valproic acid can be metabolized through other isoenzymes of the cytochrome P450 system.
Special instructions for the use of Lecoclar
Prescribe with caution to patients with liver disease and severe kidney disease, in patients with severe heart disease and a history of electrolyte imbalance. If severe diarrhea develops during treatment with the drug, it is necessary to exclude the possibility of developing pseudomembranous colitis. The safety of clarithromycin during pregnancy and lactation has not been established. Like other macrolide antibiotics, clarithromycin passes into breast milk. During pregnancy and lactation, clarithromycin is prescribed in exceptional cases, taking into account the expected therapeutic effect for the mother and its possible negative effect on the fetus or infant. The safety and effectiveness of clarithromycin in children under 6 months of age has not been established.
Drug interactions Lecoclar
Clarithromycin is metabolized in the liver and is an inhibitor of certain cytochrome P450 enzymes. As a result, the metabolism of other drugs, which is also carried out using this enzyme system, may slow down, and their serum concentrations increase, which can lead to toxic reactions. The simultaneous use of clarithromycin with terfenadine, cisapride and pimozide is contraindicated. It is not recommended to use clarithromycin simultaneously with dihydroergotamine, digoxin and astemizole. When prescribing clarithromycin concomitantly with benzodiazepines, carbamazepine, cyclosporine, ranitidine, bismuth subnitrate, rifabutin, saquinavir, tacrolimus, theophylline, warfarin and cidovoudine, careful monitoring of treatment is required; If possible, serum concentrations of these drugs should be determined to adjust their dose.
Lekoklar HL extended-release tablets p/o 500 mg No. 7x1
Name
Lekoklar HL tablet prolong. d-I coating film about 500 mg in a blister. in pack No. 7x1
Description
Film-coated tablets, light yellow in color, oval in shape. Length about 18.8 mm, width about 8.8 mm (for a dosage of 500 mg).
Main active ingredient
Clarithromycin
Release form
Pills
Dosage
500mg
special instructions
Long-term or repeated use of an antibiotic may cause overgrowth of non-susceptible bacteria and fungi. If superinfection occurs, appropriate therapy should be initiated. Cases of liver dysfunction, including elevated liver enzymes, and hepatocellular or cholestatic hepatitis, with or without jaundice, have been reported with the use of clarithromycin. This type of liver dysfunction can be severe and is usually reversible. There have also been cases of fatal liver failure that have been associated with serious underlying medical conditions or concomitant medications. If you experience symptoms of hepatitis, such as anorexia, jaundice, dark urine, itching, or a tender abdomen, you should stop using clarithromycin immediately. Most of clarithromycin is eliminated through the liver, so patients with impaired liver function should prescribe this antibiotic with caution. Cases of pseudomembranous colitis, the severity of which varies from moderate to life-threatening, have been reported with most antibacterial drugs, including macrolides. Clostridium difficile-associated diarrhea (CDAD), ranging from mild to fatal colitis, has been reported with most antibacterial drugs, including clarithromycin. Taking antibacterial drugs alters the normal intestinal flora, leading to increased growth of C. difficile. Colchicine. Post-marketing reports have reported toxicity of colchicine when coadministered with clarithromycin, especially in elderly patients who have renal impairment. Deaths have been reported in some patients. Concomitant use of clarithromycin and colchicine is contraindicated. Caution should be used when clarithromycin is administered concomitantly with triazolobenzodiazepines such as intravenous triazolam and intravenous midazolam. Caution should be exercised when co-administering clarithromycin and other ototoxic drugs, especially aminoglycosides. Vestibular and auditory functions should be monitored during and after treatment. Due to the risk of QT prolongation, clarithromycin should be used with caution in patients with coronary artery disease, severe heart failure, hypomagnesemia, bradycardia (
Pharmacological properties
Pharmacodynamics
Clarithromycin is the active ingredient of Lecoclar, a semi-synthetic antibiotic of the macrolide group. The antibacterial effect of Lecoclar is determined by its binding to the 5OS ribosomal subunit of sensitive bacteria and inhibition of protein biosynthesis. The drug Lekoklar is effective against a wide range of aerobic and anaerobic gram-positive and gram-negative microorganisms, including hospital strains. The minimum inhibitory concentrations (MICs) of clarithromycin are usually 2 times lower than the MICs of erythromycin. Clarithromycin is bactericidal against Helicobacter pylori; the activity of clarithromycin at neutral pH is higher than at acidic pH. In vitro studies have shown that strains of Enterobacteriaceae and Pseudomonas, as well as gram-negative bacteria that do not ferment lactose, are insensitive to clarithromycin. Clarithromycin is active against most strains of the following microorganisms: 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), which includes Mycobacterium avium, Mycobacterium intracellulare. Beta-lactamases of microorganisms do not affect the effectiveness of clarithromycin. Most methicillin- and oxacillin-resistant strains of staphylococci are resistant to clarithromycin. Helicobacter: H. pylori Clarithromycin is active in vitro against most strains of such microorganisms, but its clinical effectiveness against these microorganisms and the safety of its use in the treatment of infections have not been confirmed in controlled clinical studies. Aerobic gram-positive microorganisms: Streptococcus agalactiae, Streptococci (groups C,F,G), Viridans group streptococci. Aerobic gram-negative microorganisms: Bordetella pertussis, Pasteurella multocida. Anaerobic gram-positive microorganisms: Clostridium perfringens, Peptococcus niger, Propionibacterium acnes. Anaerobic gram-negative microorganisms: Bacteriodes melaninogenicus. Spirochetes: Borrelia burgdorferi, Treponema pallidum. Campylobacter: Campylobacter jejuni.
Pharmacokinetics
Clarithromycin is quickly and well absorbed from the digestive tract. Microbiologically active 14-OH-clarithromycin is formed during the first passage through the liver. When taking the drug with food, the onset of absorption and formation of 14-OH-clarithromycin is slightly delayed, but the overall bioavailability does not change. Although the pharmacokinetics of clarithromycin is nonlinear, stable concentrations are established over 2 consecutive days of dosing. Pharmacokinetic parameters after taking the fifth dose (250 mg clarithromycin suspension) were: Cmax – 1.98 µg/ml, AUC – 11.5 µg•h/ml, Tmax – 2.8 hours and T½ – 3.2 hours for clarithromycin and 0.67 µg/ml, 5.33 µg•h/ml, 2.9 hours and 4.9 hours for 14-OH-clarithromycin, respectively. Concentrations of clarithromycin in body tissues are several times higher than in blood serum. Increased concentrations of clarithromycin are observed in tonsillar and pulmonary tissues. Concentrations of clarithromycin in middle ear fluid exceed concentrations in serum. According to in vitro data, clarithromycin binds to human plasma proteins by an average of approximately 70% at clinically relevant concentrations from 0.45 to 4.5 μg/ml. 14-OH-clarithromycin is the main metabolite excreted by the kidneys and accounts for approximately 10-15% of the administered dose. Most of the remainder of the dose is excreted in the feces, mainly bile. 5–10% of the original substance is excreted in feces. Steady-state clarithromycin concentrations do not differ between patients with hepatic impairment and healthy volunteers, except for lower concentrations of 14-OH-clarithromycin in hepatic dysfunction. In patients with impaired renal function who took 500 mg of clarithromycin, the values of pharmacokinetic parameters increased in accordance with the severity of renal failure. The age of patients does not affect the pharmacokinetic parameters of clarithromycin. In HIV-infected children, higher clarithromycin plasma concentrations and a longer half-life were observed when clarithromycin was administered at doses of 15–30 mg/kg/day (in two divided doses).
Indications for use
Treatment of infectious diseases caused by microorganisms sensitive to clarithromycin: - upper respiratory tract infections, in particular tonsillitis, pharyngitis - sinusitis and acute otitis media in children - lower respiratory tract infections (community-acquired pneumonia and bronchitis) - mild to moderate skin and soft tissue infections gravity
Directions for use and doses
The drug Lecoclar is taken orally, regardless of food intake. Adults and children over 12 years of age Standard daily dose: 250 mg tablets twice a day. For severe infections, the standard dose may be increased to 500 mg twice daily. Standard course of treatment: 6-14 days Treatment is continued until clinical effectiveness of the drug is observed (the addition of other antimycobacterial drugs may be necessary). For infections with Streptococcus pyogenes (for example, beta-hemolytic streptococcus), the minimum duration of treatment is 10 days. The duration of treatment with Lecoclar depends on the patient’s condition and is determined by the doctor. Children under 12 years of age (weighing less than 30 kg) should be prescribed Lecoclar in the form of an oral suspension. Dosage for renal failure In children with creatinine clearance less than 30 ml/min, the dose of Lecoclar should be reduced by 50%. Treatment should last no more than 14 days.
Interaction with other drugs
Concomitant use of the following medications with clarithromycin is strictly contraindicated as their combination may cause severe interaction effects. Cisapride, pimozide, astemizole and terfenadine. When these drugs are used concomitantly with clarithromycin, QT interval prolongation and arrhythmias, including ventricular tachycardia, ventricular fibrillation, and torsade de pointes, may occur. Ergot alkaloids. Post-marketing studies show that co-administration of clarithromycin and ergotamine or dihydroergotamine results in ergot toxicity manifested as vasospasm, ischemia of the limbs and other tissues, including the central nervous system. HMG-CoA reductase inhibitors (statins). Co-administration of clarithromycin with lovastatin or simvostatin is contraindicated, since they are significantly metabolized by CYP3A4, and the presence of clarithromycin causes an increase in their plasma concentrations, which increases the risk of developing myopathy and rhabdomyolysis. There are reports of cases of rhabdomyolysis in patients who simultaneously took clarithromycin with these statins. If the use of clarithromycin is mandatory, then lovastatin or simvastatin should be discontinued while clarithromycin is being used. Caution should be exercised when concomitantly using clarithromycin with statins. If concomitant use of clarithromycin and statins is unavoidable, a statin that is not dependent on CYP3A metabolism, such as fluvastatin, should be considered. It is recommended to prescribe the lowest possible dose of statin. Patients should be monitored for signs and symptoms of myopathy. Drugs that induce CYP3A4 (eg, rifampicin, rifabutin, phenytoin, carbamazepine, phenobarbital, St. John's wort) accelerate the metabolism of clarithromycin. This may result in decreased clarithromycin concentrations and decreased effectiveness. When taking etravirine, the concentration of the active metabolite of clarithromycin increases, and when taking ritonavir simultaneously, the formation of the active metabolite-14-OH is completely inhibited. Antiarrhythmic drugs. In post-marketing practice, cases of bidirectional tachycardia have been reported with the simultaneous use of clarithromycin with quinidine or disopyramide. When taking clarithromycin concomitantly with these drugs, it is recommended to perform ECG monitoring for timely detection of QT interval prolongation. Serum concentrations of these drugs should be monitored during clarithromycin therapy. There are also reports of cases of hypoglycemia when taking clarithromycin and disopyramide simultaneously. Oral hypoglycemic agents and insulin. When used concomitantly with certain hypoglycemic agents such as nateglinide and repaglinide and clarithromycin, inhibition of the CYP3A enzyme may occur, which can cause hypoglycemia. Close monitoring of glucose levels is recommended. CYP3A-related interactions. Concomitant use of clarithromycin, a known inhibitor of the CYP3A enzyme, and any other drug primarily metabolized by CYP3A may lead to an increase in the concentration of the latter in the blood plasma, which, in turn, may enhance or prolong its therapeutic effect and adverse reactions. The following drugs or groups of drugs are known to be metabolized by the same CYP3A isoenzyme: alprazolam, astemizole, carbamazepine, cilostazol, cisapride, cyclosporine, disopyramide, horn alkaloids, lovastatin, methylprednisolone, midazolam, omeprazole, oral anticoagulants (eg, warfarin), pimozide, quinidine, rifabutin, sildenafil, simvastatin, tacrolimus, terfenadine, triazolam and vinblastine, but this list is not complete. A similar mechanism of interaction was noted with the use of phenytoin, theophylline and valproate, which are metabolized by another isoenzyme of the cytochrome P450 system. Omeprazole. When taken simultaneously with clarithromycin, an increase in the equilibrium concentration of omeprazole in plasma was noted (increase in Cmax, AUC0-24 and t1/2 by 30%, 89% and 34%, respectively). The average gastric pH was 5.2 when omeprazole was taken alone and 5.7 when omeprazole was taken with clarithromycin. Sildenafil, tadalafil and vardenafil. There is a possibility of increased plasma concentrations of phosphodiesterase inhibitors (sildenafil, tadalafil and vardenafil) when used together with clarithromycin, which may require a reduction in the dose of phosphodiesterase inhibitors. Theophylline, carbamazepine. The results of clinical studies show that there is a small but statistically significant (p≤0.05) increase in the circulating concentrations of theophylline and carbamazepine when taken together with clarithromycin. An increase in the concentration of a number of drugs in plasma has been established when taken simultaneously with clarithromycin: omeprazole, sildenafil, vardenafil, theophylline and carbamazepine, digoxin, colchicine, phenytoin, valproate. Triazolobenzodiazepines (eg, alprazolam, midazolam, triazolam). Concomitant use of oral midazolam and clarithromycin is contraindicated. The same precautions should be taken when using other benzodiazepines that are metabolized by CYP3A, including triazolam and alprazolam. For benzodiazepines whose elimination does not depend on CYP3A (temazepam, nitrazepam, lorazepam), the development of a clinically significant interaction with clarithromycin is unlikely. There are post-marketing reports of drug interactions and central nervous system side effects (such as drowsiness and confusion) when clarithromycin and triazolam are used together. Patients should be monitored for the possibility of increased pharmacological effects on the central nervous system. Interactions with other drugs Aminoglycosides: Caution should be exercised when co-administering clarithromycin and other ototoxic drugs, especially aminoglycosides. Colchicine is a substrate for both CYP3A and the p-glycoprotein efflux transporter. Clarithromycin and other macrolides are known to be inhibitors of CYP3A and p-glycoprotein. If clarithromycin is used concomitantly with colchicine, inhibition of p-glycoprotein and CYP3A by clarithromycin may result in increased colchicine exposure. Patients should be monitored for clinical manifestations of colchicine intoxication. Patients with normal liver and kidney function should reduce the dose of colchicine when taken concomitantly with clarithromycin. Concomitant use of clarithromycin and colchicine is contraindicated in patients with hepatic or renal insufficiency. Zidovudine. Concomitant oral administration of clarithromycin tablets and zidovudine in adult HIV-infected patients may result in a decrease in the steady-state concentration of zidovudine. Clarithromycin interferes with the absorption of zidovudine when administered concomitantly orally, which can largely be avoided by maintaining a 4-hour interval between doses of clarithromycin and zidovudine. This interaction does not occur in pediatric patients infected with HIV when taking clarithromycin suspension concomitantly with zidovudine and dideoxyinosine. Phenytoin and valproate. Spontaneous reports indicate interactions between CYP3A inhibitors, such as clarithromycin, and drugs that are theoretically not metabolized by CYP3A (eg, phenytoin and valproate). When co-prescribing such drugs with clarithromycin, it is recommended to analyze their serum levels. There is evidence of increased serum concentrations of these drugs. Bidirectional drug interactions Atazanavir and clarithromycin are substrates and inhibitors of CYP3A. There is evidence of a bidirectional interaction between these drugs. Co-administration of clarithromycin (500 mg twice daily) with atazanavir (400 mg once daily) resulted in a 2-fold increase in clarithromycin exposure, a 70% decrease in 14-OH-clarithromycin exposure, and a 28% increase in atazanavir AUC. Since clarithromycin has a large therapeutic window, no dose reduction of clarithromycin is required in patients with normal renal function. For patients with moderate renal impairment (creatinine clearance from 30 to 60 ml/min), the dose of clarithromycin should be reduced by 50%. For patients with CC less than 30 ml/min, the dose of clarithromycin should be reduced by 75% by using the appropriate dosage form. When co-administered with protease inhibitors, the dose of clarithromycin should not exceed 1000 mg per day. Calcium channel blockers. Due to the risk of arterial hypotension, clarithromycin should be used with caution concomitantly with calcium channel blockers metabolized by CYP 3A4 (for example, verapamil, amlodipine, diltiazem). When they interact, plasma concentrations of both clarithromycin and calcium channel blockers may increase. Hypotension, bradyarrhythmias and lactic acidosis have been observed in patients receiving clarithromycin with verapamil. Itraconazole and clarithromycin are substrates and inhibitors of CYP3A, and therefore clarithromycin may increase plasma levels of itraconazole and vice versa. When using itraconazole with clarithromycin, patients should be closely monitored by a physician for signs and symptoms of enhanced or prolonged pharmacological effects. Saquinavir and clarithromycin are substrates and inhibitors of CYP3A. There is evidence of a bidirectional interaction between these drugs.
Contraindications
- Hypersensitivity to antibiotics from the macrolide group or to one of the excipients. - Co-administration with the following drugs: astemizole, cisapride, pimozide, terfenadine ergot alkaloids (for example, ergotamine or dihydroergotamine) oral midazolam HMG-CoA reductase inhibitors (statins) that are widely metabolized by CYP3A4 (lovastatin or simvastatin) colchicine ticagrelor or ranolazine - History of QT interval prolongation, ventricular cardiac arrhythmia (including bidirectional tachycardia). — Hypokalemia (risk of QT interval prolongation). - Severe liver failure and/or renal failure (creatinine clearance less than 30 ml/min).
Compound
One tablet contains: active substance - clarithromycin 250 mg or 500 mg, excipients: croscarmellose sodium, microcrystalline cellulose, povidone, magnesium stearate, colloidal anhydrous silicon dioxide, talc shell composition Opadry 20J52739 yellow and Opadry 03H59005 transparent: hypromellose, pro pylene glycol, titanium dioxide (E 171), hydroxypropyl cellulose, sorbitan monooleate, quinoline yellow (E 104), vanillin.
Overdose
Symptoms: Gastrointestinal symptoms may occur, as well as changes in mental status, paranoid behavior, hypokalemia and hypoxemia. Treatment: discontinue use of Lecoclar and begin appropriate symptomatic treatment. No significant effect of hemodialysis or peritoneal dialysis on clarithromycin serum concentrations is expected.
Side effect
The following are adverse reactions that occurred during clinical trials and post-marketing use of various dosage forms and dosages of clarithromycin. Adverse reactions associated or possibly associated with clarithromycin are distributed according to the frequency of occurrence: ≥1/10 – very common, ≥1/100 to
Storage conditions
Store at a temperature not exceeding 30 °C, in the original packaging. Keep out of the reach of children!
Buy Lecoclar HL tablet prolong. d-I coating film about 500 mg in a blister. in pack No. 7x1 in the pharmacy
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Instructions for use for Lecoclar HL tablet prolong. d-I coating film about 500 mg in a blister. in pack No. 7x1
