Clarithromycin film-coated tablets 250 mg blister 10 pcs Кларитромицин таблетки покрытые пленочной оболочкой по 250 мг блистер 10 шт

Compound

Active ingredient: clarithromycin;

1 tablet contains clarithromycin, calculated as 100% substance - 250 mg or 500 mg;

Excipients: microcrystalline cellulose; sodium starch glycolate (type A); sodium lauryl sulfate; hypromellose; calcium stearate; Opadry II Yellow coating mixture (contains: triacetin; hypromellose; lactose monohydrate; titanium dioxide (E 171); polyethylene glycol; iron oxide yellow (E 172)).

Dosage form

Film-coated tablets.

Main physical and chemical properties: yellow film-coated tablets with a biconvex surface, with a score line on one side of the tablet and the embossing "KMP" on the other. A white core is visible on the cross-section.

Pharmacotherapeutic group

Antimicrobial agents for systemic use. Macrolides. ATX code J01F A09.

Pharmacological properties

Pharmacodynamics

Clarithromycin is a semisynthetic macrolide antibiotic. The antibacterial action of clarithromycin is determined by its binding to the 5OS ribosomal subunit of sensitive bacteria and inhibition of protein biosynthesis. The drug exhibits high in vitro efficacy against a wide range of aerobic and anaerobic gram-positive and gram-negative microorganisms, including hospital strains. The minimum inhibitory concentrations (MIC) of clarithromycin are usually 2 times lower than the MIC of erythromycin.

Clarithromycin is highly effective in vitro against Legionella pneumophila and Mycoplasma pneumoniae. It has a bactericidal effect against H. pylori, and its activity at neutral pH is higher than at acidic pH. In vitro and in vivo data indicate that clarithromycin is highly effective against clinically significant mycobacterial strains. In vitro studies have shown that Enterobacteriaceae and Pseudomonas strains, as well as gram-negative bacteria that do not produce lactose, are not sensitive to clarithromycin.

Microbiology.

Clarithromycin is active in vitro and in clinical practice 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 staphylococcal strains are not susceptible to clarithromycin.

Clarithromycin is active in vitro against most strains of the following microorganisms, but its clinical efficacy and safety have not been established:

aerobic gram-positive microorganisms: Streptococcus agalactiae, Streptococci (groups C, F, G), Viridans group streptococci.

Aerobic gram-negative microorganisms: Bordetella pertussis, Pasteurella multocida.

Other microorganisms: Chlamydia trachomatis.

Anaerobic gram-positive microorganisms: Clostridium perfringens, Peptococcus niger, Propionibacterium acnes.

Anaerobic gram-negative microorganisms: Bacteriodes melaninogenicus.

Spirochetes: Borrelia burgdorferi, Treponema pallidum

Campylobacter: Campylobacter jejuni.

Clarithromycin has a bactericidal effect against several strains of bacteria: Haemophilus influenzae, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Moraxella (Branhamella) catarrhalis, Neisseria gonorrhoeae, H. pylori and Campylobacter spp.

The main metabolite of clarithromycin in the human body is the microbiologically active 14-hydroxyclarithromycin (14-OH-clarithromycin). For most microorganisms, the microbiological activity of the metabolite is equal to or 1-2 times weaker than that of the parent substance, with the exception of H. influenzae, against which the effectiveness of the metabolite is 2 times higher. Under in vitro and in vivo conditions, the parent substance and its main metabolite have either an additive or synergistic effect against H. influenzae, depending on the strain of the microorganism.

Pharmacokinetics

Clarithromycin is rapidly and well absorbed from the gastrointestinal tract after oral administration of the drug in tablet form. The microbiologically active metabolite 14-hydroxyclarithromycin is formed by first-pass metabolism. Clarithromycin can be administered regardless of food intake, since food does not affect the bioavailability of clarithromycin tablets. Food slightly delays the onset of clarithromycin absorption and the formation of the 14-hydroxy metabolite.

The pharmacokinetics of clarithromycin are nonlinear; however, steady state concentrations are achieved within 2 days of dosing. At 250 mg twice daily, 15-20% of unchanged drug is excreted in the urine. At 500 mg twice daily, urinary excretion is greater (approximately 36%).

14-hydroxyclarithromycin is the major metabolite, which is excreted in urine in an amount of 10-15% of the administered dose. Most of the remainder of the dose is excreted in feces, primarily in bile. 5-10% of the parent compound is recovered in feces.

When 500 mg clarithromycin is administered 3 times daily, plasma clarithromycin concentrations are increased compared to 500 mg administered 2 times daily.

Clarithromycin concentrations in tissues are several times higher than the concentration of the drug in the blood. Increased concentrations were found in both tonsillar and pulmonary tissues. Clarithromycin at therapeutic doses binds to plasma proteins by 80%.

Clarithromycin penetrates the gastric mucosa. Clarithromycin levels in the gastric mucosa and tissue are higher when clarithromycin is administered with omeprazole than when clarithromycin is administered alone.

Indications

Treatment of infections caused by microorganisms sensitive to clarithromycin:

• upper respiratory tract infections, i.e. nasopharynx (tonsillitis, pharyngitis) and paranasal sinus infections;
• lower respiratory tract infections (eg, bronchitis, acute lobar pneumonia, primary atypical pneumonia);
• skin and soft tissue infections (such as impetigo, folliculitis, erysipeloid, furunculosis, infected wounds);
• acute and chronic odontogenic infections;
• disseminated or localized mycobacterial infections caused by Mycobacterium avium or Mycobacterium intracellulare. Localized infections caused by Mycobacterium chelonae, Mycobacterium fortuitum or Mycobacterium kansasii;
• eradication of H. pylori in patients with duodenal ulcer by inhibiting hydrochloric acid secretion (the activity of clarithromycin against H. pylori at neutral pH is higher than at acidic pH).

Contraindications

• Hypersensitivity to macrolide antibiotics and other components of the drug. Concomitant use of astemizole, cisapride, pimozide, terfenadine (since this may lead to prolongation of the QT interval and development of cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation, torsades de pointes), ergot alkaloids such as ergotamine, dihydroergotamine (since this may lead to ergotoxicity), HMG-CoA reductase inhibitors (statins), which are extensively metabolized by cyp3a4 (lovastatin or simvastatin) due to the risk of myopathy including rhabdomyolysis. Concomitant use of clarithromycin and oral midazolam. patients with a history of prolongation of the QT interval or ventricular cardiac arrhythmias, including torsades de pointes. hypokalemia (risk of prolongation of the QT interval). severe hepatic impairment and concomitant renal impairment. concomitant use of clarithromycin (and other strong cyp3a4 inhibitors) with colchicine. concomitant use of clarithromycin with ticagrelor or ranolazine.

Interaction with other medicinal products and other types of interactions

Clarithromycin does not interact with oral contraceptives.

The use of the following drugs is strictly contraindicated due to the possible development of severe consequences of interaction.

Cisapride, pimozide, astemizole, terfenadine. Increased serum levels of cisapride, pimozide, and terfenadine may be observed when co-administered with clarithromycin, which may cause prolongation of the QT interval and the occurrence of arrhythmias, including ventricular tachycardia, ventricular fibrillation, and torsades de pointes.

Similar effects have been observed with the combined use of astemizole and other macrolides.

Ergot alkaloids. Concomitant use of clarithromycin and ergotamine or dihydroergotamine has been reported to be associated with signs of acute ergotism, characterized by vasospasm and ischemia of the extremities and other tissues, including the central nervous system. Concomitant administration of clarithromycin and ergot alkaloids is contraindicated (see Contraindications).

HMG-CoA reductase inhibitors (statins).

The combined use of clarithromycin with lovastatin or simvastatin is contraindicated (see Contraindications) because these statins are extensively metabolized by CYP3A4 and concomitant use with clarithromycin increases their plasma concentrations, which in turn increases the risk of myopathy, including rhabdomyolysis. There are data on the development of rhabdomyolysis in patients with concomitant use of clarithromycin and these statins.

If clarithromycin therapy cannot be avoided, lovastatin or simvastatin should be discontinued during treatment. Clarithromycin should be used with caution when co-administered with other statins. If co-administration of clarithromycin with statins cannot be avoided, the lowest effective dose of the statin should be used. A statin that is not dependent on CYP3A4 metabolism (e.g., fluvastatin) may be used.

When combined with statins, patients should be monitored for signs and symptoms of myopathy.

Effect of other drugs on the pharmacokinetics of clarithromycin.

Drugs that are CYP3A4 inducers (e.g. rifampin, phenytoin, carbamazepine, phenobarbital, St. John's wort) may induce the metabolism of clarithromycin. This may result in subtherapeutic levels of clarithromycin and decreased efficacy. In addition, plasma levels of the CYP3A4 inducer may need to be monitored as they may be increased by CYP3A4 inhibition by clarithromycin (see also the prescribing information for the relevant CYP3A4 inducer). Concomitant use of rifabutin and clarithromycin may result in increased rifabutin levels and decreased clarithromycin serum levels, with an increased risk of uveitis.

The following drugs are known or suspected to affect clarithromycin blood concentrations and may require dosage adjustment or alternative therapy.

Efavirenz, nevirapine, rifampin, rifabutin, and rifapentine. Potent cytochrome P450 enzyme inducers such as efavirenz, nevirapine, rifampin, rifabutin, and rifapentine may accelerate the metabolism of clarithromycin, decreasing its plasma concentration but increasing the concentration of 14-OH-clarithromycin, the microbiologically active metabolite. Since the microbiological activity of clarithromycin and 14-OH-clarithromycin varies among bacteria, the expected therapeutic effect may not be achieved through the combined use of clarithromycin and cytochrome P450 enzyme inducers.

Etravirine. The effect of clarithromycin may be reduced by etravirine, but concentrations of the active metabolite 14-OH-clarithromycin are increased. Because 14-OH-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered. Therefore, alternatives to clarithromycin should be considered for the treatment of MAC.

Fluconazole: Steady-state concentrations of the active metabolite 14-OH-clarithromycin are not significantly altered by co-administration with fluconazole. No dosage adjustment of clarithromycin is required.

Ritonavir. The use of ritonavir and clarithromycin leads to significant inhibition of clarithromycin metabolism. C max of clarithromycin increases by 31%, C min - by 182% and AUC - by 77%. Complete inhibition of 14-OH-clarithromycin formation occurs. Due to the large therapeutic window, dose reduction of clarithromycin in patients with normal renal function is not required. However, for patients with renal insufficiency, dose adjustment is necessary: for patients with CL CR 30-60 ml/min, the dose of clarithromycin should be reduced by 50%. For patients with severe renal insufficiency (CL CR should be reduced by 75%. Doses of clarithromycin exceeding 1 g/day should not be used together with ritonavir.

The same dose adjustment should be made in patients with renal impairment when ritonavir is used as a pharmacokinetic enhancer with other HIV protease inhibitors, including atazanavir and saquinavir.

Effect of clarithromycin on the pharmacokinetics of other drugs.

Antiarrhythmic agents. There have been postmarketing reports of torsades de pointes occurring with concomitant use of clarithromycin with quinidine or disopyramide. ECG monitoring is recommended to detect prolongation of the QT interval. Serum concentrations of these drugs should be monitored during clarithromycin therapy.

During post-marketing use of clarithromycin preparations, there have been reports of hypoglycemia with concomitant use of clarithromycin and disopyramide, therefore, blood glucose monitoring is necessary when these agents are used concomitantly.

Oral hypoglycemic agents/insulin: Concomitant use of clarithromycin with certain oral hypoglycemic agents, such as nateglinide and repaglinide, may cause hypoglycemia. Close monitoring of glucose levels is recommended.

CYP3A-related interactions. Concomitant administration of clarithromycin, a known CYP3A inhibitor, and a drug primarily metabolized by CYP3A may result in elevated plasma concentrations of the latter, which may increase or prolong its therapeutic effect and the risk of adverse reactions. Caution should be exercised when administering clarithromycin to patients receiving drugs that are CYP3A substrates, especially if the CYP3A substrate has a narrow therapeutic index (e.g., carbamazepine) and/or is extensively metabolized by this enzyme. Dose adjustments and, if possible, careful monitoring of serum concentrations of the drug metabolized by CYP3A may be necessary in patients receiving concomitant clarithromycin.

The following drugs or classes of drugs are known (or suspected) to be metabolized by the same CYP3A isoenzyme: alprazolam, astemizole, carbamazepine, cilostazol, cisapride, cyclosporine, disopyramide, ergot 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 interaction mechanism has been observed with phenytoin, theophylline, and valproate, which are metabolized by a different cytochrome P450 isoenzyme.

Omeprazole. There is evidence that the use of clarithromycin in combination with omeprazole in healthy adult volunteers leads to an increase in the equilibrium concentrations of omeprazole. When using only omeprazole, the average pH of gastric juice when measured over 24 hours is 5.2, with the simultaneous use of omeprazole with clarithromycin - 5.7.

Sildenafil, tadalafil and vardenafil: There is a potential for increased plasma concentrations of phosphodiesterase inhibitors (sildenafil, tadalafil and vardenafil) when co-administered with clarithromycin, which may require a reduction in the dose of the phosphodiesterase inhibitor.

Theophylline, carbamazepine. There is evidence of a slight increase in the plasma concentration of theophylline or carbamazepine when administered concomitantly with clarithromycin.

Tolterodine. Tolterodine is primarily metabolized by the cytochrome P450 isoform 2D6 (CYP2D6). However, in the CYP2D6-negative population, metabolism occurs via CYP3A. In this population, inhibition of CYP3A results in significant increases in plasma tolterodine concentrations. In these patients, dose reduction of tolterodine may be necessary when co-administered with CYP3A inhibitors such as clarithromycin.

Triazolebenzodiazepines (eg, alprazolam, midazolam, triazolam). The combined use of oral midazolam and clarithromycin should be avoided. When intravenous midazolam is used with clarithromycin, the patient should be closely monitored for timely dose adjustments.

The same precautions should be observed 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 data on drug interactions and development of side effects from the central nervous system (such as drowsiness and confusion) with the combined use of clarithromycin and triazolam. The patient should be monitored for possible increase in pharmacological effects from the central nervous system.

Other types of interactions.

Aminoglycosides. Clarithromycin should be used with caution in combination with other ototoxic agents, especially aminoglycosides.

Colchicine. Colchicine is a substrate of CYP3A and P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. When clarithromycin and colchicine are coadministered, inhibition of Pgp and CYP3A by clarithromycin may result in increased exposure to colchicine. Patients should be monitored closely for clinical signs and symptoms of colchicine toxicity. The dose of colchicine should be reduced when coadministered with clarithromycin in patients with normal renal and hepatic function. Concomitant use of clarithromycin with colchicine is contraindicated in patients with renal or hepatic impairment (see Contraindications, Precautions).

Digoxin. Digoxin is considered a P-glycoprotein (Pgp) substrate. Clarithromycin is known to inhibit Pgp. When co-administered, inhibition of Pgp may result in increased digoxin exposure. Increased serum digoxin levels have been reported in patients receiving clarithromycin and digoxin. Some patients have developed signs of digitalis toxicity, including potentially fatal arrhythmias. Serum digoxin levels should be closely monitored when co-administered with clarithromycin.

Zidovudine: Concomitant administration of clarithromycin immediate-release tablets and zidovudine to HIV-infected patients may result in decreased steady-state serum concentrations of zidovudine. Because clarithromycin may interfere with the absorption of orally administered zidovudine, a 4-hour interval should be maintained between clarithromycin and zidovudine doses. No such interactions have been reported with clarithromycin suspension and zidovudine or dideoxynazine in children.

Phenytoin and valproate. There have been published reports of interactions between CYP3A inhibitors, including clarithromycin, and drugs not thought to be metabolized by CYP3A (phenytoin and valproate). Serum levels of these drugs should be measured when co-administered with clarithromycin. Increased serum levels have been reported.

Bidirectional drug interactions.

Atazanavir. Co-administration of clarithromycin (500 mg twice daily) with atazanavir (400 mg once daily), both substrates and inhibitors of CYP3A, resulted in a 2-fold increase in clarithromycin exposure and a 70% decrease in 14-OH-clarithromycin exposure with a 28% increase in atazanavir AUC. Since clarithromycin has a large therapeutic index, no dose reduction is necessary in patients with normal renal function. The clarithromycin dose should be reduced by 50% in patients with creatinine clearance 30-60 mL/min and by 75% in patients with creatinine clearance day should not be co-administered with protease inhibitors

Calcium channel blockers. Due to the risk of arterial hypotension, caution should be exercised when co-administering clarithromycin with calcium channel blockers that are metabolized by CYP3A4 (e.g., verapamil, amlodipine, diltiazem). The interaction may increase plasma concentrations of both clarithromycin and calcium channel blockers. There are data indicating that arterial hypotension, bradyarrhythmia, and lactic acidosis have been observed in patients receiving clarithromycin with verapamil.

Itraconazole. Clarithromycin and itraconazole are substrates and inhibitors of CYP3A, and clarithromycin may increase plasma levels of itraconazole and vice versa. When itraconazole is coadministered with clarithromycin, patients should be closely monitored for signs or symptoms of increased or prolonged pharmacologic effect.

Saquinavir. Co-administration of clarithromycin (500 mg twice daily) with saquinavir (soft gelatin capsules, 1200 mg three times daily), both substrates and inhibitors of CYP3A, resulted in a 177% increase in steady-state AUC and a 187% increase in Cmax compared to saquinavir alone. Clarithromycin AUC and Cmax increased by approximately 40% compared to clarithromycin alone. No dosage adjustment is necessary when both drugs are co-administered for a limited period of time at the above-mentioned doses and dosage forms. Interaction data with soft gelatin capsules may not reflect the effects observed with saquinavir hard gelatin capsules. Drug interaction data using saquinavir alone may not reflect the effects seen with saquinavir/ritonavir therapy. When saquinavir is co-administered with ritonavir, the potential effects of ritonavir on clarithromycin should be considered (see above).

Features of application

The drug contains lactose as an excipient, therefore the drug should not be used by patients with galactose intolerance, lactase deficiency or glucose/galactose malabsorption.

Prolonged or repeated use of antibiotics may result in overgrowth of non-susceptible bacteria and fungi. If superinfection occurs, discontinue clarithromycin and initiate appropriate therapy.

The drug should be used with caution in patients with severe renal insufficiency.

Liver dysfunction, including elevated liver enzymes, and hepatocellular and/or cholestatic hepatitis with or without jaundice have been reported with the use of clarithromycin. This liver dysfunction may be severe and is usually reversible. In some cases, fatal liver failure has been reported, generally associated with serious underlying diseases and/or concomitant medications. Discontinue clarithromycin immediately if signs and symptoms of hepatitis such as anorexia, jaundice, dark urine, pruritus, or abdominal pain occur.

Clostridium difficile-associated diarrhea (CDAD), ranging from mild to fatal, has been reported with nearly all antibacterial agents, including clarithromycin. The possibility of CDAD should be kept in mind in all patients who develop diarrhea after antibiotic use. In addition, a careful history should be obtained, as CDAD has been reported up to 2 months after antibacterial use.

Increased symptoms of myasthenia gravis have been reported in patients receiving clarithromycin.

The drug is excreted through the liver and kidneys. Caution should be exercised when using the drug in patients with impaired liver function, with moderate or severe renal impairment.

Colchicine toxicity (including fatalities) has been reported with concomitant use of clarithromycin and colchicine, particularly in elderly patients, including those with renal insufficiency. If concomitant use of colchicine and clarithromycin is necessary, patients should be monitored for clinical signs and symptoms of colchicine toxicity. The colchicine dose should be reduced in all patients receiving concomitant colchicine and clarithromycin. Concomitant use of clarithromycin with colchicine is contraindicated in patients with renal or hepatic impairment (see Contraindications).

Clarithromycin and triazolebenzodiazepines, such as triazolam, intravenous midazolam, should be used with caution (see Interaction with other medicinal products and other forms of interaction).

Clarithromycin should be used with caution when co-administered with other ototoxic agents, especially aminoglycosides. Vestibular and auditory function should be monitored during and after treatment.

Due to the risk of prolongation of the QT interval, clarithromycin should be used with caution in patients with ischemic heart disease, severe heart failure, hypomagnesemia, bradycardia (drugs that are associated with prolongation of the QT interval (see "Interaction with other medicinal products and other forms of interaction"). Clarithromycin should not be used in patients with congenital or history of prolongation of the QT interval, or with a history of ventricular cardiac arrhythmia (see "Contraindications").

Pneumonia. Since resistance to macrolides may exist in Streptococcus pneumoniae, it is important to perform susceptibility testing when prescribing clarithromycin for the treatment of community-acquired pneumonia. In case of hospital-acquired pneumonia, clarithromycin should be used in combination with other appropriate antibiotics.

Mild to moderate skin and soft tissue infections. These infections are most often caused by Staphylococcus aureus and Streptococcus pyogenes, which may be resistant to macrolides. Therefore, susceptibility testing is important. In cases where beta-lactam antibiotics cannot be used (eg, allergy), other antibiotics such as clindamycin may be used as first-line drugs. Macrolides currently play a role only in the treatment of certain skin and soft tissue infections (eg, Corynebacterium minutissimum infections (erythrasma), acne vulgaris, erysipelas) and in situations where penicillin therapy cannot be used.

In case of development of severe acute hypersensitivity reactions such as anaphylaxis, Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS, Schonlein-Henoch disease, therapy with clarithromycin should be stopped immediately and appropriate treatment should be started immediately.

Attention should be paid to the possibility of cross-resistance between clarithromycin and other macrolides, as well as lincomycin and clindamycin.

The use of any antimicrobial therapy, including clarithromycin, to treat H. pylori infection may result in the development of microbial resistance. A small number of patients may develop resistance of H. pylori organisms to clarithromycin.

Oral hypoglycemic agents/insulin. Concomitant use of clarithromycin and oral hypoglycemic agents and/or insulin may cause significant hypoglycemia. When co-administered with hypoglycemic agents such as nateglinide, pioglitazone, repaglinide, and rosiglitazone, clarithromycin may inhibit the CYP3A enzyme, which may cause hypoglycemia. Careful monitoring of glucose levels is recommended.

Oral anticoagulants. When clarithromycin is co-administered with warfarin, there is a risk of serious bleeding, significant increases in INR (International Normalized Ratio) and prothrombin time. While patients are receiving clarithromycin and oral anticoagulants, INR and prothrombin time should be monitored regularly.

HMG-CoA reductase inhibitors (statins). The combined use of clarithromycin with lovastatin or simvastatin is contraindicated (see "Contraindications"). Clarithromycin should be used with caution in combination with other statins. There are data on the development of rhabdomyolysis in patients with the combined use of clarithromycin and statins. When combined with statins, patients should be monitored for signs and symptoms of myopathy. In situations where the concomitant use of clarithromycin with statins cannot be avoided, it is recommended to prescribe the lowest effective dose of the statin. Possible use of a statin that is not dependent on CYP3A metabolism (eg, fluvastatin).

Clarithromycin should be used with caution when co-administered with cytochrome CYP3A4 enzyme inducers.

Children

Clarithromycin in this dosage form is contraindicated for children under 12 years of age. Children under 12 years of age should use clarithromycin in the form of an oral suspension.

Use during pregnancy or breastfeeding

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

Clarithromycin should not be used during pregnancy (especially in the first trimester) without careful benefit/risk assessment.

Clarithromycin passes into breast milk.

The ability to influence the reaction speed when driving vehicles or other mechanisms

There are no data on the effect. However, when driving a vehicle or operating other machinery, the possibility of adverse reactions from the nervous system, such as convulsions, dizziness, vertigo, hallucinations, confusion, disorientation, etc., should be taken into account.

Method of administration and dosage

The recommended dose of clarithromycin for adults and children over 12 years of age is 250 mg every 12 hours, for more severe infections the dose can be increased to 500 mg every 12 hours. The usual duration of treatment depends on the severity of the infection and ranges from 6 to 14 days.

Clarithromycin can be taken with or without food, as food does not affect the bioavailability of clarithromycin.

Treatment of odontogenic infections. The recommended dose is 250 mg every 12 hours for 5 days.

Use in patients with mycobacterial infection. The initial dose for adults is 500 mg 2 times a day. If there is no improvement in clinical signs or bacteriological parameters within 3-4 weeks of treatment, the dose of clarithromycin can be increased to 1000 mg 2 times a day.

Treatment of disseminated infections caused by MAC in AIDS patients continues as long as the clinical and microbiological effectiveness of the drug with medical confirmation lasts. Clarithromycin can be used in combination with other antimycobacterial agents.

Eradication of H. pylori in patients with duodenal ulcer (adults).

Triple therapy (7-10 days): Clarithromycin (500 mg) twice daily should be used together with amoxicillin 1000 mg twice daily and omeprazole 20 mg daily for 7-10 days.

Triple therapy (10 days): Clarithromycin (500 mg) twice daily, lansoprazole 30 mg twice daily, and amoxicillin 1000 mg twice daily for 10 days.

Dual therapy (14 days): Clarithromycin (500 mg) 3 times daily together with omeprazole 40 mg once daily orally for 14 days, then omeprazole 20 mg or 40 mg once daily orally for the next 14 days.

Dual therapy (14 days). Clarithromycin (500 mg) 3 times daily together with lansoprazole 60 mg once daily orally for 14 days. Further suppression of hydrochloric acid secretion may be required to reduce ulcer manifestations.

Clarithromycin has also been used in the following therapeutic regimens:

clarithromycin + tinidazole and omeprazole or lansoprazole; clarithromycin + metronidazole and omeprazole or lansoprazole; clarithromycin + tetracycline, bismuth subsalicylate and ranitidine; clarithromycin + amoxicillin and lansoprazole; clarithromycin + ranitidine bismuth citrate.

Use in elderly persons: as for adults.

Use in patients with renal impairment: For patients with severe renal impairment (creatinine clearance halved, e.g. 250 mg once daily or 250 mg twice daily for more severe infections. In such patients, the duration of treatment should not exceed 14 days.

Overdose

Symptoms: Existing reports indicate that overdose with clarithromycin may cause gastrointestinal symptoms.

There is one case report of changes in mental status, paranoid behavior, hypokalemia, and hypoxemia in a patient with a history of bipolar psychosis who took 8 grams of clarithromycin.

Treatment: Adverse reactions following overdose should be treated with gastric lavage and symptomatic therapy. As with other macrolides, hemodialysis or peritoneal dialysis is unlikely to significantly affect serum clarithromycin levels.

Adverse reactions

The most common and widespread adverse reactions during treatment with clarithromycin in adults and children are abdominal pain, diarrhea, nausea, vomiting, and taste disturbance. Adverse reactions associated with clarithromycin are classified by system. Within each group, adverse reactions are presented in order of decreasing severity, if severity can be estimated.

Infections and infestations: cellulitis, oral candidiasis, gastroenteritis, infection, vaginal infection, pseudomembranous colitis, erysipelas.

From the blood and lymphatic system: leukopenia, neutropenia, thrombocythemia, eosinophilia, agranulocytosis, thrombocytopenia.

From the immune system: anaphylactoid reactions, hypersensitivity, anaphylactic reactions.

From the side of metabolism and nutrition: anorexia, decreased appetite, hypoglycemia.

From the psyche: insomnia, anxiety, nervousness, psychosis, confusion, depersonalization, depression, disorientation, hallucinations, nightmares, mania.

From the central nervous system: dysgeusia (impaired taste sensitivity), headache, taste distortion, loss of consciousness, dyskinesia, dizziness, drowsiness, tremor, convulsions, ageusia (loss of taste sensitivity), parosmia, anosmia, paresthesia.

From the organs of hearing and the labyrinth: dizziness, hearing impairment, ringing in the ears, hearing loss.

Cardiac disorders: cardiac arrest, atrial fibrillation, prolongation of the QT interval, extrasystoles, palpitations, torsades de pointes, ventricular tachycardia.

From the vascular side: vasodilation, hemorrhage.

From the respiratory system, chest organs and mediastinum: asthma, nosebleed, pulmonary embolism.

From the digestive system: diarrhea, vomiting, dyspepsia, nausea, abdominal pain, esophagitis, gastroesophageal reflux disease, gastritis, proctalgia, stomatitis, glossitis, bloating, constipation, dry mouth, belching, flatulence, acute pancreatitis, discoloration of the tongue, discoloration of the teeth.

From the hepatobiliary system: abnormal liver function tests, cholestasis, hepatitis, increased levels of ALT, AST, GGT, liver failure, cholestatic jaundice, hepatocellular jaundice.

From the skin and subcutaneous tissue: rash, hyperhidrosis, bullous dermatitis, itching, urticaria, maculopapular rash, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug-induced skin reaction with eosinophilia and systemic manifestations (DRESS), acne, Henoch-Schonlein disease.

Musculoskeletal and connective tissue disorders: muscle spasms, musculoskeletal rigidity, myalgia, rhabdomyolysis (in some reports of rhabdomyolysis, clarithromycin was used in combination with other drugs known to be associated with rhabdomyolysis (such as statins, fibrates, colchicine or allopurinol)), myopathy.

From the kidneys and urinary system: increased blood creatinine, increased blood urea, renal failure, interstitial nephritis.

General disorders and administration site reactions: phlebitis at the injection site, pain, inflammation at the injection site, malaise, fever, asthenia, chest pain, chills, fatigue.

Laboratory tests: change in albumin-globulin ratio, increased alkaline phosphatase levels in the blood, increased lactate dehydrogenase levels in the blood, increased international normalized ratio, increased prothrombin time, change in urine color.

There are reports of possible paresthesia, arthralgia, angioedema, and uveitis in patients taking rifabutin concomitantly. Most reactions were reversible. There are reports of colchicine toxicity (including fatalities) with concomitant use of clarithromycin and colchicine, especially in elderly patients, including those with renal failure.

The frequency, type and severity of adverse reactions in children are expected to be the same as in adults.

From the immune system.

In patients with AIDS and other immunocompromised patients who have been treated with high doses of clarithromycin for longer periods than recommended for the treatment of mycobacterial infections, it may not be possible to distinguish between adverse reactions associated with the use of the drug and symptoms of the underlying or concomitant diseases.

There are data that in adult patients who received clarithromycin in a daily dose of 1000 mg, the most common side effects were nausea, vomiting, taste distortion, abdominal pain, diarrhea, rash, bloating, headache, constipation, hearing impairment, increased ALT, AST levels. Dyspnea, insomnia, dry mouth occurred infrequently. In some patients, a significant increase in ALT, AST levels and a significant decrease in the number of leukocytes and platelets in the blood may be observed. In some cases, an increase in the level of urea in the blood is possible.

Best before date

3 years.

Storage conditions

In the original packaging at a temperature not exceeding 25°C. Keep out of reach of children.

Состав

Действующее вещество: clarithromycin;

1 таблетка содержит кларитромицина, в пересчете на 100 % вещество — 250 мг или 500 мг;

вспомогательные вещества: целлюлоза микрокристаллическая; натрия крахмалгликолят (тип А); натрия лаурилсульфат; гипромелоза; кальция стеарат; смесь для покрытия «Opadry II Yellow» (содержит: триацетин; гипромеллозу; лактозу, моногидрат; титана диоксид (Е 171); полиэтиленгликоль; железа оксид желтый (Е 172)).

Лекарственная форма

Таблетки, покрытые пленочной оболочкой.

Основные физико-химические свойства: таблетки, покрытые пленочной оболочкой, желтого цвета, с двояковыпуклой поверхностью, с риской с одной стороны таблетки и тиснением «КМП» с другой. На поперечном разрезе заметно ядро белого цвета.

Фармакотерапевтическая группа

Противомикробные средства для системного применения. макролиды. код атх j01f а09.

Фармакологические свойства

Фармакодинамика

Кларитромицин — полусинтетический антибиотик группы макролидов. Антибактериальное действие кларитромицина определяется его связыванием с 5OS-рибосомальной субъединицей чувствительных бактерий и угнетением биосинтеза белка. Препарат проявляет высокую эффективность in vitro против широкого спектра аэробных и анаэробных грамположительных и грамотрицательных микроорганизмов, в том числе госпитальных штаммов. Минимальные подавляющие концентрации (МПК) кларитромицина обычно в 2 раза ниже МПК эритромицина.

Кларитромицин in vitro высокоэффективен против Legionella pneumophila и Mycoplasma pneumonie. Действует бактерицидно относительно Н. pylori, активность кларитромицина при нейтральном рН выше, чем при кислом рН. Данные in vitro и in vivo свидетельствуют о высокой эффективности кларитромицина относительно клинически значимых штаммов микобактерий. Исследования in vitro показали, что штаммы Enterobacteriaceae и Pseudomonas, как и грамотрицательные бактерии, не продуцирующие лактозу, не чувствительны к кларитромицину.

Микробиология.

Кларитромицин активен in vitro и в клинической практике в отношении большинства штаммов следующих микроорганизмов:

аэробные грамположительные микроорганизмы: Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Listeria monocytogenes.

Аэробные грамотрицателъные микроорганизмы: Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, Neisseria gonorrhoeae, Legionella pneumophila.

Другие микроорганизмы: Mycoplasma pneumoniae, Chlamydia pneumoniae (TWAR).

Микобактерии: Mycobacterium leprae, Mycobacterium kansasii, Mycobacterium chelonae, Mycobacterium fortuitum, Mycobacterium avium complex (MAC), которые включают Mycobacterium avium, Mycobacterium intracellulare.

Бета-лактамазы микроорганизмов не влияют на эффективность кларитромицина.

Большинство метициллин- и оксациллинрезистентных штаммов стафилококков не чувствительны к кларитромицину.

Кларитромицин активен in vitro в отношении большинства штаммов следующих микроорганизмов, однако клиническая эффективность и безопасность его применения не установлены:

аэробные грамположителъные микроорганизмы: Streptococcus agalactiae, Streptococci (группы С, F, G), Viridans group streptococci.

Аэробные грамотрицательные микроорганизмы: Bordetella pertussis, Pasteurella multocida.

Другие микроорганизмы: Chlamydia trachomatis.

Анаэробные грамположительные микроорганизмы: Clostridium perfringens, Peptococcus niger, Propionibacterium acnes.

Анаэробные грамотрицательные микроорганизмы: Bacteriodes melaninogenicus.

Спирохеты: Borrelia burgdorferi, Treponema pallidum

Кампилобактерии: Campylobacter jejuni.

Кларитромицин оказывает бактерицидное действие против нескольких штаммов бактерий: Haemophilus influenzae, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Moraxella (Branhamella) catarrhalis, Neisseria gonorrhoeae, H. pylori и Campylobacter spp.

Основным метаболитом кларитромицина в организме человека является микробиологически активный 14-гидроксикларитромицин (14-ОН-кларитромицин). Для большинства микроорганизмов микробиологическая активность метаболита равна или в 1-2 раза слабее, чем материнская субстанция, за исключением H. influenzae, против которого эффективность метаболита в 2 раза выше. В условиях in vitro и in vivo материнская субстанция и ее основной метаболит оказывают либо аддитивный, либо синергический эффект против H. influenzae, в зависимости от штамма микроорганизма.

Фармакокинетика

Кларитромицин быстро и хорошо абсорбируется из желудочно-кишечного тракта после перорального применения препарата в форме таблеток. Микробиологически активный метаболит 14-гидроксикларитромицин образуется путем метаболизма первого прохождения. Кларитромицин можно применять независимо от приема пищи, поскольку пища не влияет на биодоступность таблеток кларитромицина. Еда незначительно задерживает начало абсорбции кларитромицина и образование 14-гидроксиметаболита.

Фармакокинетика кларитромицина нелинейная; однако равновесная концентрация достигается в пределах 2 дней применения препарата. При применении 250 мг 2 раза в сутки 15-20 % неизмененного препарата выводится с мочой. При дозе 500 мг 2 раза в сутки выведение препарата с мочой интенсивней (примерно 36 %).

14-гидроксикларитромицин является основным метаболитом, который выводится с мочой в количестве 10-15 % от принятой дозы. Большая часть остатка дозы выводится с калом, преимущественно с желчью. 5-10 % исходного соединения выявляется в фекалиях.

При применении 500 мг кларитромицина 3 раза в сутки концентрации кларитромицина в плазме крови повышаются по сравнению с дозой 500 мг 2 раза в сутки.

Концентрации кларитромицина в тканях в несколько раз превышают концентрацию препарата в крови. Повышенные концентрации были обнаружены как в тонзиллярной, так и в легочной тканях. Кларитромицин при терапевтических дозах на 80 % связывается с белками плазмы крови.

Кларитромицин проникает в слизистую оболочку желудка. Содержание кларитромицина в слизистой оболочке и ткани желудка выше при применении кларитромицина вместе с омепразолом, чем при монотерапии кларитромицином.

Показания

Лечение инфекций, вызванных чувствительными к кларитромицину микроорганизмами:

• инфекции верхних дыхательных путей, то есть носоглотки (тонзиллит, фарингит) и инфекции придаточных пазух носа;
• инфекции нижних дыхательных путей (например, бронхит, острая крупозная пневмония, первичная атипичная пневмония);
• инфекции кожи и мягких тканей (такие как импетиго‚ фолликулит, эризипелоид, фурункулез, инфицированные раны);
• острые и хронические одонтогенные инфекции;
• диссеминированные или локализованные микобактериальные инфекции, вызванные Mycobacterium avium или Mycobacterium intracellulare. Локализованные инфекции, вызванные Mycobacterium chelonae, Mycobacterium fortuitum или Mycobacterium kansasii;
• эрадикация H. pylori у пациентов с язвой двенадцатиперстной кишки при угнетении секреции соляной кислоты (активность кларитромицина против H. pylori при нейтральном рН выше, чем при кислом рН).

Противопоказания

• Повышенная чувствительность к макролидным антибиотикам и другим компонентам препарата. одновременное применение астемизола, цизаприда, пимозида, терфенадина (поскольку это может привести к продлению интервала qt и развитию сердечных аритмий, включая желудочковую тахикардию, фибрилляцию желудочков, пируэтную желудочковую тахикардию (torsades de pointes)), алкалоидов спорыньи, например эрготамина, дигидроэрготамина (поскольку это может привести к эрготоксичности), ингибиторов гмг-коа-редуктазы (статинов), которые в значительной степени метаболизируются сyр3а4 (ловастатина или симвастатина) из-за риска возникновения миопатии, включая рабдомиолиз. одновременное применение кларитромицина и перорального мидазолама. пациентам, имеющим в анамнезе удлинение интервала qt или желудочковые сердечные аритмии, включая пируэтную желудочковую тахикардию (torsades de pointes). гипокалиемия (риск удлинения интервала qt ). тяжелая печеночная недостаточность и сопутствующая почечная недостаточность. одновременное применение кларитромицина (и других сильных ингибиторов сyр3а4) с колхицином. одновременное применение кларитромицина с тикагрелором или ранолазином.

Взаимодействие с другими лекарственными средствами и другие виды взаимодействий

Кларитромицин не взаимодействует с пероральными контрацептивами.

Применение нижеприведенных препаратов строго противопоказано из-за возможного развития тяжелых последствий взаимодействия.

Цизаприд, пимозид, астемизол, терфенадин. Повышение уровня цизаприда, пимозида и терфенадина в сыворотке крови может наблюдаться при их одновременном применении с кларитромицином, что может вызвать удлинение интервала QT и появление аритмий, в том числе желудочковой тахикардии, фибрилляции желудочков и torsades de pointes.

Подобные эффекты отмечались и при совместном применении астемизола и других макролидов.

Алкалоиды спорыньи. Сообщалось, что одновременное применение кларитромицина и эрготамина или дигидроэрготамина ассоциировалось с появлением признаков острого эрготизма, что характеризовалось вазоспазмом и ишемией конечностей и других тканей, включая центральную нервную систему. Одновременное назначение кларитромицина и алкалоидов спорыньи противопоказано (см. «Противопоказания»).

Ингибиторы ГМГ-КоА-редуктазы (статины).

Комбинированное применение кларитромицина с ловастатином или симвастатином противопоказано (см. «Противопоказания»), поскольку эти статины в значительной степени метаболизуются СYР3А4 и одновременное применение с кларитромицином повышает их концентрацию в плазме крови, что, в свою очередь, повышает риск возникновения миопатии, включая рабдомиолиз. Имеются данные о развитии рабдомиолиза у пациентов при совместном применении кларитромицина и этих статинов.

Если терапию кларитромицином невозможно избежать, применение ловастатина или симвастатина необходимо прекратить во время курса лечения. С осторожностью следует назначать кларитромицин одновременно с другими статинами. В случае, если одновременное применение кларитромицина со статинами невозможно избежать, рекомендуется назначение наименьшей эффективной дозы статина. Возможно применение статина, который не зависит от метаболизма СYР3А4 (например, флувастатина).

При сочетанной терапии со статинами необходим мониторинг состояния пациентов с целью выявления признаков и симптомов миопатии.

Влияние других лекарственных средств на фармакокинетику кларитромицина.

Лекарственные средства, являющиеся индукторами СYРЗА (например, рифампицин, фенитоин, карбамазепин, фенобарбитал, препараты зверобоя), могут индуцировать метаболизм кларитромицина. Это может привести к субтерапевтическим уровням кларитромицина и снижению его эффективности. Кроме того, может потребоваться мониторинг плазменных уровней индуктора СYРЗА, которые могут быть повышены через ингибирование СYРЗА кларитромицином (см. также инструкцию по медицинскому применению соответствующего индуктора СYР3А4). Одновременное применение рифабутина и кларитромицина может приводить к повышению уровней рифабутина и снижению уровней кларитромицина в сыворотке крови с одновременным повышением риска появления увеита.

Влияние нижеуказанных лекарственных средств на концентрацию кларитромицина в крови известно или предполагается, поэтому может потребоваться изменение дозы или применение альтернативной терапии.

Эфавиренц, невирапин, рифампицин, рифабутин и рифапентин. Мощные индукторы ферментов цитохрома Р450, такие как эфавиренц, невирапин, рифампицин, рифабутин и рифапентин, могут ускорять метаболизм кларитромицина, снижая его концентрацию в плазме крови, но увеличивая концентрацию 14-ОН-кларитромицина — микробиологически активного метаболита. Поскольку микробиологическая активность кларитромицина и 14-ОН-кларитромицина разная в отношении различных бактерий, ожидаемый терапевтический эффект может быть не достигнут через совместное применение кларитромицина и индукторов ферментов цитохрома Р450.

Этравирин. Действие кларитромицина может ослабляться этравирином, однако концентрации активного метаболита 14-ОН-кларитромицина при этом повышаются. Поскольку 14-ОН-кларитромицин имеет пониженную активность против Mycobacterium avium complex (МАС), общая активность против этого патогена может быть изменена. Поэтому для лечения МАС следует рассмотреть применение альтернативных кларитромицину лекарственных средств.

Флуконазол. Равновесные концентрации активного метаболита 14-ОН-кларитромицина значительно не изменяются при совместном применении с флуконазолом. Изменение дозы кларитромицина не требуется.

Ритонавир. Применение ритонавира и кларитромицина приводит к значительному подавлению метаболизма кларитромицина. Сmax кларитромицина повышается на 31 %, Сmin — на 182 % И AUC — на 77 %. Происходит полное подавление образования 14-ОН-кларитромицина. Из-за большого терапевтического окна уменьшение дозы кларитромицина у пациентов с нормальной функцией почек не требуется. Однако для пациентов с почечной недостаточностью необходима коррекция дозы: для пациентов с CLCR 30-60 мл/мин дозу кларитромицина необходимо снизить на 50 %. Для пациентов с тяжелой почечной недостаточностью (CLCR необходимо снизить на 75 %. Дозы кларитромицина, превышающие 1 г/сутки, не следует применять вместе с ритонавиром.

Такую же коррекцию дозы следует проводить у пациентов с нарушением функции почек при применении ритонавира как фармакокинетического усилителя вместе с другими ингибиторами ВИЧ-протеазы, включая атазанавир и саквинавир.

Влияние кларитромицина на фармакокинетику других лекарственных средств.

Антиаритмические средства. Существуют постмаркетинговые сообщения о развитии пируэтной желудочковой тахикардии, возникшей при одновременном применении кларитромицина с хинидином или дизопирамидом. Рекомендуется проводить ЭКГ-мониторинг для своевременного выявления удлинения интервала QT. Во время терапии кларитромицином следует следить за концентрациями этих препаратов в сыворотке крови.

Во время постмаркетингового применения препаратов кларитромицина были сообщения о гипогликемии при одновременном применении кларитромицина и дизопирамида, поэтому необходим мониторинг уровня глюкозы крови при одновременном применении этих средств.

Пероральные гипогликемические средства/инсулин. Комбинированное применение кларитромицина с определенными гипогликемическими средствами, такими как натеглинид и репаглинид, может вызвать гипогликемию. В данном случае рекомендован тщательный мониторинг уровня глюкозы.

СYРЗА-связанные взаимодействия. Совместное применение кларитромицина, известного как ингибитор фермента СYРЗА, и препарата, что главным образом метаболизируется СYРЗА, может привести к повышению концентрации последнего в плазме крови, что в свою очередь может усилить или продлить его терапевтический эффект и риск возникновения побочных реакций. Следует соблюдать осторожность при применении кларитромицина пациентам, получающим терапию лекарственными средствами — субстратами СYРЗА, особенно если СYРЗА-субстрат имеет узкий терапевтический диапазон (например, карбамазепин) и/или экстенсивно метаболизируется этим энзимом. Может потребоваться изменение дозы и, если возможно, тщательный мониторинг сывороточных концентраций лекарственного средства, что метаболизируется СYРЗА, для пациентов, которые одновременно применяют кларитромицин.

Известно (или предполагается), что такие лекарственные препараты или группы препаратов метаболизируются одним и тем же СYРЗА изоферментом: альпразолам, астемизол, карбамазепин, цилостазо<