Clarithromycin-zdorovya

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KLAZITROMYCIN-ZDOROVIYA (CLARITHROMYCIN-ZDOROVYE)

Composition:

Active ingredient: clarithromycin;

One tablet contains clarithromycin 250 mg or 500 mg;

Excipients: pregelatinized starch, corn starch, magnesium stearate, colloidal anhydrous silicon dioxide, talc, microcrystalline cellulose, sodium croscarmellose, sodium lauryl sulfate, hypromellose, titanium dioxide (E 171); colouring agent: sunset yellow FCF (E 110) (250 mg dosage) or tartrazine (E 102) (500 mg dosage).

Pharmaceutical form. Film-coated tablets.

Main physico-chemical properties: film-coated tablets: 250 mg – round-shaped, light orange to orange in colour, biconvex surface; 500 mg – oval-shaped, yellow in colour, biconvex surface, with a score line. Marbling on the tablet surface may be observed. Two layers are visible in cross-section.

Pharmacotherapeutic group: Antimicrobial agents for systemic use. Macrolides.

ATC code J01FA09.

Pharmacological Properties.

Pharmacodynamics.

Clarithromycin is a semi-synthetic antibiotic of the macrolide group. The antibacterial action of clarithromycin is due to its binding to the 50S ribosomal subunit of susceptible bacteria and inhibition of protein biosynthesis. The drug demonstrates high in vitro efficacy against a broad spectrum of aerobic and anaerobic gram-positive and gram-negative microorganisms, including hospital strains. Minimum inhibitory concentrations (MICs) of clarithromycin are generally two times lower than those of erythromycin.

Clarithromycin is highly effective in vitro against Legionella pneumophila and Mycoplasma pneumoniae. It exerts bactericidal activity against H. pylori; the activity of clarithromycin at neutral pH is higher than at acidic pH. In vitro and in vivo data indicate high efficacy of clarithromycin against clinically significant strains of mycobacteria. In vitro studies have shown that strains of Enterobacteriaceae and Pseudomonas, as well as non-lactose-producing gram-negative bacteria, are not susceptible 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.

β-lactamases produced by microorganisms do not affect the efficacy of clarithromycin.

Most methicillin- and oxacillin-resistant strains of staphylococci are not susceptible to clarithromycin.

Helicobacter: H. pylori.

Clarithromycin is active in vitro against most strains of the following microorganisms; however, clinical efficacy and safety of its use 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.

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

Anaerobic gram-negative microorganisms: Bacteroides melaninogenicus.

Spirochetes: Borrelia burgdorferi, Treponema pallidum.

Campylobacters: Campylobacter jejuni.

Clarithromycin exerts bactericidal action against several bacterial strains: Haemophilus influenzae, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Moraxella (Branhamella) catarrhalis, Neisseria gonorrhoeae, H. pylori, and Campylobacter spp.

The primary 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 compound, except for H. influenzae, against which the metabolite is twice as effective. In vitro and in vivo, the parent compound and its main metabolite exhibit either additive or synergistic effects against H. influenzae, depending on the microbial strain.

Susceptibility Testing. Quantitative methods requiring measurement of zone diameter provide the most accurate assessment of bacterial susceptibility to antimicrobial agents. One of the recommended procedures for susceptibility testing uses disks impregnated with 15 mcg of clarithromycin (Kirby-Bauer diffusion test); the zone diameter for this disk is interpreted in relation to MIC values for clarithromycin. MIC is determined by broth or agar dilution methods.

When these procedures are followed, a laboratory report of "susceptible" indicates that the infecting microorganism is likely to respond to therapy. A report of "resistant" indicates that the infecting microorganism is unlikely to respond to therapy. A report of "intermediate susceptibility" suggests that the therapeutic effect of the drug may be uncertain or that the microorganism may be susceptible if higher doses are used (intermediate susceptibility is also referred to as moderate susceptibility).

Country- or region-specific data on absolute breakpoints for susceptibility, resistance, and intermediate susceptibility should be taken into account.

Pharmacokinetics.

Clarithromycin is rapidly and well absorbed from the gastrointestinal tract after oral administration in tablet form. The microbiologically active metabolite, 14-hydroxyclarithromycin, is formed via first-pass metabolism. Clarithromycin can be administered independently of food intake, as food does not affect the bioavailability of clarithromycin tablets. Food slightly delays the onset of absorption of clarithromycin and formation of the 14-hydroxy metabolite. The pharmacokinetics of clarithromycin is nonlinear, but steady-state concentrations are achieved within 2 days of drug administration. After administration of 250 mg twice daily, 15–20% of unchanged drug is excreted in urine. At a dose of 500 mg twice daily, urinary excretion is more intense (approximately 36%).

14-Hydroxyclarithromycin is the main metabolite excreted in urine, accounting for 10–15% of the administered dose. The majority of the remainder is excreted in feces, primarily via bile. 5–10% of the parent compound is found in feces.

When 500 mg of clarithromycin is administered three times daily, plasma concentrations of clarithromycin are higher compared to those achieved with a dose of 500 mg twice daily.

Tissue concentrations of clarithromycin exceed plasma concentrations by several times. Elevated concentrations have been found in both tonsillar and lung tissues. At therapeutic doses, clarithromycin is approximately 80% bound to plasma proteins.

Clarithromycin penetrates into the gastric mucosa. The concentration of clarithromycin in the gastric mucosa and gastric tissue is higher when clarithromycin is administered concomitantly with omeprazole than with clarithromycin monotherapy.

Clinical characteristics.

Indications.

Treatment of infections caused by microorganisms sensitive to clarithromycin:

• Infections of the upper respiratory tract, i.e. nasopharynx (tonsillitis, pharyngitis), and infections of the paranasal sinuses.
• Infections of the lower respiratory tract (bronchitis, acute lobar pneumonia, and primary atypical pneumonia).
• Skin and soft tissue infections (impetigo, folliculitis, erysipeloïd, 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 under conditions of inhibited hydrochloric acid secretion (clarithromycin activity against H. pylori at neutral pH is higher than at acidic pH).

Contraindications.

Hypersensitivity to macrolide antibiotics and to other components of the drug.

Concomitant use of clarithromycin and any of the following drugs: astemizole, cisapride, pimozide, terfenadine (since this may lead to QT interval prolongation and development of cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation, and torsades de pointes), ergot alkaloids, e.g. ergotamine, dihydroergotamine (since this may lead to ergot toxicity), HMG-CoA reductase inhibitors (statins) that are extensively metabolized by CYP3A4 (lovastatin or simvastatin), due to increased risk of myopathy, including rhabdomyolysis (see sections "Interaction with other medicinal products and other types of interactions", "Special precautions for use").

Concomitant use of clarithromycin and lomitapide (see section "Interaction with other medicinal products and other types of interactions").

Concomitant use of clarithromycin and oral midazolam (see section "Interaction with other medicinal products and other types of interactions").

Congenital or documented acquired QT interval prolongation or ventricular cardiac arrhythmias in history, including torsades de pointes (see sections "Interaction with other medicinal products and other types of interactions", "Special precautions for use").

Clarithromycin should not be used in patients with electrolyte imbalance (hypokalemia or hypomagnesemia) due to the risk of QT interval prolongation.

Severe hepatic insufficiency in combination with renal insufficiency.

Concomitant use of clarithromycin (and other potent CYP3A4 inhibitors) with colchicine (see sections "Interaction with other medicinal products and other types of interactions", "Special precautions for use").

Concomitant use of clarithromycin with ticagrelor, ivabradine, or ranolazine.

Interaction with other medicinal products and other types of interactions.

Clarithromycin does not interact with oral contraceptives.

Use of the following medicinal products is strictly contraindicated due to possible development of severe consequences of interaction.

Cisapride, pimozide, astemizole, terfenadine. Increased serum levels of cisapride have been reported in patients receiving clarithromycin and cisapride simultaneously. This may lead to QT interval prolongation and arrhythmias, including ventricular tachycardia, ventricular fibrillation, and torsades de pointes. Similar effects have been observed in patients taking clarithromycin and pimozide simultaneously (see section "Contraindications").

Macrolides have been reported to alter the metabolism of terfenadine, leading to increased serum levels of terfenadine. This has sometimes been associated with arrhythmias such as QT interval prolongation, ventricular tachycardia, ventricular fibrillation, and torsades de pointes (see section "Contraindications"). When clarithromycin and terfenadine were used concomitantly, a 2- to 3-fold increase in the serum level of the acid metabolite of terfenadine and QT interval prolongation were observed, which did not result in any clinically apparent effect. Similar effects were observed with concomitant use of astemizole and other macrolides.

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

Oral midazolam. When midazolam was administered with clarithromycin tablets (500 mg twice daily), the AUC of midazolam increased 7-fold after oral administration of midazolam. Concomitant use of oral midazolam and clarithromycin is contraindicated (see section "Contraindications").

Ivabradine. Use of clarithromycin with ivabradine is contraindicated (see section "Contraindications").

HMG-CoA reductase inhibitors (statins). Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated (see section "Contraindications"), as these statins are extensively metabolized by CYP3A4 and concomitant use with clarithromycin increases their plasma concentration, thereby increasing the risk of myopathy, including rhabdomyolysis. Cases of rhabdomyolysis have been reported in patients receiving clarithromycin concomitantly with these statins. If clarithromycin treatment cannot be avoided, therapy with lovastatin or simvastatin must be discontinued during the course of treatment.

Clarithromycin should be used cautiously when administered concomitantly with other statins. In situations where concomitant use of clarithromycin with statins cannot be avoided, it is recommended to prescribe the lowest registered dose of the statin. Use of a statin not dependent on CYP3A metabolism (e.g., fluvastatin) may be considered. Monitoring of patients for signs and symptoms of myopathy is required.

Lomitapide. Concomitant use of clarithromycin with lomitapide is contraindicated due to the possibility of significant increase in transaminase levels (see section "Contraindications").

Effect of other medicinal products on clarithromycin. Medicinal products that are CYP3A inducers (e.g., rifampicin, phenytoin, carbamazepine, phenobarbital, St. John's wort preparations) may induce clarithromycin metabolism. This may lead to subtherapeutic levels of clarithromycin and reduced efficacy. Additionally, monitoring of plasma levels of the CYP3A inducer may be required, as they may be increased due to CYP3A inhibition by clarithromycin (see also the instructions for medical use of the corresponding CYP3A4 inducer). Concomitant use of rifabutin and clarithromycin led to increased rifabutin levels and decreased clarithromycin levels in serum, with a simultaneous increased risk of uveitis.

The following medicinal products are known or suspected to affect clarithromycin blood concentration, thus dose adjustment of clarithromycin or alternative therapy may be required.

Efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine. Potent inducers of cytochrome P450 enzymes, such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine, may accelerate clarithromycin metabolism, reducing its plasma concentration but increasing the concentration of 14-OH-clarithromycin – a microbiologically active metabolite. Since the microbiological activity of clarithromycin and 14-OH-clarithromycin varies against different bacteria, the expected therapeutic effect may not be achieved with concomitant use of clarithromycin and cytochrome P450 enzyme inducers.

Etravirine. The effect of clarithromycin was reduced by etravirine, however, concentrations of the active metabolite 14-OH-clarithromycin were increased. Since 14-OH-clarithromycin has reduced activity against MAC, overall activity against this pathogen may be altered. Therefore, alternative drugs to clarithromycin should be considered for treatment of MAC.

Fluconazole. Concomitant use of fluconazole 200 mg daily and clarithromycin 500 mg twice daily led to a 33 % increase in steady-state Cmin of clarithromycin and an 18 % increase in AUC. Steady-state concentrations of the active metabolite 14-OH-clarithromycin were not significantly altered with concomitant use of fluconazole. Dose adjustment of clarithromycin is not required.

Ritonavir. Concomitant use of ritonavir 200 mg every 8 hours and clarithromycin 500 mg every 12 hours led to significant inhibition of clarithromycin metabolism. Cmax of clarithromycin increased by 31 %, Cmin by 182 %, and AUC by 77 % with concomitant use of ritonavir. Complete inhibition of 14-OH-clarithromycin formation was observed. Due to the wide therapeutic range, dose reduction of clarithromycin is not required for patients with normal renal function. However, dose adjustment is required for patients with renal insufficiency: for patients with CLCR 30-60 ml/min, the clarithromycin dose should be reduced by 50 %. For patients with CLCR < 30 ml/min, the clarithromycin dose should be reduced by 75 %. Clarithromycin doses exceeding 1 g daily should not be used concomitantly with ritonavir.

The same dose adjustment should be applied for patients with impaired renal function when ritonavir is used as a pharmacokinetic booster with other HIV protease inhibitors, including atazanavir and saquinavir (see below "Bidirectional drug interactions").

Effect of clarithromycin on other medicinal products.

Antiarrhythmic agents. There are reports of torsades de pointes development with concomitant use of clarithromycin and quinidine or disopyramide. ECG monitoring is recommended for timely detection of QT interval prolongation during concomitant use of clarithromycin with these drugs. Serum concentrations of these drugs should be monitored during clarithromycin therapy.

There have been reports of hypoglycemia with concomitant use of clarithromycin and disopyramide; therefore, glucose level monitoring is required when these agents are used concomitantly.

Oral hypoglycemic agents/insulin. Clarithromycin may inhibit the CYP3A enzyme when used concomitantly with certain hypoglycemic agents such as nateglinide and repaglinide, potentially causing hypoglycemia. Careful glucose level monitoring is recommended.

CYP3A-related interactions. Concomitant use of clarithromycin, a known CYP3A enzyme inhibitor, and a drug primarily metabolized by CYP3A may lead to increased plasma concentration of the latter, thereby enhancing or prolonging its therapeutic effect and adverse effects. Caution should be exercised when using clarithromycin in patients receiving therapy with CYP3A substrate drugs, especially if the CYP3A substrate has a narrow therapeutic range (e.g., carbamazepine) and/or is extensively metabolized by this enzyme. Dose adjustment may be required and, if possible, careful monitoring of serum concentrations of the drug primarily metabolized by CYP3A is recommended for patients concomitantly receiving clarithromycin.

It is known (or suspected) that the following drugs or drug groups are metabolized by the same CYP3A isoenzyme: alprazolam, astemizole, carbamazepine, cilostazol, cisapride, cyclosporine, disopyramide, ergot alkaloids, lovastatin, methylprednisolone, midazolam, omeprazole, oral anticoagulants (e.g., warfarin, rivaroxaban, apixaban), atypical antipsychotics (e.g., quetiapine), pimozide, quinidine, rifabutin, sildenafil, simvastatin, tacrolimus, terfenadine, triazolam, and vinblastine, among others. A similar interaction mechanism has been noted with phenytoin, theophylline, and valproate, which are metabolized by other isoenzymes of the cytochrome P450 system.

Direct oral anticoagulants. Direct oral anticoagulants dabigatran and edoxaban are substrates of the efflux transporter P-glycoprotein (Pgp). Rivaroxaban and apixaban are metabolized by CYP3A4 and are also Pgp substrates. Use of direct oral anticoagulants such as dabigatran, rivaroxaban, and apixaban concomitantly with clarithromycin requires caution, especially in patients at high risk of bleeding (see section "Special precautions for use").

Omeprazole. Clarithromycin (500 mg every 8 hours) was used in combination with omeprazole (40 mg daily) in healthy adult volunteers. Steady-state plasma concentrations of omeprazole were increased (Cmax, AUC0-24, and t1/2 increased by 30 %, 89 %, and 34 %, respectively). When omeprazole was used alone, the mean gastric juice pH measured over 24 hours was 5.2; with concomitant use of omeprazole and clarithromycin, it was 5.7.

Sildenafil, tadalafil, and vardenafil. Each of these phosphodiesterase inhibitors is metabolized (at least partially) via CYP3A, and CYP3A may be inhibited by concomitantly administered clarithromycin. Concomitant use of clarithromycin with sildenafil, tadalafil, or vardenafil may lead to increased exposure to the phosphodiesterase inhibitor; therefore, consideration should be given to reducing the dose of sildenafil, tadalafil, or vardenafil.

Theophylline, carbamazepine. It is known that there is a slight but statistically significant (p≤0.05) increase in plasma concentrations of theophylline or carbamazepine when used concomitantly with clarithromycin.

Tolterodine. Tolterodine is primarily metabolized by the cytochrome P450 2D6 isoenzyme (CYP2D6). However, in the population of patients without CYP2D6, metabolism occurs via CYP3A. In this population, inhibition of CYP3A leads to a significant increase in tolterodine plasma concentrations. Dose reduction of tolterodine may be necessary in such patients when used concomitantly with CYP3A inhibitors such as clarithromycin.

Triazolobenzodiazepines (e.g., alprazolam, midazolam, triazolam). When midazolam was administered with clarithromycin tablets (500 mg twice daily), the AUC of midazolam increased 2.7-fold after intravenous administration of midazolam. With intravenous administration of midazolam with clarithromycin, careful patient monitoring is required for timely dose adjustment. With oromucosal administration of midazolam, where presystemic elimination of the drug may be bypassed, an interaction similar to that observed with intravenous midazolam rather than oral administration is more likely. The same precautions should be observed when using other benzodiazepines metabolized by CYP3A, including triazolam and alprazolam. For benzodiazepines whose elimination does not depend on CYP3A (temazepam, nitrazepam, lorazepam), clinically significant interaction with clarithromycin is unlikely.

There are reports of drug interaction and development of adverse CNS effects (such as drowsiness and confusion) with concomitant use of clarithromycin and triazolam. Patients should be monitored, considering the possible increase in pharmacological effects on the CNS.

Other types of interactions.

Colchicine. Colchicine is a substrate of CYP3A and the efflux transporter P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. With concomitant use of clarithromycin and colchicine, inhibition of Pgp and/or CYP3A by clarithromycin may lead to increased colchicine exposure. Concomitant use of clarithromycin and colchicine is contraindicated (see sections "Contraindications", "Special precautions for use").

Digoxin. Digoxin is considered a substrate of the efflux transporter Pgp. Clarithromycin is known to inhibit Pgp. With concomitant use of clarithromycin and digoxin, inhibition of Pgp by clarithromycin may lead to increased digoxin exposure. Increased serum digoxin concentrations have been reported in patients taking clarithromycin with digoxin. In some patients, signs of digoxin toxicity developed, including potentially fatal arrhythmias. Serum digoxin concentrations should be carefully monitored in patients receiving digoxin concomitantly with clarithromycin.

Zidovudine. Concomitant oral administration of clarithromycin tablets and zidovudine in HIV-infected adult patients may cause decreased steady-state serum concentrations of zidovudine. Since clarithromycin may interfere with absorption of oral zidovudine when taken concomitantly, this can largely be avoided by maintaining a 4-hour interval between administration of clarithromycin and zidovudine. Such interaction has not been reported with use of clarithromycin suspension with zidovudine or didanosine in HIV-infected children. This interaction is unlikely with intravenous infusion of clarithromycin.

Phenytoin and valproate. There have been spontaneous or published reports of interaction between CYP3A inhibitors, including clarithromycin, and drugs not considered to be metabolized by CYP3A (e.g., phenytoin and valproate). Serum levels of these drugs should be determined when used concomitantly with clarithromycin. Increased serum levels have been reported.

Hydroxychloroquine and chloroquine. Clarithromycin should be used with caution in patients receiving drugs that prolong the QT interval, due to the potential risk of cardiac arrhythmia and serious cardiovascular adverse reactions.

Glucocorticoids. Caution should be exercised when using clarithromycin concomitantly with systemic or inhaled glucocorticoids that are primarily metabolized by CYP3A, due to the potential for increased systemic effects of glucocorticoids. Patients should be closely monitored for adverse reactions of systemic glucocorticoids when used concomitantly.

Bidirectional drug interactions.

Atazanavir. Concomitant use of clarithromycin (500 mg twice daily) with atazanavir (400 mg once daily), both substrates and inhibitors of CYP3A, led to a doubling of clarithromycin exposure and a 70 % reduction in 14-OH-clarithromycin exposure, with a 28 % increase in atazanavir AUC. Since clarithromycin has a wide therapeutic range, dose reduction is not required for patients with normal renal function. The clarithromycin dose should be reduced by 50 % for patients with CLCR 30-60 ml/min and by 75 % for patients with CLCR < 30 ml/min, using the appropriate formulation of clarithromycin. Clarithromycin doses higher than 1000 mg daily should not be used concomitantly with protease inhibitors.

Calcium channel blockers. Due to the risk of arterial hypotension, clarithromycin should be used cautiously concomitantly with calcium channel blockers metabolized by CYP3A4 (such as verapamil, amlodipine, diltiazem). Plasma concentrations of both clarithromycin and calcium channel blockers may increase during interaction. Arterial hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving clarithromycin and verapamil concomitantly.

itraconazole. Clarithromycin and itraconazole are substrates and inhibitors of CYP3A, thus clarithromycin may increase itraconazole plasma levels and vice versa. When itraconazole is used concomitantly with clarithromycin, patients should be closely monitored for signs or symptoms of enhanced or prolonged pharmacological effect.

Saquinavir. Concomitant use of clarithromycin (500 mg twice daily) and saquinavir (soft gelatin capsules, 1200 mg three times daily), both substrates and inhibitors of CYP3A, led to a 177 % and 187 % increase in steady-state AUC and Cmax of saquinavir, respectively, compared to those observed with saquinavir alone. At the same time, AUC and Cmax of clarithromycin increased by approximately 40 % compared to clarithromycin alone. Dose adjustment is not required if both drugs are used concomitantly for a limited period at the studied doses/forms. Results of drug interaction studies using soft gelatin capsules may not correspond to effects observed with hard gelatin capsules of saquinavir. Results of drug interaction studies using saquinavir alone may not correspond to effects observed with saquinavir/ritonavir therapy. When saquinavir is used with ritonavir, possible effects of ritonavir on clarithromycin should be considered (see above).

Special precautions for use.

The use of any antimicrobial therapy, including clarithromycin, for the treatment of H. pylori infection may lead to the development of microbial resistance.

Clarithromycin should not be prescribed during pregnancy without careful assessment of the benefit-risk ratio, particularly during the first trimester of pregnancy.

Prolonged use of clarithromycin, as with other antibiotics, may result in overgrowth of nonsusceptible bacteria and fungi. If superinfection occurs, appropriate therapy should be initiated.

Since clarithromycin is metabolized in the liver and primarily excreted via the liver and kidneys, the drug should be used with particular caution in patients with hepatic impairment, moderate to severe renal impairment, and elderly patients (over 65 years of age).

The drug should be used with caution in patients with severe renal impairment (see section "Dosage and administration").

Hepatic function abnormalities, including elevated levels of liver enzymes, and hepatocellular and/or cholestatic hepatitis, with or without jaundice, have been reported during clarithromycin use. These hepatic abnormalities may be severe in nature but are usually reversible. In some cases, fatal hepatic failure has been reported, primarily associated with serious underlying diseases and/or concomitant medications. Clarithromycin therapy should be discontinued immediately upon the onset of signs and symptoms of hepatitis such as anorexia, jaundice, dark urine, pruritus, or abdominal tenderness.

Pseudomembranous colitis, ranging from moderate to life-threatening severity, has been reported with nearly all antibacterial agents, including macrolides. Clostridium difficile-associated diarrhea, ranging from mild to fatal colitis, has been reported with the use of nearly all antibacterial agents, including clarithromycin. Antibacterial therapy alters the normal gut flora, potentially leading to overgrowth of C. difficile. C. difficile-associated diarrhea should always be considered in all patients presenting with diarrhea following antibiotic use. A careful medical history is essential, as cases have been reported up to two months after antibiotic administration. If pseudomembranous colitis develops, clarithromycin therapy should be discontinued regardless of the indication for which it was prescribed. Microbiological testing should be performed and appropriate treatment initiated. Antiperistaltic agents should be avoided.

Colchicine. Cases of colchicine toxicity have been reported with concomitant use of clarithromycin and colchicine, particularly in elderly patients, including those with renal impairment. Fatal outcomes have been reported in some of these patients (see section "Interaction with other medicinal products and other forms of interaction"). Concomitant use of clarithromycin with colchicine is contraindicated (see section "Contraindications").

Concomitant use of clarithromycin with triazolobenzodiazepines such as triazolam, intravenous or oromucosal midazolam, should be done with caution (see section "Interaction with other medicinal products and other forms of interaction").

Cardiovascular complications.

QT interval prolongation. Prolongation of cardiac repolarization and QT interval, indicating a risk of cardiac arrhythmia and torsades de pointes, has been observed with macrolide therapy, including clarithromycin (see section "Adverse reactions"). Since the situations listed below may increase the risk of ventricular arrhythmias (including torsades de pointes), clarithromycin should be used with caution in the following patient groups:

• Patients with ischemic heart disease, severe heart failure, conduction disorders, or clinically significant bradycardia.
• Patients concurrently taking other drugs associated with QT interval prolongation (see section "Interaction with other medicinal products and other forms of interaction").

Concomitant use of clarithromycin with astemizole, cisapride, pimozide, and terfenadine is contraindicated (see section "Contraindications").

Clarithromycin should not be used in patients with congenital or documented acquired QT prolongation or with a history of ventricular arrhythmias (see section "Contraindications").

Epidemiological studies investigating the risk of adverse cardiovascular outcomes with macrolide use have shown variable results. A rare, short-term risk of arrhythmia, myocardial infarction, and cardiovascular mortality associated with macrolide use, including clarithromycin, has been identified. These findings should be weighed against the benefits of treatment when prescribing clarithromycin.

Pneumonia. Due to emerging resistance of Streptococcus pneumoniae to macrolides, susceptibility testing should be performed when prescribing clarithromycin for community-acquired pneumonia. For hospital-acquired pneumonia, clarithromycin should be used in combination with other appropriate antibiotics.

Skin and soft tissue infections of mild to moderate severity. These infections are most commonly caused by Staphylococcus aureus and Streptococcus pyogenes, both of which may be resistant to macrolides. Therefore, susceptibility testing is important. When β-lactam antibiotics (e.g., due to allergy) cannot be used, other antibiotics such as clindamycin may be considered as first-line therapy. To date, macrolides have only a limited role in treating certain skin and soft tissue infections (e.g., infections caused by Corynebacterium minutissimum, acne vulgaris, erysipelas) and in situations where penicillins cannot be used.

In the event of severe acute hypersensitivity reactions such as anaphylaxis, severe skin adverse reactions (e.g., acute generalized exanthematous pustulosis, Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS), or Henoch-Schönlein purpura, clarithromycin therapy should be discontinued immediately and appropriate treatment initiated promptly.

Clarithromycin should be used with caution when coadministered with inducers of the cytochrome P450 enzyme CYP3A4 (see section "Interaction with other medicinal products and other forms of interaction").

Cross-resistance between clarithromycin and other macrolides, as well as with lincomycin and clindamycin, should be considered.

HMG-CoA reductase inhibitors (statins). Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated (see section "Contraindications"). Caution is advised when prescribing clarithromycin with other statins. Cases of rhabdomyolysis have been reported in patients receiving clarithromycin concomitantly with statins. Patients should be monitored for signs and symptoms of myopathy. When concomitant use of clarithromycin with statins cannot be avoided, it is recommended to prescribe the lowest approved statin dose. A statin not metabolized by CYP3A (e.g., fluvastatin) may be considered (see section "Interaction with other medicinal products and other forms of interaction").

Oral hypoglycemic agents/insulin. Concomitant use of clarithromycin with oral hypoglycemic agents (such as sulfonylureas) and/or insulin may cause pronounced hypoglycemia. Close monitoring of blood glucose levels is recommended.

Oral anticoagulants. Concomitant use of direct oral anticoagulants such as dabigatran, rivaroxaban, apixaban, and edoxaban with clarithromycin requires caution, especially in patients at high risk of bleeding. When clarithromycin is used concomitantly with warfarin, there is a risk of serious bleeding, significant increase in INR (International Normalized Ratio), and prolonged prothrombin time. Frequent monitoring of INR and prothrombin time is required while patients are receiving both clarithromycin and oral anticoagulants (see section "Interaction with other medicinal products and other forms of interaction").

Yellow FCF (E 110) and tartrazine (E 102) may cause allergic reactions.

Use during pregnancy or breastfeeding.

The safety of clarithromycin use during pregnancy or breastfeeding has not been established. Based on animal studies and human experience, the possibility of harmful effects on embryonic and fetal development cannot be excluded. Some observational studies assessing the use of clarithromycin during the first or second trimester of pregnancy have shown an increased risk of pregnancy loss compared to no antibacterial therapy or use of other antibacterial agents during the same period. Available epidemiological studies on the risk of congenital malformations with macrolide use, including clarithromycin, during pregnancy have shown conflicting results. Clarithromycin should not be used during pregnancy without careful benefit-risk assessment.

Clarithromycin passes into breast milk in small amounts. The amount of clarithromycin ingested by an exclusively breastfed infant is estimated to be approximately 1.7% of the maternal dose adjusted for body weight.

Ability to affect reaction speed when driving or operating machinery.

Data on the effect are lacking.

However, when driving or operating machinery, consideration should be given to the possible occurrence of nervous system adverse reactions such as seizures, dizziness, vertigo, hallucinations, confusion, disorientation, etc.

Method of Administration and Dosage.

The recommended dose of clarithromycin for adults and children aged 12 years and older is 250 mg every 12 hours. In more severe infections, the dose may 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.

The drug may be administered regardless of food intake, 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 twice daily. If there is no clinical or bacteriological improvement after 3–4 weeks of treatment, the clarithromycin dose may be increased to 1000 mg twice daily.

Treatment of disseminated infections caused by MAC in AIDS patients should continue as long as clinically and microbiologically confirmed efficacy is maintained. Clarithromycin may be used in combination with other antimycobacterial agents.

H. pylori eradication in patients with duodenal ulcer (adults).

Triple therapy (7–10 days). Clarithromycin (500 mg) twice daily should be administered 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, lanseprazole 30 mg twice daily, and amoxicillin 1000 mg twice daily for 10 days.

Double therapy (14 days). Clarithromycin (500 mg) three times daily together with omeprazole 40 mg once daily orally for 14 days, followed by omeprazole 20 mg or 40 mg once daily orally for the next 14 days.

Double therapy (14 days). Clarithromycin (500 mg) three times daily together with lansoprazole 60 mg once daily orally for 14 days. Additional acid secretion suppression may be required to reduce ulcer symptoms.

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 subcitrate, and ranitidine;

clarithromycin + amoxicillin and lansoprazole;

clarithromycin + ranitidine and bismuth citrate.

Use in elderly patients: as for adults.

Use in patients with renal impairment: in patients with severe renal impairment (CLCR <30 mL/min), the dose should be halved, e.g., 250 mg once daily or 250 mg twice daily in more severe infections. In such patients, the duration of treatment should not exceed 14 days.

Children. Clarithromycin should be administered to children under 12 years of age in the form of a suspension, as the use of clarithromycin tablets has not been studied in this age group.

Overdose.

Symptoms. Available reports indicate that clarithromycin overdose may cause gastrointestinal symptoms. In one patient with a history of bipolar psychosis who ingested 8 grams of clarithromycin, altered mental status, paranoid behavior, hypokalemia, and hypoxemia developed.

Treatment. Adverse reactions associated with overdose should be managed by gastric lavage and symptomatic therapy. As with other macrolides, hemodialysis or peritoneal dialysis are unlikely to significantly affect serum clarithromycin levels.

Adverse Reactions.

The most common and frequent adverse reactions associated with clarithromycin treatment in adults and children are abdominal pain, diarrhea, nausea, vomiting, and taste disturbances. These adverse reactions are usually mild and consistent with the known safety profile of macrolide antibiotics. No significant difference in the frequency of these gastrointestinal adverse reactions was observed between patient groups with or without mycobacterial infections.

Adverse reactions considered at least possibly related to clarithromycin are listed by system organ class and frequency of occurrence: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), frequency not known* (cannot be estimated from available data). Within each frequency group, adverse reactions are listed in order of decreasing severity, when severity could be assessed.

Infections and infestations: uncommon – cellulitis¹, candidiasis, gastroenteritis², infection³, vaginal infection; frequency not known – pseudomembranous colitis, tetanus.

Blood and lymphatic system disorders: uncommon – leukopenia, neutropenia⁴, thrombocytosis³, eosinophilia⁴; frequency not known – agranulocytosis, thrombocytopenia.

Immune system disorders: uncommon – anaphylactoid reactions¹, hypersensitivity; frequency not known – anaphylactic reactions, angioedema.

Metabolism and nutrition disorders: uncommon – anorexia, decreased appetite; frequency not known – hypoglycemia.

Psychiatric disorders: common – insomnia; uncommon – anxiety, nervousness³; frequency not known – psychosis, confusion, depersonalization, depression, disorientation, hallucinations, nightmares, mania.

Nervous system disorders: common – dysgeusia (disturbance of taste sensation), headache; uncommon – loss of consciousness¹, dyskinesia¹, dizziness, somnolence, tremor; frequency not known – convulsions, ageusia (loss of taste sensation), parosmia, anosmia, paresthesia.

Ear and labyrinth disorders: uncommon – vertigo, hearing impairment, tinnitus; frequency not known – hearing loss.

Cardiac disorders: uncommon – cardiac arrest¹, atrial fibrillation¹, QT interval prolongation, extrasystoles¹, palpitations; frequency not known – torsades de pointes, ventricular tachycardia, ventricular fibrillation.

Vascular disorders: common – vasodilation¹; frequency not known – hemorrhage.

Respiratory, thoracic and mediastinal disorders: uncommon – asthma¹, epistaxis², pulmonary embolism¹.

Gastrointestinal disorders: common – diarrhea, vomiting, dyspepsia, nausea, abdominal pain; uncommon – esophagitis¹, gastroesophageal reflux disease², gastritis, proctalgia², stomatitis, glossitis, abdominal distension⁴, constipation, dry mouth, eructation, flatulence; frequency not known – acute pancreatitis, tongue discoloration, tooth discoloration.

Hepatobiliary disorders: common – abnormal liver function tests; uncommon – cholestasis⁴, hepatitis⁴, increased levels of ALT, AST, GGT⁴; frequency not known – liver failure, hepatocellular jaundice.

Skin and subcutaneous tissue disorders: common – rash, hyperhidrosis; uncommon – bullous dermatitis¹, pruritus, urticaria, maculopapular rash³; frequency not known – severe cutaneous adverse reactions (e.g., acute generalized exanthematous pustulosis, Stevens–Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS)), acne, Schönlein–Henoch purpura.

Musculoskeletal and connective tissue disorders: uncommon – muscle spasms³, skeletal muscle rigidity¹, myalgia²; frequency not known – rhabdomyolysis^2**, myopathy.

Renal and urinary disorders: uncommon – increased blood creatinine¹, increased blood urea¹; frequency not known – renal failure, interstitial nephritis.

General disorders: uncommon – malaise⁴, fever³, asthenia, chest pain⁴, chills⁴, fatigue⁴.

Investigations: uncommon – altered albumin-globulin ratio¹, increased blood alkaline phosphatase⁴, increased blood lactate dehydrogenase⁴; frequency not known – increased MCV, prolonged prothrombin time, urine discoloration.

* These reactions have been reported voluntarily, and due to the unknown size of the patient population, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The overall clinical experience with clarithromycin exceeds 1 billion patient-days.

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

1,2,3,4 These adverse reactions were reported only when the drug was administered in the following dosage forms: 1 – lyophilized powder for solution for infusion, 2 – extended-release tablets, 3 – suspension, 4 – immediate-release tablets.

The frequency, type, and severity of adverse reactions in children are expected to be similar to those in adults.

Patients with immune system disorders. In patients with AIDS and other patients with impaired immune systems who received high doses of clarithromycin for prolonged periods to treat mycobacterial infections, it may not always be possible to distinguish adverse reactions related to drug administration from symptoms of the underlying or concomitant diseases.

In adult patients receiving clarithromycin at a daily dose of 1000 mg, the most commonly reported adverse effects were nausea, vomiting, taste disturbances, abdominal pain, diarrhea, rash, abdominal distension, headache, constipation, hearing impairment, and elevated serum ALT and AST levels. Dyspnea, insomnia, and dry mouth occurred less frequently.

In these immunocompromised patients, laboratory parameters were evaluated by analyzing those values exceeding the significant abnormal range (i.e., extreme upper or lower limits) for a given test. By this criterion, 2–3% of these patients receiving 1000 mg of clarithromycin daily experienced significantly abnormal elevations in ALT and AST levels and abnormal decreases in white blood cell and platelet counts. A smaller number of patients showed increased blood urea nitrogen levels.

Shelf life. 3 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging. 250 mg tablets: № 7×2, № 10 in blister packs in a box; or 500 mg tablets: № 7, № 7×2, № 10 in blister packs in a box.

Prescription status. Prescription only.

Manufacturer. LIMITED LIABILITY COMPANY "CORPORATION "ZDOROV'YA".

Limited Liability Company "FARMEKS GROUP".

Manufacturer's address and place of business. Ukraine, 61013, Kharkiv region, Kharkiv, Shevchenka Street, 22.

(LIMITED LIABILITY COMPANY "CORPORATION "ZDOROV'YA")

Ukraine, 08301, Kyiv region, Boryspil, Shevchenka Street, 100.

(Limited Liability Company "FARMEKS GROUP")