Clarithromycin-astrafarm

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

Composition:

Active ingredient: clarithromycin;

One tablet contains clarithromycin (calculated as 100 % substance) 250 mg or 500 mg;

Excipients: maize starch, povidone, microcrystalline cellulose, sodium croscarmellose, colloidal anhydrous silicon dioxide, stearic acid, talc, magnesium stearate;

Coating "Selacote™" (hypromellose, polyethylene glycol, titanium dioxide (E 171)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: oval-shaped, biconvex film-coated tablets of white color.

Pharmacotherapeutic group. Antimicrobial agents for systemic use. Macrolides.

ATC code J01FA09.

Pharmacological Properties

Pharmacodynamics

Clarithromycin is a semisynthetic antibiotic of the macrolide group. The antibacterial action of clarithromycin is determined by 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 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, the 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.

Other microorganisms: Chlamydia trachomatis.

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 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.

Pharmacokinetics

Clarithromycin is rapidly and well absorbed from the gastrointestinal tract after oral administration of the 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 the formation of the 14-hydroxy metabolite. The pharmacokinetics of clarithromycin is nonlinear; however, 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. With 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 initial compound is found in feces.

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

Tissue concentrations of clarithromycin exceed plasma concentrations by several times. Elevated concentrations have been detected 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 or to any of the components of the drug.

Concomitant use of clarithromycin and 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, e.g., ergotamine, dihydroergotamine (as this may lead to ergot toxicity), HMG-CoA reductase inhibitors (statins) that are predominantly metabolized by CYP3A4 (lovastatin or simvastatin), due to increased risk of myopathy, including rhabdomyolysis.

Concomitant use of clarithromycin and oral midazolam.

Congenital or known acquired QT interval prolongation or history of ventricular cardiac arrhythmias, including torsades de pointes.

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

Severe hepatic insufficiency and concomitant renal insufficiency.

Concomitant use of clarithromycin (and other strong CYP3A4 inhibitors) with colchicine.

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

Concomitant administration of Clarithromycin and Lomitapide is contraindicated.

Interaction with other medicinal products and other forms of interaction.

Clarithromycin does not interact with oral contraceptives.

The use of the following medicinal products is strictly contraindicated due to the potential for severe interaction consequences.

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 concurrently.

Macrolides have been reported to alter the metabolism of terfenadine, 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. In a study conducted in volunteers, simultaneous administration of clarithromycin and terfenadine resulted in a 2–3-fold increase in serum levels of the acid metabolite of terfenadine and QT interval prolongation, which did not result in any clinically apparent effect. Similar effects have also been observed with concurrent use of astemizole and other macrolides.

Ergot alkaloids

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.

Oral midazolam

When midazolam was administered with clarithromycin tablets (500 mg twice daily), the AUC (area under the concentration-time curve) of midazolam increased 7-fold after oral administration of midazolam. Concomitant use of oral midazolam and clarithromycin is contraindicated.

HMG-CoA reductase inhibitors (statins)

Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated, as these statins are predominantly metabolized by CYP3A4, and their 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 and these statins concurrently. If clarithromycin treatment cannot be avoided, therapy with lovastatin or simvastatin should be discontinued during the course of treatment.

Clarithromycin should be used with caution 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 of myopathy is required.

Effect of other medicinal products on the pharmacokinetics of clarithromycin

Medicinal products that are inducers of CYP3A (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 necessary, as they may be increased due to CYP3A inhibition by clarithromycin (see also the package leaflet for the respective CYP3A4 inducer). Concomitant use of rifabutin and clarithromycin leads to increased rifabutin levels and decreased clarithromycin levels in serum, with a concomitant increased risk of uveitis.

The following medicinal products are known or suspected to affect clarithromycin blood concentration and may therefore require dose adjustment 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 attenuated by etravirine; however, 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, for the treatment of MAC, alternative drugs to clarithromycin should be considered.

Fluconazole

Concomitant administration of fluconazole 200 mg daily and clarithromycin 500 mg twice daily in healthy volunteers 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

Studies have shown that concomitant administration of ritonavir 200 mg every 8 hours and clarithromycin 500 mg every 12 hours led to significant inhibition of clarithromycin metabolism. Maximum concentration (Cmax) of clarithromycin increased by 31%, minimum concentration 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 necessary for patients with renal insufficiency: for patients with creatinine clearance (CrCl) of 30–60 mL/min, the clarithromycin dose should be reduced by 50%. For patients with severe renal insufficiency (CrCl < 30 mL/min), the clarithromycin dose should be reduced by 75%. Clarithromycin doses exceeding 1 g daily should not be used 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.

Effect of clarithromycin on the pharmacokinetics of other medicinal products

Oral anticoagulants (e.g., warfarin, rivaroxaban, apixaban)

Direct oral anticoagulants (DOACs).

Oral DOACs dabigatran and edoxaban are substrates of the efflux transporter P-glycoprotein (P-gp). Rivaroxaban and apixaban are metabolized by CYP3A4 and are also substrates of P-gp. Caution is advised when using clarithromycin concomitantly with these medicinal products, especially in patients at high risk of bleeding (see section "Special precautions for use").

Antiarrhythmic agents

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

Hypoglycemia has been reported with concomitant use of clarithromycin and disopyramide; therefore, blood glucose monitoring is necessary when these drugs 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 monitoring of glucose levels is recommended.

CYP3A-related interactions

Concomitant use of clarithromycin, a known inhibitor of the CYP3A enzyme, and a drug primarily metabolized by CYP3A may lead to increased plasma concentration of the latter, thereby potentially enhancing or prolonging its therapeutic effect and increasing the risk of adverse reactions. 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 predominantly metabolized by this enzyme. Dose adjustment and, if possible, careful monitoring of serum concentrations of the CYP3A-metabolized drug may be required 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), pimozide, quinidine, rifabutin, sildenafil, simvastatin, sirolimus, 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 another isoenzyme of the cytochrome P450 system.

The use of clarithromycin is also contraindicated with ergot alkaloids, oral midazolam, HMG-CoA reductase inhibitors predominantly metabolized by CYP3A4 (e.g., lovastatin and simvastatin), colchicine, ticagrelor**, ivabradine**, and ranolazine (see section "Contraindications").

Omeprazole

Administration of clarithromycin in combination with omeprazole in healthy adult volunteers led to increased steady-state concentrations of omeprazole. 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

There is a potential for increased plasma concentrations of phosphodiesterase inhibitors (sildenafil, tadalafil, and vardenafil) when used concomitantly with clarithromycin, which may require dose reduction of the phosphodiesterase inhibitors.

Theophylline, carbamazepine

Study results have shown a slight but statistically significant (p ≤ 0.05) increase in plasma concentrations of theophylline or carbamazepine when used concomitantly with clarithromycin.

Solifenacin

Solifenacin 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 solifenacin plasma concentrations. Dose reduction of solifenacin may be necessary when used 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 and clarithromycin, careful monitoring of the patient's condition 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 have been reports of drug interaction and CNS adverse effects (such as somnolence and confusion) with concomitant use of clarithromycin and triazolam. Patients should be monitored, considering the potential for increased pharmacological effects on the CNS.

Other types of interactions

Aminoglycosides

Clarithromycin should be used with caution when administered concomitantly with other ototoxic agents, especially aminoglycosides.

Colchicine

Colchicine is a substrate of CYP3A and P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. Concomitant use of clarithromycin and colchicine may lead to increased colchicine exposure due to inhibition of Pgp and/or CYP3A by clarithromycin. Patients should be monitored for clinical signs of colchicine toxicity. The colchicine dose should be reduced when used concomitantly with clarithromycin in patients with normal renal and hepatic function. Concomitant use of clarithromycin with colchicine in patients with renal or hepatic insufficiency is contraindicated.

Digoxin

Digoxin is considered a substrate of P-glycoprotein (Pgp). Clarithromycin is known to inhibit Pgp. Concomitant use may lead to increased

digoxin exposure due to Pgp inhibition. Increased serum digoxin concentrations have been reported in patients taking clarithromycin with digoxin. In some patients, signs of digitalis toxicity, including potentially fatal arrhythmias, developed. Serum digoxin concentrations should be carefully monitored in patients receiving digoxin with clarithromycin.

Zidovudine

Concomitant use of immediate-release clarithromycin tablets and zidovudine in HIV-infected patients may lead to decreased steady-state serum concentrations of zidovudine. Since clarithromycin may interfere with the absorption of oral zidovudine when taken simultaneously, a 4-hour interval between administration of clarithromycin and zidovudine should be maintained. Such interaction has not been reported with use of clarithromycin suspension and zidovudine or didanosine in children. This interaction is unlikely when clarithromycin is administered as an intravenous infusion.

Phenytoin and valproate

There have been 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 administered concomitantly with clarithromycin. Increased serum levels have been reported.

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.

Lomitapide

Concomitant administration of clarithromycin with lomitapide is contraindicated due to the potential for significant increase in transaminases.

Bidirectional drug interactions

Atazanavir

Administration 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 necessary for patients with normal renal function. The clarithromycin dose should be reduced by 50% in patients with creatinine clearance of 30–60 mL/min and by 75% in patients with creatinine clearance below 30 mL/min, using the appropriate dosage form. Clarithromycin doses exceeding 1000 mg daily should not be used with protease inhibitors.

Calcium channel blockers

Due to the risk of arterial hypotension, clarithromycin should be used with caution when administered 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 taking clarithromycin with verapamil.

Itraconazole

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

Saquinavir

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

Corticosteroids

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

Special precautions for use.

Clarithromycin should not be prescribed to pregnant women without careful assessment of the benefit/risk ratio, especially during the first trimester of pregnancy.

Prolonged or repeated use of antibiotics may lead to overgrowth of resistant bacteria and fungi. If superinfection occurs, appropriate therapy should be initiated.

Clarithromycin is primarily eliminated via the liver. Therefore, caution should be exercised when administering the drug to patients with hepatic impairment. The drug should also be used with caution in patients with moderate or severe renal impairment.

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

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 and are usually reversible. In some cases, fatal hepatic failure has been reported, which was primarily associated with serious underlying diseases and/or concomitant medication. Clarithromycin therapy should be discontinued immediately if signs and symptoms of hepatitis occur, such as anorexia, jaundice, dark urine, pruritus, or abdominal pain.

Cases of pseudomembranous colitis, ranging from moderate to life-threatening severity, have been reported with nearly all antibacterial agents, including macrolides. Cases of diarrhea, ranging from mild to pseudomembranous colitis with fatal outcome caused by Clostridium difficile, have been reported with nearly all antibacterial agents, including clarithromycin. The possibility of Clostridium difficile-associated diarrhea should always be considered in all patients presenting with diarrhea after antibiotic use. Furthermore, a careful medical history should be obtained, as cases of Clostridium difficile-associated diarrhea have been reported even up to 2 months after antibacterial therapy. Therefore, clarithromycin treatment should be discontinued regardless of the therapeutic indication. Microbiological testing should be performed and appropriate treatment initiated. The use of antiperistaltic agents should be avoided.

Clarithromycin is primarily eliminated via the liver. Therefore, caution should be exercised when administering the drug to patients with hepatic impairment, as well as those with moderate or severe renal impairment.

Cases of colchicine toxicity (including fatal outcomes) have been reported with concomitant use of clarithromycin and colchicine, particularly in elderly patients, including those with renal impairment. Concomitant use of clarithromycin with colchicine is contraindicated.

Caution should be exercised when clarithromycin is used concomitantly with triazolobenzodiazepines, such as triazolam, or intravenous midazolam.

Clarithromycin should be used with caution when administered concomitantly with other ototoxic agents, especially aminoglycosides. Monitoring of vestibular and auditory function should be performed during and after treatment.

Cardiovascular complications

Prolongation of cardiac repolarization and QT interval, indicating a risk of cardiac arrhythmias including torsades de pointes, has been observed with macrolide therapy, including clarithromycin (see "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 (< 50 beats/min).
• Clarithromycin should not be used in patients with hypokalemia.
• Patients who are concurrently taking other drugs associated with QT interval prolongation.

Concomitant use of clarithromycin with astemizole, cisapride, pimozide, and terfenadine is contraindicated.

Clarithromycin should not be used in patients with congenital or documented acquired QT interval prolongation, or with a history of ventricular arrhythmias.

Epidemiological studies investigating the risk of adverse cardiovascular outcomes with macrolide use have shown variable results. These studies have identified a rare short-term risk of arrhythmias, 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 possible 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, mild to moderate

These infections are most commonly caused by Staphylococcus aureus and Streptococcus pyogenes, which may be resistant to macrolides. Therefore, susceptibility testing is important. When β-lactam antibiotics cannot be used (e.g., due to allergy), other antibiotics such as clindamycin may be used as first-line agents. Currently, macrolides play a role only in the treatment of certain skin and soft tissue infections (e.g., infections caused by Corynebacterium minutissimum, acne vulgaris, or folliculitis) and in situations where penicillins cannot be used.

In the event of severe acute hypersensitivity reactions, such as anaphylaxis, severe skin reactions (e.g., acute generalized exanthematous pustulosis, Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS), or Henoch-Schönlein purpura, clarithromycin therapy should be immediately discontinued and appropriate treatment initiated without delay.

Clarithromycin should be used with caution when co-administered with inducers of the cytochrome P450 CYP3A4 enzyme.

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

The use of any antimicrobial therapy, including clarithromycin, for the treatment of H. pylori infection may lead to the development of microbial resistance. In a small number of patients, resistance of H. pylori to clarithromycin may develop.

HMG-CoA reductase inhibitors (statins)

Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated. Clarithromycin should be used with caution when co-administered with other statins. Cases of rhabdomyolysis have been reported in patients receiving clarithromycin and statins concurrently. Patients should be monitored for signs of myopathy. When concomitant use of clarithromycin with statins cannot be avoided, the lowest registered dose of the statin should be prescribed. A statin not metabolized by CYP3A (e.g., fluvastatin) may be considered.

Oral hypoglycemic agents/insulin

Concomitant use of clarithromycin with oral hypoglycemic agents (e.g., sulfonylurea derivatives) and/or insulin may cause marked hypoglycemia. Close monitoring of blood glucose levels is recommended.

Oral anticoagulants

Concomitant use of clarithromycin with warfarin increases the risk of serious bleeding, significant elevation of the INR (International Normalized Ratio), and prothrombin time. While patients are receiving both clarithromycin and oral anticoagulants, INR and prothrombin time should be monitored frequently. Caution is advised when clarithromycin is used concomitantly with direct oral anticoagulants such as dabigatran, rivaroxaban, apixaban, and edoxaban, especially in patients at high risk of bleeding (see section "Interaction with other medicinal products and other forms of interaction").

Excipients.

The medicinal product contains sodium carmellose. If patients on a sodium-restricted diet take 2 tablets (500 mg each) once daily, the total sodium intake (30.6 mg per dose) should be taken into account.

Use during pregnancy or breastfeeding.

The safety of clarithromycin use during pregnancy has not been established. Based on varying results from animal studies and human experience, a potential adverse effect on embryofetal development cannot be excluded. Some observational studies assessing the use of clarithromycin during the first and second trimesters have reported an increased risk of miscarriage compared to no antibiotic use or use of other antibiotics during the same period. Available epidemiological studies on the risk of major congenital malformations associated with macrolide use, including clarithromycin, during pregnancy have yielded conflicting results. Therefore, use during pregnancy is not recommended without careful consideration of benefit versus risk.

Breastfeeding

The safety of clarithromycin use during breastfeeding has not been established. Clarithromycin passes into human breast milk in small amounts. It has been estimated that an exclusively breastfed infant would receive approximately 1.7% of the mother's weight-adjusted dose of clarithromycin.

Ability to affect reaction speed when driving or operating machinery.

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

Dosage and Administration.

The recommended dose of clarithromycin for adults and children aged 12 years and older is 250 mg (1 tablet) every 12 hours. In more severe infections, the dose may be increased to 500 mg (2 tablets) every 12 hours. The usual duration of treatment depends on the severity of infection and typically ranges from 6 to 14 days.

Clarithromycin-AstraPharm 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 no clinical or bacteriological improvement is observed within 3–4 weeks of treatment, the dose of clarithromycin may be increased to 1000 mg twice daily.

Treatment of disseminated infections caused by MAC in AIDS patients should continue for as long as clinically and microbiologically confirmed efficacy of the drug persists. 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 in combination with amoxicillin 1000 mg twice daily and omeprazole 20 mg daily for 7–10 days.

Triple therapy (10 days)

Clarithromycin (500 mg) twice daily, lanzoprazole 30 mg twice daily, and amoxicillin 1000 mg twice daily for 10 days.

Double therapy (14 days)

Clarithromycin (500 mg) three times daily in combination 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 in combination with lanzoprazole 60 mg once daily orally for 14 days. Further 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 lanzoprazole;

clarithromycin + metronidazole and omeprazole or lanzoprazole;

clarithromycin + tetracycline, bismuth subcitrate, and ranitidine;

clarithromycin + amoxicillin and lanzoprazole;

clarithromycin + ranitidine bismuth citrate.

Use in elderly patients: same as for adults.

Use in patients with renal impairment: in patients with severe renal impairment (creatinine clearance < 30 mL/min), the dose should be reduced by half, 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.

The drug is indicated for children aged 12 years and older. The use of clarithromycin tablets in children under 12 years of age has not been studied. For children under 12 years of age, clarithromycin should be administered in suspension form.

Overdose.

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

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

Side effects.

The most common and frequent side effects associated with clarithromycin treatment in adults and children are abdominal pain, diarrhea, nausea, vomiting, and taste disturbances. These side effects are usually mild and consistent with the known safety profile of macrolide antibiotics.

The side effects listed below were observed during clinical trials and post-marketing use of various dosage forms and strengths of clarithromycin. Adverse reactions are categorized according to the following frequency of occurrence: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), frequency not known* (reactions reported during post-marketing surveillance; frequency cannot be estimated from available data). Within each category, 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, erysipelas.

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

Immune system disorders: uncommon – anaphylactoid¹ reactions, 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, taste disturbance, 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: common – vasodilation¹; uncommon – cardiac arrest¹, atrial fibrillation¹, QT interval prolongation, extrasystoles¹, palpitations; frequency not known – torsades de pointes, ventricular tachycardia, hemorrhage, ventricular fibrillation.

Respiratory system 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 alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamyl transferase (GGT); frequency not known – hepatic failure, cholestatic jaundice, hepatocellular jaundice.

Skin and subcutaneous tissue disorders: common – rash, hyperhidrosis; uncommon – bullous dermatitis¹, pruritus, urticaria, maculopapular rash³; frequency not known – severe 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, musculoskeletal 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: uncommon – malaise⁴, fever³, asthenia, chest pain⁴, chills⁴, increased fatigue⁴.

Investigations: uncommon – altered albumin-globulin ratio¹, increased blood alkaline phosphatase⁴, increased blood lactate dehydrogenase⁴; frequency not known – increased international normalized ratio (INR), prolonged prothrombin time, urine discoloration.

* Frequency not known: these reactions have been reported voluntarily from a population of uncertain size. 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 rhabdomyolysis reports, 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 dosage forms: 1 – lyophilized powder for solution for infusion, 2 – extended-release tablets, 3 – suspension, 4 – immediate-release tablets.

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

Patients with impaired immune system.

In patients with AIDS and other immunocompromised patients who received high doses of clarithromycin for longer than recommended for the treatment of mycobacterial infections, it was often difficult to distinguish adverse reactions related to the drug from symptoms of the underlying or concomitant diseases.

In adult patients receiving clarithromycin at a daily dose of 1000 mg, the most common adverse effects were nausea, vomiting, taste disturbance, abdominal pain, diarrhea, rash, abdominal distension, headache, constipation, hearing impairment, and increased ALT and AST levels. Dyspnea, insomnia, and dry mouth occurred uncommonly.

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, 2–3% of patients receiving 1000 mg of clarithromycin daily experienced markedly abnormal elevations in ALT and AST levels and abnormal decreases in white blood cell and platelet counts. A smaller percentage of patients had elevated 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.

7 tablets in a blister; 1 or 2 blisters per carton.

Prescription status. Prescription only.

Manufacturer.

LLC "ASTRAFARM".

Manufacturer's address and location of business activity.

6, Kyivska St., Vyshneve, Kyiv-Sviatoshyn District, Kyiv Oblast, 08132, Ukraine.