INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT AZICLAR 250 AZICLAR 500 (AZICLAR 250 AZICLAR 500)

Composition:

Active substance: 1 film-coated tablet contains clarithromycin 250 mg or 500 mg;

Excipients: lactose monohydrate, corn starch, povidone, sodium croscarmellose, microcrystalline cellulose, talc, sodium lauryl sulfate, film coating (hydroxypropylmethylcellulose, patent blue (E 133), polyethylene glycol) (250 mg tablets);

lactose monohydrate, corn starch, povidone, sodium croscarmellose, magnesium stearate, microcrystalline cellulose, talc, sodium lauryl sulfate, film coating (hydroxypropylmethylcellulose, tartrazine (E 102), polyethylene glycol) (500 mg tablets).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

250 mg tablets: round, biconvex, film-coated tablets of blue color;

500 mg tablets: oval, biconvex, film-coated tablets of yellow color.

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

Pharmacological Properties.

Pharmacodynamics.

Clarithromycin is a semi-synthetic antibiotic of the macrolide group.

Microbiology

The antibacterial action of clarithromycin is due to its binding to the 50S ribosomal subunit of susceptible bacteria and inhibition of protein biosynthesis. The drug demonstrates high in vitro efficacy against a broad spectrum of aerobic and anaerobic Gram-positive and Gram-negative microorganisms, including hospital strains. Minimum inhibitory concentrations (MICs) of clarithromycin are typically 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 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 Enterobacteriaceae and Pseudomonas strains, as well as other lactose-nonfermenting Gram-negative bacteria, are not susceptible to clarithromycin.

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 and Mycobacterium intracellulare.

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

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

Helicobacter: H. pylori.

Clarithromycin is active in vitro against most strains of the following microorganisms; however, the clinical significance of these data is unknown, and the efficacy and safety of its use have not been established in controlled clinical trials.

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 primary metabolite of clarithromycin in humans is the microbiologically active 14-hydroxyclarithromycin (14-OH-clarithromycin). For most microorganisms, the microbiological activity of the metabolite is equal to or 1–2 times weaker than that of the parent compound, except for H. influenzae, against which the metabolite is twice as effective. In vitro and in vivo, the parent compound and its main metabolite exhibit either additive or synergistic effects against H. influenzae, depending on the microbial strain.

Susceptibility Testing

Quantitative methods requiring measurement of the diameter of inhibition zones provide a more accurate assessment of bacterial susceptibility to antimicrobial agents. In one of the recommended procedures for susceptibility testing, disks impregnated with 15 µg of clarithromycin (Kirby-Bauer diffusion method) 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 of "intermediate susceptibility" indicates that the therapeutic effect of the drug may be uncertain or that the microorganism may respond if higher doses are administered (intermediate susceptibility is also referred to as moderate susceptibility).

Country- or region-specific data on the 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 the formation of the 14-hydroxy metabolite. The pharmacokinetics of clarithromycin is nonlinear, but steady-state concentrations are achieved within 2 days of treatment. After administration of 250 mg twice daily, 15–20% of unchanged drug is excreted in urine. With a dose of 500 mg twice daily, renal excretion is more pronounced (approximately 36%). 14-Hydroxyclarithromycin is the main metabolite excreted in urine, accounting for 10–15% of the administered dose. Most of the remaining dose is excreted in feces, primarily via bile. 5–10% of the parent compound is recovered in feces.

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

Tissue concentrations of clarithromycin are several times higher than plasma concentrations. 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 gastric mucosa and 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, erysipeloid, furunculosis, infected wounds).
Acute and chronic odontogenic infections.
Disseminated or localized mycobacterial infections caused by Mycobacterium avium or Mycobacterium intracellulare. Localized infections caused by Mycobacterium chelonae, Mycobacterium fortuitum, or Mycobacterium kansasii.
Eradication of H. pylori in patients with duodenal ulcer under conditions of acid secretion inhibition (clarithromycin activity against H. pylori at neutral pH is higher than at acidic pH).

Contraindications.

Hypersensitivity to clarithromycin or to any component of the medicinal product, or to other macrolide antibiotics. 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, such as 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 (see sections "Interaction with other medicinal products and other forms of interaction", "Special precautions for use").

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

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

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

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

Severe hepatic insufficiency and concomitant renal insufficiency.

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

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.

Cisapride, pimozide, astemizole, terfenadine

Increased serum levels of cisapride have been reported 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 observed in patients receiving clarithromycin and pimozide concomitantly (see section "Contraindications").

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 (see section "Contraindications"). Concomitant 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 lead to any clinically evident effect. Similar effects have also been observed with concomitant use of astemizole and other macrolides.

Ergot alkaloids

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

Oral midazolam

When midazolam was administered with clarithromycin tablets (500 mg twice daily), the area under the plasma concentration-time curve (AUC) of midazolam increased 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 predominantly metabolized by CYP3A4; 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 with caution when administered concomitantly with other statins. If concomitant use of clarithromycin with statins cannot be avoided, it is recommended to prescribe the lowest registered dose of the statin. Use of a statin not dependent on CYP3A metabolism (e.g., fluvastatin) may be considered. Monitoring of patients for signs and symptoms of myopathy is required.

Lomitapide

Concomitant use of clarithromycin with lomitapide is contraindicated due to the potential for significant elevation of transaminase levels (see section "Contraindications").

Ticagrelor, ivabradine, and ranolazine

Concomitant use of clarithromycin with ticagrelor, ivabradine, or ranolazine is also contraindicated (see section "Contraindications").

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 these may be increased due to CYP3A inhibition by clarithromycin (see also the prescribing information for the respective CYP3A4 inducer). Concomitant use of rifabutin and clarithromycin has led to increased rifabutin levels and decreased clarithromycin serum levels, with a concomitant increased risk of uveitis.

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

Efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine

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

Etravirine

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

Fluconazole

Steady-state concentrations of the active metabolite 14-OH-clarithromycin were not significantly altered when administered concomitantly with fluconazole. Dose adjustment of clarithromycin is not required.

Ritonavir

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% when ritonavir was co-administered. Complete inhibition of 14-OH-clarithromycin formation was observed. Due to the wide therapeutic range, dose reduction of clarithromycin is not required in patients with normal renal function. Dose adjustment is required in 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 per day should not be used concomitantly with ritonavir.

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

Effect of clarithromycin on other medicinal products

Antiarrhythmic agents

There are data on the development 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 agents. Serum concentrations of these agents should be monitored during clarithromycin therapy.

Post-marketing reports have included cases of 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 CYP3A enzyme inhibitor, with a medicinal product primarily metabolized by CYP3A, may lead to increased plasma concentrations of the latter, thereby enhancing or prolonging its therapeutic effect and adverse effects. Caution should be exercised when prescribing clarithromycin to patients receiving therapy with CYP3A substrate medicinal products, especially if the CYP3A substrate has a narrow therapeutic range (e.g., carbamazepine) and/or is predominantly metabolized by this enzyme. Dose adjustment and, where possible, careful monitoring of serum concentrations of the medicinal product primarily metabolized by CYP3A may be required for patients receiving clarithromycin concomitantly.

The following medicinal products or groups of medicinal products are known (or suspected) to be metabolized by the same CYP3A isoenzyme: alprazolam, astemizole, carbamazepine, cilostazol, cisapride, cyclosporine, disopyramide, ergot alkaloids, lovastatin, methylprednisolone, midazolam, omeprazole, oral anticoagulants (e.g., warfarin, rivaroxaban, apixaban), atypical antipsychotics (e.g., quetiapine), pimozide, quinidine, rifabutin, sildenafil, simvastatin, tacrolimus, terfenadine, triazolam, and vinblastine, although 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.

Direct oral anticoagulants

Direct oral anticoagulants dabigatran and edoxaban are substrates of the efflux transporter P-glycoprotein (Pgp). Rivaroxaban and apixaban are metabolized by CYP3A and are also Pgp substrates.

Use of direct oral anticoagulants such as dabigatran, rivaroxaban, and apixaban concomitantly with clarithromycin requires caution, especially in patients at high risk of bleeding (see section "Special precautions for use").

Omeprazole

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

There is a slight but statistically significant increase in plasma concentrations of theophylline or carbamazepine when administered concomitantly with clarithromycin.

Solifenacin

Solifenacin is primarily metabolized by the CYP2D6 isoenzyme of cytochrome P450 (CYP2D6). However, in a subgroup of patients lacking CYP2D6, metabolism occurs via CYP3A. In this population, inhibition of CYP3A leads to a significant increase in plasma concentrations of solifenacin. Dose reduction of solifenacin may be necessary in such patients when used concomitantly with CYP3A inhibitors such as clarithromycin.

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

When midazolam was administered with clarithromycin tablets (500 mg twice daily), the AUC of midazolam increased 2.7-fold after intravenous administration of midazolam. With intravenous administration of midazolam and 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 is not dependent on CYP3A (temazepam, nitrazepam, lorazepam), clinically significant interaction with clarithromycin is unlikely.

There are reports of drug interaction and development of CNS adverse effects (such as somnolence and confusion) with concomitant use of clarithromycin and triazolam. Patients should be monitored, considering the potential for enhanced pharmacological effects on the CNS.

Other types of interactions

Colchicine

Colchicine is a substrate of CYP3A and the efflux transporter P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. 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 precautions for use").

Digoxin

Digoxin is considered a substrate of the efflux transporter P-glycoprotein (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. Increased serum digoxin concentrations have been reported in patients receiving 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 receiving concomitant clarithromycin and digoxin.

Zidovudine

Concomitant oral administration of clarithromycin tablets and zidovudine in HIV-infected adult patients may cause decreased steady-state serum concentrations of zidovudine. Clarithromycin may interfere with the absorption of oral zidovudine when administered concomitantly; this 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 HIV-infected children.

Phenytoin and valproate

There are reports of interaction between CYP3A inhibitors, including clarithromycin, and medicinal products not considered to be metabolized by CYP3A (e.g., phenytoin and valproate). Serum level monitoring of these medicinal products is recommended when co-administered 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 risk of cardiac arrhythmia and serious cardiovascular adverse reactions.

Corticosteroids

Caution is required when using clarithromycin concomitantly with systemic or inhaled corticosteroids that are predominantly metabolized by CYP3A, as systemic corticosteroid effects may be increased. 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 index, dose reduction is not necessary in patients with normal renal function. The clarithromycin dose should be reduced by 50% in patients with CLCR 30–60 mL/min and by 75% in patients with CLCR <30 mL/min. Clarithromycin doses exceeding 1000 mg per day should not be used concomitantly 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 (such as verapamil, amlodipine, diltiazem). Plasma concentrations of both clarithromycin and calcium channel blockers may increase during interaction. Cases of arterial hypotension, bradyarrhythmia, and lactic acidosis have been observed in patients receiving clarithromycin and verapamil concomitantly.

Itraconazole

Clarithromycin and itraconazole are both substrates and inhibitors of CYP3A; therefore, clarithromycin may increase itraconazole plasma levels and vice versa. Patients receiving itraconazole concomitantly with clarithromycin should be closely monitored for signs or symptoms of enhanced or prolonged pharmacological effect.

Saquinavir

Concomitant use of clarithromycin (500 mg twice daily) and saquinavir (soft gelatin capsules, 1200 mg three times daily), both substrates and inhibitors of CYP3A, in 12 healthy volunteers resulted in a 177% and 187% increase in AUC and Cmax of saquinavir at steady state, respectively, compared to use of saquinavir alone. Meanwhile, AUC and Cmax of clarithromycin increased by approximately 40% compared to use of clarithromycin alone. Dose adjustment is not required if both medicinal products are used concomitantly for a limited period at the studied doses/forms. Results of drug interaction studies using soft gelatin capsules may not correspond to effects observed with hard gelatin capsules of saquinavir. Results of drug interaction studies using saquinavir alone may not correspond to effects observed during saquinavir/ritonavir therapy. When saquinavir is used with ritonavir, possible effects of ritonavir on clarithromycin should be considered (see above).

Special precautions for use

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

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

Prolonged use of clarithromycin, as with other antibiotics, may lead to overgrowth of resistant bacteria and fungi. If superinfection occurs, appropriate therapy should be initiated.

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

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

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

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 to fatal colitis, have been reported with the use of nearly all antibacterial agents, including clarithromycin. Antibacterial therapy alters the normal gut flora, which may lead to overgrowth of C. difficile. The possibility of C. difficile-associated diarrhea should always be considered in all patients who develop diarrhea following antibiotic use. A careful medical history is essential, as cases of C. difficile-associated diarrhea have been reported up to two months after antibacterial therapy. If pseudomembranous colitis develops, clarithromycin therapy should be discontinued immediately, regardless of the indication for which it was prescribed. Microbiological testing should be performed and appropriate treatment initiated. Antiperistaltic agents should be avoided.

Colchicine

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

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

Cardiovascular complications

Prolongation of cardiac repolarization and QT interval, indicating a risk of cardiac arrhythmia and torsades de pointes, has been observed with macrolide therapy, including clarithromycin (see section "Adverse reactions"). 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 with electrolyte imbalances (see section "Contraindications").
Patients receiving concomitant medications associated with QT interval prolongation (see section "Interaction with other medicinal products and other forms of interaction").

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

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

Epidemiological studies investigating the risk of adverse cardiovascular outcomes with macrolide use have shown variable results. Some observational studies have identified 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

Given the increasing resistance of Streptococcus pneumoniae to macrolides, it is important to perform susceptibility testing when prescribing clarithromycin for community-acquired pneumonia. For hospital-acquired pneumonia, clarithromycin should be used in combination with other appropriate antibiotics.

Skin and soft tissue infections of mild to moderate severity

These infections are most commonly caused by Staphylococcus aureus and Streptococcus pyogenes, 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), alternative antibiotics such as clindamycin may be considered as first-line therapy. Currently, macrolides play a limited role in the treatment of certain skin and soft tissue infections, including those caused by Corynebacterium minutissimum, acne vulgaris, and erysipelas, as well as in situations where penicillins cannot be used.

If severe acute hypersensitivity reactions occur, 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 CYP3A4 enzyme (see section "Interaction with other medicinal products and other forms of interaction").

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

HMG-CoA reductase inhibitors (statins)

Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated (see section "Contraindications"). Clarithromycin should be used with caution when co-administered 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 approved statin dose. A statin not dependent on CYP3A metabolism (e.g., fluvastatin) may be considered (see section "Interaction with other medicinal products and other forms of interaction").

Oral hypoglycemic agents/insulin

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

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").

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. INR and prothrombin time should be frequently monitored while patients are receiving both clarithromycin and oral anticoagulants.

Excipients

The product contains lactose; therefore, patients with rare hereditary forms of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

AZIKLAR 500 tablets contain the coloring agent tartrazine (E 102), which may cause allergic reactions.

Use during pregnancy or breastfeeding

The safety of clarithromycin use during pregnancy 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 assessing the use of clarithromycin during the first or second trimester of pregnancy have shown an increased risk of pregnancy loss compared to no antibacterial therapy or use of other antibacterial agents during the same period. Available epidemiological studies on the risk of congenital malformations associated with macrolide use, including clarithromycin, during pregnancy have yielded conflicting results.

Clarithromycin should not be used during pregnancy without careful assessment of the benefit-risk ratio.

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

Ability to affect reaction speed when driving or operating machinery

No data are available. However, possible adverse reactions affecting the nervous system, such as seizures, dizziness, vertigo, hallucinations, confusion, and disorientation, should be considered before driving or operating machinery.

Method of Administration and Dosage

Tablets should be taken whole (not crushed or chewed) with liquid. Food intake has virtually no effect on the absorption of the drug, although it may slightly slow this process.

Adults and children aged 12 years and older: The recommended dose is 250 mg of clarithromycin every 12 hours; in severe infections, the dose may be increased to 500 mg every 12 hours.

The usual treatment duration is 6–14 days. The length of treatment depends on the course of the disease and is determined individually by the physician for each patient.

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 improvement in clinical signs or bacteriological parameters 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 clinically and microbiologically confirmed efficacy of the drug 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)

Claritromycin (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)

Claritromycin (500 mg) twice daily, lanseprazole 30 mg twice daily, and amoxicillin 1000 mg twice daily for 10 days.

Double therapy (14 days)

Claritromycin (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)

Claritromycin (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.

Claritromycin has also been used in the following therapeutic regimens:

clarithromycin + tinidazole and omeprazole or lansoprazole;

clarithromycin + metronidazole and omeprazole or lansoprazole;

clarithromycin + tetracycline, bismuth subcitrate, and ranitidine;

clarithromycin + amoxicillin and lansoprazole;

clarithromycin + ranitidine and bismuth citrate.

Use in elderly patients: as for adults.

Use in patients with renal impairment: in patients with severe renal impairment (creatinine clearance less than 30 mL/min), the total daily dose should be reduced by half, i.e., 250 mg once daily or 250 mg twice daily in 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 in this age group, the drug should be administered in the form of suspension.

Overdose.

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

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

Adverse reactions.

The most common and frequent adverse reactions during clarithromycin treatment in adults and children are abdominal pain, diarrhoea, nausea, vomiting, and taste disturbances. These adverse reactions are usually mild and consistent with the known safety profile of macrolide antibiotics.

The adverse reactions listed below occurred during clinical trials 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 classified by organ systems and frequency of occurrence: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), frequency not known* (reactions reported during post-marketing surveillance; frequency cannot be estimated from available data). Within each group, adverse reactions are listed in decreasing order of severity, where severity could be assessed.

Infections and infestations: uncommon – cellulitis\textsuperscript{1}, candidiasis, gastroenteritis\textsuperscript{2}, infection\textsuperscript{3}, vaginal infection; frequency not known – pseudomembranous colitis, black hairy tongue.

Blood and lymphatic system disorders: uncommon – leucopenia, neutropenia\textsuperscript{4}, thrombocytosis\textsuperscript{3}, eosinophilia\textsuperscript{4}; frequency not known – agranulocytosis, thrombocytopenia.

Immune system disorders: uncommon – anaphylactoid reactions\textsuperscript{1}, hypersensitivity; frequency not known – anaphylactic reactions, angioneurotic oedema.

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

Psychiatric disorders: common – insomnia; uncommon – anxiety, nervousness\textsuperscript{3}; frequency not known – psychosis, confusion, depersonalisation, depression, disorientation, hallucinations, nightmares, mania.

Nervous system disorders: common – dysgeusia (disturbance of taste sensation), headache; uncommon – loss of consciousness\textsuperscript{1}, dyskinesia\textsuperscript{1}, dizziness, somnolence, tremor; frequency not known – convulsions, ageusia (loss of taste sensation), parosmia, anosmia, paraesthesia.

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

Cardiac disorders: uncommon – cardiac arrest\textsuperscript{1}, atrial fibrillation\textsuperscript{1}, QT interval prolongation, extrasystoles\textsuperscript{1}, palpitations; frequency not known – torsades de pointes, ventricular tachycardia, ventricular fibrillation.

Vascular disorders: common – vasodilation\textsuperscript{1}; frequency not known – haemorrhage.

Respiratory, thoracic and mediastinal disorders: uncommon – asthma\textsuperscript{1}, epistaxis\textsuperscript{2}, pulmonary embolism\textsuperscript{1}.

Gastrointestinal disorders: common – diarrhoea, vomiting, dyspepsia, nausea, abdominal pain; uncommon – oesophagitis\textsuperscript{1}, gastro-oesophageal reflux disease\textsuperscript{2}, gastritis, proctalgia\textsuperscript{2}, stomatitis, glossitis, abdominal distension\textsuperscript{4}, constipation, dry mouth, belching, flatulence; frequency not known – acute pancreatitis, tongue discoloration, tooth discoloration.

Hepatobiliary disorders: common – abnormal liver function tests; uncommon – cholestasis\textsuperscript{4}, hepatitis\textsuperscript{4}, increased levels of ALT, AST, GGT\textsuperscript{4}; frequency not known – hepatic failure, hepatocellular jaundice.

Skin and subcutaneous tissue disorders: common – rash, hyperhidrosis; uncommon – bullous dermatitis\textsuperscript{1}, pruritus, urticaria, maculopapular rash\textsuperscript{3}; frequency not known – severe skin reactions (e.g., acute generalised 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 spasms\textsuperscript{3}, skeletal muscle rigidity\textsuperscript{1}, myalgia\textsuperscript{2}; frequency not known – rhabdomyolysis\textsuperscript{2**}, myopathy.

Renal and urinary disorders: uncommon – increased blood creatinine\textsuperscript{1}, increased blood urea\textsuperscript{1}; frequency not known – renal failure, interstitial nephritis.

General disorders and administration site conditions: very common – phlebitis at injection site\textsuperscript{1}; common – pain at injection site\textsuperscript{1}, inflammation at injection site\textsuperscript{1}; uncommon – malaise\textsuperscript{4}, fever\textsuperscript{3}, asthenia, chest pain\textsuperscript{4}, chills\textsuperscript{4}, fatigue\textsuperscript{4}.

Investigations: uncommon – change in albumin-globulin ratio\textsuperscript{1}, increased blood alkaline phosphatase\textsuperscript{4}, increased blood lactate dehydrogenase\textsuperscript{4}; frequency not known – increased INR, prolonged prothrombin time, change in urine colour.

*Frequency not known: these reactions have been reported voluntarily from a population of uncertain size. Therefore, 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).

\textsuperscript{1,2,3,4} These adverse reactions were reported only with the following formulations: \textsuperscript{1} – lyophilisate for solution for infusion, \textsuperscript{2} – prolonged-release tablets, \textsuperscript{3} – suspension, \textsuperscript{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 patients with AIDS and other patients with impaired immune systems who received high doses of clarithromycin for prolonged periods for the treatment of mycobacterial infections, it was often 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 commonly reported adverse effects were nausea, vomiting, taste disturbances, abdominal pain, diarrhoea, rash, abdominal distension, headache, constipation, hearing disturbances, and increased serum ALT and AST levels. Dyspnoea, insomnia, and dry mouth occurred less frequently.

In these immunocompromised patients, laboratory parameters were evaluated by analysing those values outside the significant abnormal range (i.e., extreme upper or lower limits) 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 patients receiving 1000 mg of clarithromycin daily. A smaller percentage of patients showed increased blood urea nitrogen levels.

Reporting of adverse reactions

Reporting suspected adverse reactions after a medicinal product is authorised is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients are encouraged to report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

Store at temperatures not exceeding 30 °C in the original packaging.

Keep out of the reach of children.

Packaging.

10 tablets in a blister; 1 blister per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Flamingo Pharmaceuticals Ltd.

Manufacturer's address and location of manufacturing site.

E-28, Opp. Fire Brigade, M.I.D.C., Taloda, Raigad District, Maharashtra, IN – 410208, India.

Marketing Authorisation Holder.

Ananta Medicare Ltd.

Address of the Marketing Authorisation Holder and/or its representative.

Suite 1, 2 Station Court, Imperial Wharf, Townmead Road, Fulham, London, United Kingdom.

Aziklar 500