Clarithromycin-darnitsa

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

Composition:

Active substance: clarithromycin;

1 tablet contains 250 mg or 500 mg of clarithromycin;

Excipients: microcrystalline cellulose, povidone, crospovidone, sodium lauryl sulfate, talc, stearic acid, magnesium stearate, Sepifilm 752 white, polyethylene glycol 4000 (macrogol 4000).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

250 mg tablets: film-coated tablets, white in color, round-shaped, with a biconvex surface;

500 mg tablets: film-coated tablets, white in color, oblong-shaped, with a biconvex surface.

Pharmacotherapeutic group. Antimicrobial agents for systemic use. Macrolides. ATC code J01FA09.

Pharmacological Properties

Pharmacodynamics

Clarithromycin is a semi-synthetic antibiotic of the macrolide group. Its antibacterial activity is determined by 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 is higher at neutral pH 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 lactose-nonproducing gram-negative bacteria, are resistant 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 resistant to clarithromycin.

Helicobacter pylori

Clarithromycin is active in vitro against most strains of this microorganism; 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.

Other microorganisms: Chlamydia trachomatis.

Spirochetes: Borrelia burgdorferi, Treponema pallidum.

Camphylobacters: Campylobacter jejuni.

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

The main metabolite of clarithromycin in the human body is microbiologically active 14-hydroxyclarithromycin (14-OH clarithromycin). In most microorganisms, the microbiological activity of the metabolite is similar to that of the parent substance or 1–2 times weaker, 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 drug 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 the formation of the 14-hydroxymetabolite. The pharmacokinetics of clarithromycin is nonlinear; however, steady-state concentrations are achieved within 2 days of drug administration. After administration of 250 mg twice daily, 15–20% of unchanged drug is excreted in urine. With a dose of 500 mg twice daily, urinary excretion of the drug is more intensive (approximately 36%). 14-Hydroxyclarithromycin is the main metabolite excreted in urine, amounting to 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 found in feces.

When 500 mg of clarithromycin is administered three times daily, plasma concentrations of clarithromycin are higher compared to 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, erysipelas, 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 when gastric acid secretion is suppressed (clarithromycin activity against H. pylori is higher at neutral pH than at acidic pH).

Contraindications.

Hypersensitivity to macrolide antibiotics or to any of the components of the medicinal product.

Concomitant use of clarithromycin and any of the following medicinal products: 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; oral midazolam; lomitapide (see section "Interaction with other medicinal products and other forms of interaction").

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

Electrolyte disturbances (hypokalemia or hypomagnesemia) – due to the risk of QT interval prolongation (see sections "Special precautions for use", "Interaction with other medicinal products and other forms of interaction").

Severe hepatic insufficiency in combination with renal insufficiency (see sections "Special precautions for use", "Interaction with other medicinal products and other forms of interaction").

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

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

Interaction with other medicinal products and other forms of interaction.

Clarithromycin does not interact with oral contraceptives.

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

Chloroquine, cisapride, pimozide, astemizole, terfenadine

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

Increased serum levels of cisapride have been observed in patients receiving clarithromycin and cisapride concomitantly. This may lead to QT interval prolongation and 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").

There have been reports of macrolides altering 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 (see section "Contraindications"). In a study of 14 volunteers, concomitant administration of clarithromycin and terfenadine resulted in a 2–3-fold increase in the serum level of the acid metabolite of terfenadine and QT interval prolongation, which did not cause any clinically apparent effect.

Similar effects are observed with concomitant use of astemizole and other macrolides.

Ergot alkaloids.

Concomitant use of clarithromycin and ergotamine or dihydroergotamine is associated with signs of acute ergotism, characterized by vasospasm and ischemia of extremities and other tissues, including the central nervous system.

Concomitant use of clarithromycin and ergot-containing alkaloids is contraindicated (see section "Contraindications").

Oral midazolam

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

Oral colchicine

Concomitant use of clarithromycin with colchicine is contraindicated (see section "Contraindications").

Oral ticagrelor

Concomitant use of clarithromycin with ticagrelor is contraindicated (see section "Contraindications").

Oral ivabradine

Concomitant use of clarithromycin with ivabradine is contraindicated (see section "Contraindications").

Oral ranolazine

Concomitant use of clarithromycin with ranolazine 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 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 concomitantly with these statins. If clarithromycin treatment cannot be avoided, therapy with lovastatin or simvastatin should be discontinued during the course of treatment.

Caution should be exercised when prescribing clarithromycin 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 symptoms of myopathy is necessary.

Effect of 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 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.

Effect of other medicinal products on clarithromycin blood concentration, known or hypothetical, which may require dose adjustments 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, while 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, consideration should be given to using alternative medicinal products to clarithromycin.

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 are not significantly altered with concomitant use of fluconazole. 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 led to significant inhibition of clarithromycin metabolism. The Cmax of clarithromycin increased by 31%, Cmin by 182%, and AUC by 77% with concomitant use of ritonavir. Complete inhibition of 14-OH-clarithromycin formation was observed. Due to the wide therapeutic window, 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 of 30–60 ml/min, the dose of clarithromycin should be reduced by 50%. For patients with severe renal insufficiency (creatinine clearance < 30 ml/min), the dose of clarithromycin should be reduced by 75%. Doses of clarithromycin exceeding 1 g/day should not be used with ritonavir.

The same dose adjustments should be applied to patients with impaired renal function when ritonavir is used as a pharmacokinetic booster with other protease inhibitors, including atazanavir and saquinavir.

Effect of clarithromycin on the pharmacokinetics of other medicinal products.

Corticosteroids

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

Antiarrhythmic agents.

There have been reports of torsades de pointes occurring with concomitant use of clarithromycin and quinidine or disopyramide. ECG monitoring is recommended for timely detection of QT interval prolongation. During clarithromycin therapy, serum concentrations of these medicinal products should be monitored.

Post-marketing reports have indicated hypoglycemia with concomitant use of clarithromycin and disopyramide. Therefore, blood glucose levels should be monitored when clarithromycin is used concomitantly with disopyramide.

Interactions related to CYP3A.

Concomitant use of clarithromycin, a known inhibitor of CYP3A enzyme, and a medicinal product primarily metabolized by CYP3A, may lead to increased plasma concentrations 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 medicinal products, especially if the CYP3A substrate has a narrow therapeutic range (e.g., carbamazepine) and is extensively metabolized by this enzyme.

Dose adjustments and careful monitoring of serum concentrations of the CYP3A-metabolized medicinal product may be required in patients receiving clarithromycin concomitantly.

It is known (or presumed) that the following medicinal products or groups of medicinal products are metabolized by the same CYP3A isoenzyme: alprazolam, astemizole, carbamazepine, cyclosporine, cisapride, colchicine, lovastatin, methylprednisolone, midazolam, omeprazole, oral anticoagulants (warfarin), atypical antipsychotics (e.g., quetiapine), pimozide, quinidine, rifabutin, sildenafil, simvastatin, tacrolimus, terfenadine, triazolam, and vinblastine.

However, this list is incomplete. A similar interaction mechanism has been observed with phenytoin, theophylline, and valproate, which are metabolized by another isoenzyme of the cytochrome P450 system.

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.

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

Combined use of clarithromycin and oral anticoagulants may potentiate the effect of the latter, requiring careful monitoring of prothrombin time in patients.

Direct oral anticoagulants dabigatran and edoxaban are substrates for the P-glycoprotein (P-gp) efflux transporter. Rivaroxaban and apixaban are metabolized via CYP3A4 and are also substrates for P-gp. Caution should be exercised when using clarithromycin concomitantly with these medicinal products, especially in patients at high risk of bleeding (see section "Special precautions for use").

Omeprazole.

Administration of clarithromycin (500 mg every 8 hours) in combination with omeprazole (40 mg daily) in healthy adult volunteers resulted in increased steady-state plasma concentrations of omeprazole (Cmax, AUC0-24, and t1/2 increased by 30%, 89%, and 34%, respectively). When omeprazole was used alone, the mean gastric juice pH value 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. There is a possibility of 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.

A slight but statistically significant increase in plasma concentrations of theophylline or carbamazepine may occur with concomitant use of 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 plasma concentrations of tolterodine. Dose reduction of tolterodine may be necessary in such patients when used concomitantly with CYP3A inhibitors, such as clarithromycin.

Triazolobenzodiazepines (alprazolam, midazolam, triazolam).

Combined use of oral midazolam and clarithromycin (500 mg twice daily) should be avoided. 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 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 taken 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 adverse effects on the central nervous system (such as somnolence and confusion) with concomitant use of clarithromycin and triazolam. Patients should be monitored, considering the possibility of increased pharmacological effects on the central nervous system.

Other forms of interaction.

Aminoglycosides.

Clarithromycin should be used with caution concomitantly with other ototoxic agents, especially aminoglycosides (see section "Special precautions for use").

Colchicine.

Colchicine is a substrate of CYP3A and the P-glycoprotein (P-gp) efflux transporter. It is known that clarithromycin and other macrolides can inhibit CYP3A and P-gp. With concomitant use of clarithromycin and colchicine, inhibition of P-gp and CYP3A by clarithromycin may lead to increased colchicine exposure. Patients should be monitored for clinical symptoms of colchicine toxicity. The dose of colchicine 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 (see sections "Contraindications", "Special precautions for use").

Digoxin.

Digoxin is considered a substrate of the P-glycoprotein (P-gp) efflux transporter. It is known that clarithromycin can inhibit P-gp. With concomitant use of clarithromycin and digoxin, inhibition of P-gp by clarithromycin may lead to increased digoxin exposure. Post-marketing surveillance has reported increased serum digoxin concentrations in patients who took clarithromycin concomitantly with digoxin. In some patients, signs of digitalis toxicity developed, including potentially fatal arrhythmias. Serum digoxin concentrations should be carefully monitored in patients when used concomitantly 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 used concomitantly, this interaction can be largely 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 children. This interaction is unlikely when clarithromycin is administered via intravenous infusion.

Phenytoin and valproate

There have been reports of interaction between CYP3A inhibitors, including clarithromycin, and medicinal products not considered to be metabolized by CYP3A (e.g., phenytoin and valproate). Monitoring of serum levels of these medicinal products is recommended when prescribed concomitantly with clarithromycin. Increased serum levels have been reported.

Lomitapide.

Concomitant use of clarithromycin with lomitapide is contraindicated due to the potential for markedly elevated transaminases (see section "Contraindications***"***).

Mutual influence of medicinal products.

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 dose of clarithromycin should be reduced by 50% for patients with creatinine clearance of 30–60 ml/min and by 75% for patients with creatinine clearance < 30 ml/min, using the appropriate formulation of clarithromycin. Doses of clarithromycin 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 concomitantly with calcium channel blockers metabolized by CYP3A4 (verapamil, amlodipine, diltiazem). Plasma concentrations of both clarithromycin and calcium channel blockers may increase during interaction. Arterial hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving clarithromycin with verapamil.

Itraconazole.

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

Saquinavir.

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 led to a 177% increase in AUC at steady state and an 187% increase in Cmax compared to saquinavir alone. Meanwhile, AUC and Cmax of clarithromycin increased by approximately 40% compared to clarithromycin alone. Dose adjustment is not necessary if both medicinal products are used concomitantly for a limited period and at the aforementioned doses/forms. The results of the drug interaction study using soft gelatin capsules may not correspond to effects observed with saquinavir in hard gelatin capsule form. The results of the drug interaction study 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 (see above).

Special precautions for use.

Clarithromycin should not be used in 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, clarithromycin should be discontinued and appropriate therapy initiated.

Abnormal liver function, including elevated liver enzymes, as well as hepatocellular and/or cholestatic hepatitis with or without jaundice, has been reported during clarithromycin therapy. These liver function abnormalities may be severe but are usually reversible. In some cases, fatal liver failure has been reported, primarily associated with serious underlying diseases and/or concomitant medications. Clarithromycin should be discontinued immediately if signs or symptoms of hepatitis occur, such as anorexia, jaundice, dark urine, pruritus, or abdominal pain.

The drug should be used with caution in patients with impaired liver function and in those with moderate to severe renal impairment, since clarithromycin is primarily eliminated via the liver and kidneys.

Clostridium difficile-associated diarrhea (CDAD), ranging from mild diarrhea to fatal pseudomembranous colitis, has been reported with nearly all antibacterial agents, including clarithromycin. Antibacterial therapy may disrupt the normal intestinal flora, leading to overgrowth of C. difficile.

Clostridium difficile-associated diarrhea should always be considered in any patient presenting with diarrhea after antibiotic use. A careful medical history should be taken, as cases of C. difficile-associated diarrhea have been reported even up to two months after antibacterial therapy. If pseudomembranous colitis develops, clarithromycin therapy should be discontinued regardless of the indication for which it was prescribed. Microbiological testing should be performed and appropriate treatment initiated. Medicinal products that inhibit peristalsis should be avoided.

Exacerbation of symptoms of myasthenia gravis has been reported in patients receiving clarithromycin.

Colchicine.

Colchicine toxicity (including fatal outcomes) has been reported when colchicine is used concomitantly with clarithromycin, particularly in elderly patients and those with renal impairment. Concomitant use of colchicine and clarithromycin is contraindicated (see section "Contraindications").

Caution should be exercised when clarithromycin is used concomitantly with triazolobenzodiazepines, such as triazolam, and intravenous midazolam (see section "Interaction with other medicinal products and other forms of interaction").

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

QT interval prolongation.

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 section "Adverse reactions"). Due to the increased 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 medicinal products associated with QT interval prolongation (see section "Interaction with other medicinal products and other forms of interaction").

Clarithromycin is contraindicated in patients with electrolyte imbalances such as hypokalemia or hypomagnesemia (see section "Contraindications").

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 personal/family history of QT interval prolongation or ventricular arrhythmias (see section "Contraindications").

Pneumonia.

As resistance of Streptococcus pneumoniae to macrolides may exist, susceptibility testing is important when prescribing clarithromycin for treatment of community-acquired pneumonia. For hospital-acquired pneumonia, clarithromycin should be used in combination with other appropriate antibiotics.

Soft tissue and skin 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. In cases where β-lactam antibiotics cannot be used (e.g., due to allergy), other antibiotics such as clindamycin may be considered first-line agents. Currently, macrolides play a limited role in the treatment of certain skin and soft tissue infections (e.g., infections caused by Corynebacterium minutissimum (erythrasma), acne vulgaris, and cat-scratch disease) and in situations where penicillin therapy is contraindicated. If severe hypersensitivity reactions occur, such as anaphylaxis or severe skin 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.

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

Oral hypoglycemic agents/insulin.

Concomitant use of clarithromycin with oral hypoglycemic agents (e.g., sulfonylureas) and/or insulin may result in pronounced hypoglycemia. When used concomitantly with hypoglycemic agents such as nateglinide, pioglitazone, repaglinide, and rosiglitazone, clarithromycin may inhibit the CYP3A enzyme, potentially leading to hypoglycemia. Close monitoring of blood glucose levels is recommended.

Oral anticoagulants.

Concomitant use of clarithromycin with warfarin may increase the risk of serious bleeding, significantly elevated INR (International Normalized Ratio), and prolonged prothrombin time. INR and prothrombin time should be monitored regularly while patients are receiving both clarithromycin and oral anticoagulants.

Caution should be exercised 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").

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 co-administration with clarithromycin significantly increases their plasma concentrations, thereby increasing the risk of myopathy, including rhabdomyolysis.

Cases of rhabdomyolysis have been reported in patients receiving clarithromycin concomitantly with these statins. Patients should be monitored for symptoms of myopathy. If clarithromycin therapy cannot be avoided, treatment with lovastatin or simvastatin should be discontinued during the course of therapy. Clarithromycin should be prescribed with caution when used concomitantly with statins. When concomitant use of clarithromycin with statins cannot be avoided, the lowest registered dose of the statin should be used. Consideration may be given to using a statin not dependent on CYP3A metabolism (e.g., fluvastatin).

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

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.

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

Use during pregnancy or breastfeeding.

Pregnancy. The safety of clarithromycin use during pregnancy or breastfeeding has not been established. Based on animal studies and human experience, a harmful effect on embryonic and fetal development cannot be excluded.

Some observational studies on the use of clarithromycin during the first and second trimesters of pregnancy have shown an increased risk of miscarriage compared to no antibiotic exposure and to other antibiotics used during the same period. Epidemiological studies on the risk of major congenital malformations associated with macrolide use, including clarithromycin, during pregnancy have yielded conflicting results.

Clarithromycin should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus.

Breastfeeding. Clarithromycin passes into breast milk in small amounts. It has been estimated that an exclusively breastfed infant receives approximately 1.7% of the clarithromycin dose adjusted for maternal weight. Therefore, breastfeeding should be discontinued during treatment.

Ability to influence reaction speed when driving or operating machinery.

Currently, no reports are available. However, caution is recommended when driving or operating machinery due to the potential for adverse neurological reactions such as seizures, dizziness, vertigo, hallucinations, confusion, and disorientation.

Dosage and Administration.

Clarithromycin tablets should be taken orally, without chewing, with a small amount of water. The drug can be administered regardless of food intake, as food does not affect the bioavailability of clarithromycin.

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

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 Mycobacterium avium complex (MAC) in AIDS patients should continue as long as clinically and microbiologically confirmed efficacy is maintained. Clarithromycin may be used in combination with other antimycobacterial agents.

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

Triple therapy (7–10 days).

Clarithromycin 500 mg twice daily should be administered together with amoxicillin 1000 mg twice daily and omeprazole 20 mg daily for 7–10 days.

Triple therapy (10 days).

Clarithromycin 500 mg twice daily, lansoprazole 30 mg twice daily, and amoxicillin 1000 mg twice daily for 10 days.

Double therapy (14 days).

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

Double therapy (14 days).

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

Clarithromycin may also be used in the following therapeutic regimens:

clarithromycin + tinidazole and omeprazole or lansoprazole;

clarithromycin + metronidazole and omeprazole or lansoprazole;

clarithromycin + tetracycline, bismuth subsalicylate, and ranitidine;

clarithromycin + amoxicillin and lansoprazole;

clarithromycin + ranitidine + bismuth citrate.

Use in elderly 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. For such patients, the duration of treatment should not exceed 14 days.

Children.

The medicinal product Clarithromycin-Darnitsya is indicated for children aged 12 years and older.

For children under 12 years of age, clarithromycin should be administered in another pharmaceutical form (e.g., suspension).

Overdose.

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

Treatment. Activated charcoal, gastric lavage, and symptomatic therapy aimed at supporting vital functions should be administered.

As with other macrolides, hemodialysis or peritoneal dialysis are unlikely to significantly affect serum clarithromycin concentrations.

Adverse Reactions

The most common and frequent adverse reactions observed 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 studies, no significant difference in the frequency of these adverse reactions was observed between patient groups with or without mycobacterial infections.

Below are described adverse reactions that occurred during clinical trials and post-marketing use of various dosage forms and strengths of clarithromycin, including immediate-release formulations. Adverse reactions probably associated with clarithromycin are categorized by system organ class and frequency of occurrence: >10% – very common, 1–10% – common, 0.1–1% – uncommon, frequency not known* (reactions reported during post-marketing surveillance; frequency cannot be estimated from available data). Within each category, adverse reactions are listed in decreasing order of severity when severity could be assessed.

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

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

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

* Hepatobiliary disorders: common – abnormal liver function tests; uncommon – cholestasis⁴, hepatitis⁴, increased alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase⁴; frequency not known – hepatic failure, cholestatic jaundice, hepatocellular jaundice.

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

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

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

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

* 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.

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

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

* Skin and subcutaneous tissue disorders: common – rash, hyperhidrosis; uncommon – bullous dermatitis¹, erythema, 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, Henoch–Schönlein purpura).

* Musculoskeletal and connective tissue disorders: uncommon – muscle spasms³, skeletal-muscle rigidity¹, myalgia²; frequency not known – arthralgia, rhabdomyolysis² [in some reports of rhabdomyolysis, clarithromycin was co-administered with other medicinal products known to be associated with rhabdomyolysis (such as statins, fibrates, colchicine or allopurinol)], myopathy.

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

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

Investigations: uncommon – altered albumin/globulin ratio¹, increased alkaline phosphatase in blood⁴, increased lactate dehydrogenase in blood⁴; frequency not known – increased international normalized ratio (INR), prolonged prothrombin time, change in urine color.

* Frequency not known: these reactions have been reported spontaneously, and the size of the patient population is unknown. The frequency or causal relationship to drug administration cannot always be precisely determined. The overall clinical experience with clarithromycin exceeds 1 billion patient-days.

^1,2,3,4 These adverse reactions were reported only during administration of the medicinal product in the following forms: ¹ – lyophilized powder for solution for infusion, ² – prolonged-release tablets, ³ – suspension, ⁴ – immediate-release tablets.

Very rare cases of uveitis have been reported, predominantly in patients receiving concomitant rifabutin. Most cases were reversible.

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.

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

Patients with Immune System Disorders

In AIDS patients and other immunocompromised patients receiving high doses of clarithromycin for longer than recommended for the treatment of mycobacterial infections, it may be difficult to distinguish adverse reactions related to the drug from symptoms of the underlying or concurrent diseases.

In adult patients receiving clarithromycin at a daily dose of 1000 mg, the most common adverse effects were nausea, vomiting, taste distortion, abdominal pain, diarrhea, rash, abdominal distension, headache, constipation, hearing impairment, and increased ALT and AST levels. Dyspnea, insomnia, and dry mouth occurred uncommonly. In 2–3% of patients taking 1000 mg of clarithromycin per day, marked elevations in ALT and AST levels and significant decreases in white blood cell and platelet counts were observed. Increased blood urea levels were observed in several patients.

Shelf Life

250 mg tablets – 2 years.
500 mg tablets – 3 years.

Storage Conditions

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

Packaging

7 tablets in a blister pack; 2 blisters per carton.

Prescription Category
Prescription only.

Manufacturer
JSC "Pharmaceutical Company "Darnytsia"

Manufacturer's Address and Location of Business Activity
13, Boryspilska Street, Kyiv, 02093, Ukraine