Clarithromycin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CLARITHROMYCIN (CLARITHROMYCIN)

Composition:

Active substance: clarithromycin;

One tablet contains clarithromycin equivalent to 100% substance – 250 mg or 500 mg;

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

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics: film-coated tablets, yellow in color, with a biconvex surface, with a score line on one side of the tablet and embossing "KMP" on the other side. A white core is 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 activity of clarithromycin is due to its binding to the 50S ribosomal subunit of susceptible bacteria and inhibition of protein biosynthesis. The drug demonstrates high efficacy in vitro against a broad spectrum of aerobic and anaerobic Gram-positive and Gram-negative microorganisms, including hospital strains. Minimum inhibitory concentrations (MICs) of clarithromycin are usually two times lower than those of erythromycin.

Clarithromycin is highly effective in vitro against Legionella pneumophila and Mycoplasma pneumoniae. It exerts a bactericidal effect 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-fermenting 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.

Beta-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 activity against several bacterial strains: 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 compound, except for H. influenzae, against which the metabolite is two times more 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 inhibition zone diameters provide a more accurate assessment of bacterial susceptibility to antimicrobial agents. In one of the recommended procedures for susceptibility testing, disks impregnated with 15 mcg of clarithromycin (Kirby-Bauer diffusion test) are used; the diameter of the inhibition zone for this disk is correlated with MIC values for clarithromycin. MIC is determined by broth or agar dilution methods.

When performing these procedures, a laboratory report stating "susceptible" indicates that the infecting microorganism is likely to respond to therapy. A report stating "resistant" indicates that the infecting microorganism is unlikely to respond to therapy. A report stating "intermediate susceptibility" suggests that the therapeutic effect of the drug may be uncertain or that the microorganism may be susceptible if higher doses are administered (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. When administering 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 intensive (approximately 36%). 14-Hydroxyclarithromycin is the main metabolite excreted in urine, accounting for 10–15% of the administered dose. The majority of the remaining dose is excreted in feces, primarily via bile. 5–10% of the parent compound is recovered in feces.

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

The concentration of clarithromycin in tissues is several times higher than in blood. Elevated concentrations have been found in both tonsillar and lung tissues. Clarithromycin is 80% bound to plasma proteins at therapeutic doses.

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) (see sections "Pharmacological properties. Pharmacodynamics" and "Special instructions" regarding sensitivity testing).
• Skin and soft tissue infections (impetigo, folliculitis, erysipelas, furunculosis, infected wounds) (see sections "Pharmacological properties. Pharmacodynamics" and "Special instructions" regarding sensitivity testing).
• 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 is higher at neutral pH than at acidic pH).

Contraindications.

Hypersensitivity to macrolide antibiotics or to any other components of the drug.

Concomitant use of clarithromycin with any of the following drugs: astemizole, cisapride, pimozide, terfenadine (as this may lead to QT interval prolongation and development of cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation, and torsades de pointes), ergot alkaloids, such as ergotamine, dihydroergotamine (as 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 forms of interaction", "Special instructions").

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

Congenital or documented acquired QT interval prolongation or history of ventricular cardiac arrhythmias, including torsades de pointes (see sections "Interaction with other medicinal products and other forms of interaction", "Special instructions").

Clarithromycin should not be administered to patients with electrolyte disturbances (hypokalemia or hypomagnesemia), due to the risk of QT interval prolongation.

Severe hepatic impairment in combination with renal impairment.

Concomitant use of clarithromycin and other strong CYP3A4 inhibitors with colchicine (see sections "Interaction with other medicinal products and other forms of interaction", "Special instructions").

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

Concomitant use of clarithromycin with lomitapide is contraindicated (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Clarithromycin does not interact with oral contraceptives.

The following drugs are strictly contraindicated due to the potential for severe interaction outcomes.

Cisapride, pimozide, astemizole, terfenadine

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

Macrolides have been reported to alter terfenadine metabolism, leading to increased serum levels of terfenadine, which has sometimes been associated with arrhythmias such as QT interval prolongation, ventricular tachycardia, ventricular fibrillation, and torsades de pointes (see section "Contraindications"). In a study involving 14 volunteers, concomitant administration of clarithromycin and terfenadine resulted in a 2- to 3-fold increase in the serum concentration of the acid metabolite of terfenadine and QT interval prolongation, without any clinically apparent effect. Similar effects have been observed with concomitant use of astemizole and other macrolides.

Ergot alkaloids

Post-marketing reports indicate that concomitant use of clarithromycin with 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 is administered with clarithromycin tablets (500 mg twice daily), the area under the plasma concentration-time curve (AUC) of midazolam increases 7-fold after oral administration of midazolam. Concomitant use of oral midazolam and clarithromycin 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 should be discontinued during the course of treatment.

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

Clarithromycin use is also contraindicated with ivabradine (see section "Contraindications").

Hydroxychloroquine and chloroquine

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

Effect of other medicinal products on clarithromycin

Medicinal products that are inducers of CYP3A (e.g., rifampicin, phenytoin, carbamazepine, phenobarbital, St. John's wort) 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 necessary, as they may be increased due to CYP3A inhibition by clarithromycin (see also the instructions for medical use of the respective CYP3A4 inducer). Concomitant use of rifabutin and clarithromycin has led to increased rifabutin levels and decreased clarithromycin levels in serum, with an increased risk of uveitis.

The following medicinal products are known or suspected to affect clarithromycin blood concentration, and therefore may require dose adjustment of clarithromycin or alternative therapy.

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, but concentrations of the active metabolite 14-OH-clarithromycin were increased. Since 14-OH-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), the overall activity against this pathogen may be altered. Therefore, alternative agents to clarithromycin should be considered for the treatment of MAC.

Fluconazole

Concomitant administration of fluconazole 200 mg daily and clarithromycin 500 mg twice daily in 21 healthy volunteers resulted in a 33% increase in the 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 fluconazole use. Dose adjustment of clarithromycin is not required.

Ritonavir

A pharmacokinetic study showed that concomitant administration of ritonavir 200 mg every 8 hours and clarithromycin 500 mg every 12 hours resulted in significant inhibition of clarithromycin metabolism. Cmax of clarithromycin increased by 31%, Cmin by 182%, and AUC by 77% with concomitant ritonavir. Complete inhibition of 14-OH-clarithromycin formation was observed. Due to the wide therapeutic range, dose reduction of clarithromycin is not necessary for patients with normal renal function. However, dose adjustment is required for patients with renal impairment: 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/day should not be used concomitantly with ritonavir.

The same dose adjustment should be applied for patients with renal impairment 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

Post-marketing reports exist of torsades de pointes occurring with concomitant use of clarithromycin and quinidine or disopyramide. ECG monitoring is recommended to detect QT interval prolongation promptly during concomitant use of clarithromycin with these drugs. Serum concentrations of these drugs should be monitored during clarithromycin therapy.

Post-marketing use has reported hypoglycemia with concomitant use of clarithromycin and disopyramide; therefore, glucose monitoring is necessary when these agents are used together.

Oral hypoglycemic agents/insulin

When used concomitantly with certain hypoglycemic agents such as nateglinide and repaglinide, clarithromycin may inhibit the CYP3A enzyme, potentially causing hypoglycemia. Careful glucose monitoring is recommended.

CYP3A-related interactions

Concomitant use of clarithromycin, a known inhibitor of the CYP3A enzyme, with a drug primarily metabolized by CYP3A, may lead to increased plasma concentration of the latter, thereby enhancing or prolonging its therapeutic and adverse effects. Caution should be exercised when using clarithromycin in patients receiving medicinal products that are CYP3A substrates, 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 receiving clarithromycin concomitantly.

It is known (or suspected) that the following medicinal products or groups of drugs 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), atypical antipsychotics (e.g., quetiapine), pimozide, quinidine, rifabutin, sildenafil, simvastatin, tacrolimus, terfenadine, triazolam, and vinblastine, but this list is not exhaustive. A similar interaction mechanism has been observed with phenytoin, theophylline, and valproate, which are metabolized by other cytochrome P450 isoenzymes.

Omeprazole

Clarithromycin (500 mg every 8 hours) was administered in combination with omeprazole (40 mg daily) in healthy adult volunteers. Steady-state plasma concentrations of omeprazole increased (Cmax, AUC0-24, and t1/2 increased by 30%, 89%, and 34%, respectively). When omeprazole was administered 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

Clinical study results showed 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 CYP2D6 isoenzyme of cytochrome P450 (CYP2D6). However, in the population of patients lacking CYP2D6, metabolism occurs via CYP3A. In this population, inhibition of CYP3A leads to a significant increase in tolterodine plasma concentrations. In such patients, dose reduction of tolterodine may be necessary when used with CYP3A inhibitors such as clarithromycin.

Triazolobenzodiazepines (e.g., alprazolam, midazolam, triazolam)

When midazolam is administered with clarithromycin tablets (500 mg twice daily), the AUC of midazolam increases 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, 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 post-marketing reports of drug interaction and development of CNS adverse effects (such as somnolence and confusion) with concomitant use of clarithromycin and triazolam. Patient observation is recommended, considering the possible increase in CNS pharmacological effects.

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. Concomitant use of clarithromycin and colchicine may lead to increased colchicine exposure due to inhibition of Pgp and/or CYP3A by clarithromycin. Concomitant use of clarithromycin and colchicine is contraindicated (see sections "Contraindications", "Special instructions").

Digoxin

Digoxin is considered a substrate of the efflux transporter Pgp. Clarithromycin is known to inhibit Pgp. Concomitant use of clarithromycin and digoxin may lead to increased digoxin exposure due to Pgp inhibition by clarithromycin. Post-marketing surveillance has reported increased serum digoxin concentrations 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 lead to decreased steady-state serum concentrations of zidovudine. Since clarithromycin may interfere with the absorption of oral zidovudine when taken concomitantly, this can largely be avoided by maintaining a 4-hour interval between doses of clarithromycin and zidovudine. Such interaction has not been reported with use of clarithromycin suspension and 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 medicinal products not considered to be metabolized by CYP3A (e.g., phenytoin and valproate). Serum levels of these medicinal products should be determined when co-administered with clarithromycin. Increased serum levels have been reported.

Corticosteroids

Caution should be exercised when using clarithromycin concomitantly with systemic or inhaled corticosteroids that are predominantly metabolized by CYP3A, due to the potential for increased systemic corticosteroid effects. Patients should be closely monitored for adverse reactions of systemic corticosteroids 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, resulted in 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 necessary 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 clarithromycin formulation. Clarithromycin doses exceeding 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 (e.g., verapamil, amlodipine, diltiazem). Plasma concentrations of both clarithromycin and calcium channel blockers may increase with 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 administration of clarithromycin (500 mg twice daily) and saquinavir (soft gelatin capsules, 1200 mg three times daily), both substrates and inhibitors of CYP3A, in 12 healthy volunteers resulted in a 177% and 187% increase in the steady-state AUC and Cmax of saquinavir, respectively, compared to administration of saquinavir alone. Meanwhile, AUC and Cmax of clarithromycin increased by approximately 40% compared to administration of clarithromycin alone. Dose adjustment is not necessary if both medicinal products are used concomitantly for a limited period at the studied doses/forms. The results of the drug interaction study using soft gelatin capsules may not correspond to effects observed with hard gelatin capsules of saquinavir. The results of the drug interaction study 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).

Direct oral anticoagulants (DOACs) (rivaroxaban, apixaban)

Direct oral anticoagulants dabigatran and edoxaban are substrates of the P-gp efflux transporter.

Rivaroxaban and apixaban are metabolized via CYP3A4 and are also P-gp substrates.

Clarithromycin should be used cautiously concomitantly with these agents, especially in patients at high risk of bleeding (see section "Special instructions").

Lomitapide

Concomitant use of clarithromycin with lomitapide may lead to increased transaminase levels (see section "Contraindications").

Special precautions for use.

The medicinal product contains lactose as an excipient; therefore, it should not be administered to patients with galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

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 to pregnant women without careful assessment of the benefit-risk ratio, especially during the first trimester of pregnancy.

Prolonged use of clarithromycin, as with other antibiotics, may lead to overgrowth of non-susceptible 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 medicinal product should be used with particular caution in patients with hepatic impairment, moderate to severe renal impairment, and elderly patients (aged 65 years and older).

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

During clarithromycin therapy, hepatic function abnormalities have been reported, including elevated levels of liver enzymes, and hepatocellular and/or cholestatic hepatitis, with or without jaundice. 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 should be discontinued immediately if signs and symptoms of hepatitis occur, such as anorexia, jaundice, dark urine, pruritus, or abdominal tenderness.

Cases of pseudomembranous colitis, ranging from moderate to life-threatening severity, have been reported with nearly all antibacterial agents, including macrolides. Cases of Clostridium difficile-associated diarrhea (CDAD), ranging from mild severity to fatal colitis, have been reported with the use of virtually all antibacterial agents, including clarithromycin. Antibacterial therapy may disrupt the normal gastrointestinal flora, leading to overgrowth of C. difficile. The possibility of C. difficile-associated diarrhea should always be considered in patients who develop diarrhea after antibiotic use. A careful medical history is essential, as cases of C. difficile-associated diarrhea have been reported up to two months after antibiotic administration. If pseudomembranous colitis develops, treatment with clarithromycin should be discontinued regardless of the indication for which it was prescribed. Microbiological testing should be performed and appropriate therapy initiated. Medicinal products that inhibit gastrointestinal motility should be avoided.

Colchicine

Colchicine toxicity has 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 and colchine is contraindicated (see section "Contraindications").

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

Cardiovascular complications

Prolongation of cardiac repolarization and QT interval, indicating a risk of developing cardiac arrhythmias and torsades de pointes, has been observed with macrolide therapy, including clarithromycin (see section "Adverse reactions"). Given that the following conditions 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 receiving concomitant medications known to prolong the QT interval (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 a history of ventricular arrhythmias (see section "Contraindications").

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

Pneumonia

Due to increasing resistance of Streptococcus pneumoniae to macrolides, it is important to perform susceptibility testing when prescribing clarithromycin for the treatment of 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, each of which may be resistant to macrolides. Therefore, susceptibility testing is essential. When beta-lactam antibiotics cannot be used (e.g., due to allergy), other antibiotics such as clindamycin may be considered as first-line therapy. To date, macrolides have played a limited role in the treatment of certain skin and soft tissue infections (e.g., infections caused by Corynebacterium minutissimum, acne vulgaris, or 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 without delay.

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

Potential 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"). Clarithromycin should be prescribed with caution when used concomitantly with other statins. Cases of rhabdomyolysis have been reported in patients receiving clarithromycin and 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 registered dose of the statin. A statin not metabolized by CYP3A (e.g., fluvastatin) may be used (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 sulfonylurea derivatives) and/or insulin may result in pronounced hypoglycemia. Close monitoring of blood glucose levels is recommended.

Oral anticoagulants

When clarithromycin is used concomitantly with warfarin, there is a risk of serious bleeding, marked elevation of the INR (International Normalized Ratio), and prolonged prothrombin time. The INR and prothrombin time should be monitored frequently while patients are receiving both clarithromycin and oral anticoagulants.

Caution is advised when clarithromycin is used concomitantly with direct oral anticoagulants such as dabigatran, rivaroxaban, apixaban, and edoxaban, particularly in patients at high risk of bleeding (see section "Interaction with other medicinal products and other forms of interaction").

Use during pregnancy or breastfeeding.

The safety of clarithromycin use during pregnancy and breastfeeding has not been established. Based on variable results from animal studies and human experience, a potential adverse effect on embryonic development cannot be excluded. Some studies evaluating the use of clarithromycin during the first and second trimesters of pregnancy have reported an increased risk of miscarriage compared to control groups of patients who did not take antibiotics or used antibiotics from other classes.

Available epidemiological studies on the risk of congenital malformations in infants following maternal use of macrolides, including clarithromycin, during pregnancy have yielded conflicting results. Nevertheless, clarithromycin should not be used during pregnancy without careful benefit-risk assessment.

Clarithromycin is excreted in breast milk in small amounts. It has been estimated that an exclusively breastfed infant would receive approximately 1.7% of the clarithromycin dose, adjusted for maternal weight.

Ability to influence reaction speed when driving or operating machinery.

Data on the effect of clarithromycin are lacking. However, when driving or operating machinery, potential nervous system adverse reactions such as seizures, dizziness, vertigo, hallucinations, confusion, and disorientation should be taken into account.

Dosage and Administration.

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

Clarithromycin may be administered 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 twice daily. If no clinical or bacteriological improvement is observed within 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 for as long as medically confirmed clinical and microbiological efficacy is observed. Clarithromycin may 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 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.

Dual 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.

Dual 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.

Other therapeutic regimens in which clarithromycin has been used include:

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

Use in elderly patients: same as for adults.

Use in patients with renal impairment: for patients with severe renal impairment (creatinine clearance < 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, treatment duration should not exceed 14 days.

Children.

For children under 12 years of age, the drug should be administered in the form of 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. There is one reported case of altered mental status, paranoid behavior, hypokalemia, and hypoxemia in a patient with a history of bipolar psychosis who ingested 8 grams of clarithromycin.

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 during 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. During clinical trials of clarithromycin, no significant difference was observed in the frequency of these gastrointestinal adverse reactions between patient groups with or without mycobacterial infections.

The adverse reactions listed below occurred during clinical studies and post-marketing use of various dosage forms and strengths of clarithromycin, including immediate-release tablets. Adverse reactions at least possibly related to clarithromycin are categorized 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), and frequency not known* (reactions reported during post-marketing surveillance; frequency cannot be estimated from available data). Within each 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, trench mouth.

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, angioneurotic edema.

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 – seizures, 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, belching, 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 – hepatic failure, hepatocellular jaundice.

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

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 and administration site conditions: very common – phlebitis at injection site¹; common – pain at injection site¹, inflammation at injection site¹; uncommon – malaise⁴, fever³, asthenia, chest pain⁴, chills⁴, fatigue⁴.

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

* These reactions were 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 (e.g., statins, fibrates, colchicine, or allopurinol).

^1,2,3,4 These adverse reactions were reported only with the following formulations of clarithromycin: ¹ – lyophilized powder for infusion solution, ² – extended-release tablets, ³ – suspension, ⁴ – immediate-release tablets.

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

Patients with immune system disorders.

In AIDS patients and other patients with immune system disorders who received high doses of clarithromycin for prolonged periods for the treatment of mycobacterial infections, it may be difficult 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 increased 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 outside the significant abnormal range (i.e., extreme upper or lower limit) for a given test. By this criterion, significant abnormal elevations in ALT and AST levels and abnormal decreases in white blood cell and platelet counts were observed in 2–3% of these patients receiving 1000 mg of clarithromycin per day. A smaller percentage 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. 10 film-coated tablets in a blister, 1 blister per carton.

Prescription category. Prescription only.

Manufacturer. JSC "Kyivmedpreparat".

Manufacturer's address and location of business activity.
139 Saksaganskogo Street, Kyiv, 01032, Ukraine.