Oradro

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

Composition:

Active substance: clarithromycin;

One film-coated tablet contains 250 mg or 500 mg of clarithromycin;

Excipients: microcrystalline cellulose (type 101), microcrystalline cellulose (type 102), sodium croscarmellose, povidone K30, polysorbate 80, colloidal anhydrous silicon dioxide, pregelatinized starch, talc, magnesium stearate, stearic acid; film coating: Opadry yellow II 85F32085 (partially hydrolyzed polyvinyl alcohol, macrogol, titanium dioxide (E 171), talc, quinoline yellow aluminium lake (E 104), iron oxide yellow (E 172), sunset yellow FCF aluminium lake (E 110)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: oval, biconvex, film-coated tablets of yellow color, with a dividing line on one side.

Pharmacotherapeutic group.

Antibacterials for systemic use. Macrolides. ATC code J01F A09.

Pharmacological properties.

Pharmacodynamics.

Clarithromycin is a semi-synthetic antibiotic of the macrolide group. The antibacterial action of clarithromycin is determined by its binding to the 50S ribosomal subunit of susceptible bacteria and inhibition of protein synthesis. It demonstrates high in vitro efficacy against a broad spectrum of aerobic and anaerobic, gram-positive and gram-negative microorganisms, including hospital strains. The minimum inhibitory concentration (MIC) of clarithromycin is typically two times lower than that of erythromycin.

Clarithromycin is highly effective in vitro against Legionella pneumophila and Mycoplasma pneumoniae. It exerts bactericidal activity against Helicobacter pylori (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 non-lactose-producing 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, Mycobacterium intracellulare.

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

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

Helicobacter: H. pylori.

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

Aerobic gram-positive microorganisms: Streptococcus agalactiae, Streptococci (groups C, F, G), Viridans group streptococci.

Aerobic gram-negative microorganisms: Bordetella pertussis, Pasteurella multocida.

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

Anaerobic gram-negative microorganisms: Bacteroides melaninogenicus.

Spirochetes: Borrelia burgdorferi, Treponema pallidum.

Campylobacters: Campylobacter jejuni.

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

The main metabolite of clarithromycin in the human body is the microbiologically active 14-hydroxyclarithromycin (14-OH-clarithromycin). For most microorganisms, the microbiological activity of the metabolite is equal to or 1–2 times weaker than that of the parent compound, except for Haemophilus 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 Haemophilus influenzae, depending on the microbial strain.

Susceptibility testing

Quantitative methods requiring measurement of zone diameter provide the most accurate assessment of bacterial susceptibility to antimicrobial agents. One of the recommended procedures for susceptibility testing uses disks impregnated with 15 µg of clarithromycin (Kirby-Bauer diffusion test); the zone inhibition diameter for this disk is correlated with MIC values for clarithromycin. The 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 be susceptible if higher doses are used (intermediate susceptibility is also referred to as moderate susceptibility).

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

Pharmacokinetics.

After oral administration, clarithromycin is rapidly and well absorbed from the gastrointestinal tract. Food slightly delays the onset of absorption of clarithromycin and formation of the 14-hydroxy metabolite, but does not affect bioavailability. Clarithromycin can be administered independently of food intake. The microbiologically active metabolite, 14-hydroxyclarithromycin, is formed via first-pass metabolism.

Clarithromycin is approximately 80% bound to plasma proteins at therapeutic doses. The pharmacokinetics of clarithromycin is nonlinear, but steady-state concentrations are achieved within 2 days of clarithromycin administration. When administered at a dose of 500 mg three times daily, plasma concentrations of clarithromycin increase compared to those achieved with 500 mg twice daily. Clarithromycin concentrations in tissues are several times higher than in blood. Elevated concentrations have been found in both tonsillar and lung tissues. Clarithromycin penetrates into the gastric mucosa. The content of clarithromycin in gastric mucosa and tissue is higher when clarithromycin is administered concomitantly with omeprazole than with clarithromycin monotherapy.

After administration of 250 mg twice daily, 15–20% of unchanged clarithromycin is excreted in urine. At a dose of 500 mg twice daily, urinary excretion of clarithromycin is more intense (approximately 36%). 14-Hydroxyclarithromycin is the main metabolite excreted in urine, accounting for 10–15% of the administered dose. Most of the remainder is excreted in feces, primarily via bile. Approximately 5–10% of the original compound is recovered in feces.

Clinical characteristics.

Indications.

Treatment of infections caused by microorganisms sensitive to clarithromycin:

• Infections of the upper respiratory tract, i.e., nasopharynx (tonsillitis, pharyngitis), and infections of the paranasal sinuses;
• Infections of the lower respiratory tract (bronchitis, acute lobar pneumonia, and primary atypical pneumonia) (see sections "Pharmacological properties. Pharmacodynamics" and "Special precautions" regarding susceptibility testing);
• Skin and soft tissue infections (impetigo, folliculitis, erysipeloïd, furunculosis, infected wounds) (see sections "Pharmacological properties. Pharmacodynamics" and "Special precautions" regarding susceptibility testing);
• Acute and chronic odontogenic infections;
• Disseminated or localized mycobacterial infections caused by Mycobacterium avium or Mycobacterium intracellulare; localized infections caused by Mycobacterium chelonae, Mycobacterium fortuitum, or Mycobacterium kansasii;
• Eradication of H. pylori in patients with duodenal ulcer under conditions of suppressed hydrochloric acid secretion (clarithromycin activity against H. pylori at neutral pH is higher than at acidic pH).

Contraindications.

• Hypersensitivity to clarithromycin, other macrolides, or any component of the medicinal product;
• Congenital or acquired QT interval prolongation or history of ventricular cardiac arrhythmia, including torsades de pointes (see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions");
• Electrolyte imbalance (hypokalemia or hypomagnesemia due to the risk of QT interval prolongation);
• Severe hepatic impairment and concomitant renal impairment;
• Concomitant use with cisapride, pimozide, astemizole, or terfenadine (as this may lead to QT interval prolongation and development of cardiac arrhythmia, including ventricular tachycardia, ventricular fibrillation, and torsades de pointes);
• Concomitant use with ergot alkaloids (e.g., ergotamine, dihydroergotamine), as this may lead to ergot toxicity;
• Concomitant use with oral midazolam (see section "Interaction with other medicinal products and other forms of interaction");
• Concomitant use with HMG-CoA reductase inhibitors (statins) that are predominantly metabolized by CYP3A4 (lovastatin or simvastatin), as this may lead to myopathy, including rhabdomyolysis (see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions");
• Concomitant use (as with other potent CYP3A4 inhibitors) with colchicine (see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions");
• Concomitant use with ticagrelor, ivabradine, or ranolazine;
• Concomitant use with lomitapide (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Clarithromycin does not interact with oral contraceptives.

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

Cisapride, pimozide, astemizole, terfenadine

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

Macrolides have been reported to alter terfenadine metabolism, leading to increased terfenadine plasma levels, which have sometimes been associated with arrhythmias such as QT interval prolongation, ventricular tachycardia, ventricular fibrillation, and torsades de pointes (see section "Contraindications"). In a study involving 14 volunteers, concomitant administration of clarithromycin and terfenadine resulted in a 2–3-fold increase in the plasma level of terfenadine's acid metabolite and QT interval prolongation, although no clinically apparent effect was observed. Similar effects have been noted with concomitant use of astemizole and other macrolides.

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

Ergot alkaloids

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

Oral midazolam

When midazolam is administered with clarithromycin tablets (500 mg twice daily), the area under the plasma concentration-time curve (AUC) of midazolam 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, and concomitant use with clarithromycin increases their plasma concentration, thereby increasing the risk of myopathy, including rhabdomyolysis. Cases of rhabdomyolysis have been reported in patients receiving clarithromycin and these statins concomitantly. 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 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. Patients should be monitored for signs and symptoms of myopathy.

Lomitapide

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

Effect of other medicinal products on clarithromycin

Observational data suggest that concomitant use of azithromycin and hydroxychloroquine in patients with rheumatoid arthritis is associated with an increased risk of cardiovascular disease and cardiovascular mortality. Due to the potential for similar risk with other macrolides in combination with hydroxychloroquine or chloroquine, the benefit-risk ratio should be carefully weighed before prescribing clarithromycin to patients taking hydroxychloroquine or chloroquine.

Medicinal products that are CYP3A inducers (e.g., rifampicin, phenytoin, carbamazepine, phenobarbital, St. John's wort) may induce clarithromycin metabolism. This may lead to subtherapeutic clarithromycin levels and reduced efficacy. Additionally, monitoring of plasma levels of the CYP3A inducer may be necessary, as they may be increased due to CYP3A inhibition by clarithromycin (see also the package leaflet of the respective CYP3A4 inducer). Concomitant use of rifabutin and clarithromycin has led to increased rifabutin levels and decreased clarithromycin levels in plasma, with a concomitant increased risk of uveitis.

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

Hydroxychloroquine and chloroquine

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

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 diminished 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, alternative agents to clarithromycin should be considered for the treatment of MAC.

Fluconazole

Concomitant administration of fluconazole 200 mg daily and clarithromycin 500 mg twice daily in 21 healthy volunteers resulted in a 33% increase in the steady-state minimum concentration (Cmin) of clarithromycin and an 18% increase in AUC. Steady-state concentrations of the active metabolite 14-OH-clarithromycin were not significantly altered with concomitant fluconazole use. Dose adjustment of clarithromycin is not required.

Ritonavir

A pharmacokinetic study showed that concomitant administration of ritonavir 200 mg every 8 hours and clarithromycin 500 mg every 12 hours resulted in significant inhibition of clarithromycin metabolism. The maximum concentration (Cmax) of clarithromycin increased by 31%, Cmin by 182%, and AUC by 77% with concomitant ritonavir use. Complete inhibition of 14-OH-clarithromycin formation was observed. Due to the wide therapeutic range, dose reduction of clarithromycin is not necessary for patients with normal renal function. However, dose adjustment is required for patients with renal impairment: for patients with CLCR 30–60 mL/min, the clarithromycin dose should be reduced by 50%; for patients with CLCR < 30 mL/min, the clarithromycin dose should be reduced by 75%. Clarithromycin doses exceeding 1 g daily should not be used concomitantly with ritonavir.

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

Effect of clarithromycin on other medicinal products

Antiarrhythmics

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

Post-marketing use has reported hypoglycemia with concomitant use of clarithromycin and disopyramide; therefore, glucose monitoring is necessary with concomitant use of these medicinal products.

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, and medicinal products primarily metabolized by CYP3A, may lead to increased plasma concentrations of the latter, thereby enhancing or prolonging their therapeutic effect and adverse reactions. Clarithromycin should be used with caution in patients receiving CYP3A substrate agents, especially if the CYP3A substrate has a narrow therapeutic range (e.g., carbamazepine) and/or is extensively metabolized by this enzyme. Dose adjustment and, if possible, careful monitoring of plasma concentrations of the medicinal product primarily metabolized by CYP3A may be required for patients receiving clarithromycin concomitantly.

It is known (or suspected) that the following medicinal products or groups of products are metabolized by the same CYP3A isoenzyme: alprazolam, astemizole, carbamazepine, cilostazol, cisapride, cyclosporine, disopyramide, ergot alkaloids, lovastatin, methylprednisolone, midazolam, omeprazole, oral anticoagulants (e.g., warfarin, rivaroxaban, apixaban), atypical antipsychotics (e.g., quetiapine), pimozide, quinidine, rifabutin, sildenafil, simvastatin, tacrolimus, terfenadine, triazolam, and vinblastine, but this list is not exhaustive. A similar interaction mechanism has been observed with phenytoin, theophylline, and valproate, which are metabolized by other isoenzymes of the cytochrome P450 system.

Omeprazole

Clarithromycin (500 mg every 8 hours) was administered in combination with omeprazole (40 mg daily) to healthy adult volunteers. Steady-state omeprazole plasma concentration increased (Cmax, AUC0-24, elimination half-life increased by 30%, 89%, and 34%, respectively) with concomitant clarithromycin use. With omeprazole alone, the mean gastric juice pH measured over 24 hours was 5.2; with concomitant omeprazole and clarithromycin, it was 5.7.

Sildenafil, tadalafil, and vardenafil

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

Theophylline, carbamazepine

Clinical study results showed a slight but statistically significant (p ≤ 0.05) increase in theophylline or carbamazepine plasma concentration when used concomitantly with clarithromycin.

Tolterodine

Tolterodine is primarily metabolized by the cytochrome P450 2D6 isoenzyme (CYP2D6). However, in patients lacking CYP2D6, metabolism occurs via CYP3A. In this group, CYP3A inhibition leads to a significant increase in tolterodine plasma concentrations. Dose reduction of tolterodine may be necessary in these patients when used concomitantly with CYP3A inhibitors such as clarithromycin.

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

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

Post-marketing reports exist of drug interaction and CNS adverse effects (drowsiness and confusion) with concomitant use of clarithromycin and triazolam. Patients should be monitored, considering the potential for increased CNS pharmacological effects.

Corticosteroids

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

Direct oral anticoagulants (DOACs)

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

Bidirectional interactions

Atazanavir

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

Calcium channel blockers

Due to the risk of arterial hypotension, clarithromycin should be used with caution concomitantly with calcium channel blockers metabolized by CYP3A4 (such as verapamil, amlodipine, diltiazem). Interaction may increase plasma concentrations of both clarithromycin and calcium channel blockers. In patients receiving clarithromycin and verapamil concomitantly, arterial hypotension, bradyarrhythmia, and lactic acidosis have been observed.

Itraconazole

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

Saquinavir

Concomitant use of clarithromycin (500 mg twice daily) and saquinavir (soft gelatin capsules, 1200 mg three times daily), both substrates and inhibitors of CYP3A, in 12 healthy volunteers resulted in a 177% and 187% increase in steady-state AUC and Cmax of saquinavir, respectively, compared to those observed with saquinavir alone. Meanwhile, AUC and Cmax of clarithromycin increased by approximately 40% compared to clarithromycin alone. No dose adjustment is necessary if both medicinal products are used concomitantly for a limited period at the studied doses/forms. The results of the drug interaction study using soft gelatin capsules may not correspond to effects observed with 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. When saquinavir is used with ritonavir, possible effects of ritonavir on clarithromycin should be considered (see above).

Other forms of interaction

Colchicine

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

Digoxin

Digoxin is considered a substrate of the efflux transporter P-gp. Clarithromycin is known to inhibit P-gp. Concomitant use of clarithromycin and digoxin may lead to increased digoxin exposure due to P-gp inhibition by clarithromycin. Post-marketing reports have documented increased digoxin plasma concentrations in patients using clarithromycin with digoxin. In some patients, signs of digoxin toxicity, including potentially fatal arrhythmia, developed. Digoxin plasma concentrations should be closely monitored in patients using it concomitantly with clarithromycin.

Zidovudine

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

Phenytoin and valproate

Spontaneous or published reports exist of interaction between CYP3A inhibitors, including clarithromycin, and medicinal products not considered to be metabolized by CYP3A (e.g., phenytoin and valproate). Plasma level determination of these medicinal products is recommended when used concomitantly with clarithromycin. Increased plasma levels have been reported.

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.

The medicinal product should not be administered to pregnant women without careful assessment of the benefit-risk ratio, especially during the first trimester of pregnancy.

Prolonged use of clarithromycin, as with other antibacterial agents, may result in overgrowth of non-susceptible microorganisms, including fungi. If superinfection occurs, appropriate therapy should be initiated.

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

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

Hepatobiliary disorders risk

During clarithromycin use, hepatic function abnormalities have been reported, including elevated liver enzymes, and hepatocellular and/or cholestatic hepatitis, with or without jaundice. These hepatic abnormalities may be severe in nature but are usually reversible. In some cases, fatal hepatic failure has been reported, primarily associated with serious underlying diseases and/or concomitant medications. The medicinal product should be discontinued immediately and medical advice sought if signs and symptoms of hepatitis occur, such as anorexia, jaundice, dark urine, pruritus, or abdominal tenderness.

Clostridium difficile–associated disorders risk (C. difficile)

Pseudomembranous colitis, ranging from mild to life-threatening severity, has been reported with the use of nearly all antibacterial agents, including macrolides. Clostridium difficile-associated diarrhea (CDAD), ranging from mild to fatal colitis, has also been reported with the use of nearly all antibacterial agents, including clarithromycin. Antibacterial therapy may alter the normal gut flora, leading to overgrowth of C. difficile. Clostridium difficile-associated diarrhea should always be considered in any patient presenting with diarrhea following antibacterial use. A careful medical history is necessary, as CDAD has been reported to occur up to two months after administration of antibacterial agents. If pseudomembranous colitis develops, the medicinal product 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.

QT interval prolongation risk

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

• Patients with ischemic heart disease, severe heart failure, conduction disorders, or clinically significant bradycardia.
• Patients concurrently taking other 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 hypokalemia or hypomagnesemia (see section "Contraindications").
• 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 with a history of ventricular arrhythmias (see section "Contraindications").
• The benefit-risk ratio should be carefully evaluated before prescribing clarithromycin to patients taking hydroxychloroquine or chloroquine, due to the potential for increased risk of cardiovascular disorders or cardiovascular mortality (see section "Interaction with other medicinal products and other forms of interaction").

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.

Hypersensitivity reactions risk

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

Use in pneumonia

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

Use in mild to moderate skin and soft tissue infections

These infections are most commonly caused by Staphylococcus aureus and Streptococcus pyogenes, both of which may be macrolide-resistant. Therefore, susceptibility testing is important. When beta-lactam antibiotics cannot be used (e.g., due to allergy), other antibiotics such as clindamycin may be considered as first-line agents. Macrolides have so far played a limited role in the treatment of certain skin and soft tissue infections (e.g., infections caused by Corynebacterium minutissimum, acne vulgaris, erysipelas) and in situations where penicillins cannot be used.

Interaction with colchicine

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

Interaction with triazolobenzodiazepines

The medicinal product should be used with caution when administered concomitantly with triazolobenzodiazepines such as triazolam, intravenous or oromucosal midazolam (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with HMG-CoA reductase inhibitors (statins)

Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated (see section "Contraindications"). The medicinal product should be used with caution when co-administered with other statins. Cases of rhabdomyolysis have been reported in patients receiving clarithromycin and statins concurrently. Patients should be monitored for signs and symptoms of myopathy. When concomitant use of clarithromycin with statins cannot be avoided, it is recommended to prescribe the lowest recommended dose of the statin. Use of a statin not metabolized by CYP3A, such as fluvastatin, may be considered (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with oral hypoglycemic agents/insulin

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

Interaction with oral anticoagulants

When clarithromycin is used concomitantly with warfarin, there is a risk of serious bleeding, significant increase in the international normalized ratio (INR), and prothrombin time. Frequent monitoring of INR and prothrombin time is required while patients are receiving both clarithromycin and oral anticoagulants.

The medicinal product should be used with caution in patients receiving 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").

Excipients

The medicinal product contains Sunset Yellow FCF aluminum lake (E 110), which may cause allergic reactions.

Use during pregnancy or breastfeeding

Pregnancy

The safety of clarithromycin use during pregnancy and breastfeeding has not been established. Based on data from animal and human studies, the possibility of harmful effects on embryonic and fetal development cannot be excluded. Some observational studies assessing the impact of clarithromycin during the first and second trimesters of pregnancy have indicated an increased risk of miscarriage compared to no treatment or use of other antibiotics during the same period. Available epidemiological studies on the risk of major congenital malformations associated with macrolide use, including clarithromycin, during pregnancy have shown conflicting results.

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

Breastfeeding period

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

The safety of clarithromycin use during breastfeeding has not been established.

Ability to affect reaction speed when driving or operating machinery

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

Dosage and Administration

The medicinal product is intended for oral administration. Tablets can be taken independently of food intake.

Adults and children aged 12 years and older

The recommended dose of the medicinal product is 250 mg every 12 hours. In more severe infections, the dose may be increased to 500 mg every 12 hours. The usual duration of treatment depends on the severity of infection and ranges from 6 to 14 days.

Odontogenic infections

The recommended dose of the medicinal product is 250 mg every 12 hours for 5 days.

Mycobacterial infection (adults)

The initial dose is 500 mg twice daily. If there is no improvement in clinical or bacteriological parameters 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 medicinal product is maintained. The medicinal product may be used in combination with other antimycobacterial agents.

Eradication of H. pylori (adults)

Triple therapy (7–10 days)

Clarithromycin 500 mg twice daily + amoxicillin 1000 mg twice daily + omeprazole 20 mg daily. Treatment duration: 7–10 days.

Triple therapy (10 days)

Clarithromycin 500 mg twice daily + amoxicillin 1000 mg twice daily + lansoprazole 30 mg twice daily. Treatment duration: 10 days.

Dual therapy (14 days)

Clarithromycin 500 mg three times daily + omeprazole 40 mg once daily. Treatment duration: 14 days. Continue omeprazole 20 mg or 40 mg once daily for the following 14 days.

Dual therapy (14 days)

Clarithromycin 500 mg three times daily + lansoprazole 60 mg once daily. Treatment duration: 14 days.

Further suppression of gastric acid secretion may be required to reduce ulcer symptoms.

Clarithromycin has also been used in the following therapeutic regimens:

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

Patients with renal impairment

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

Elderly patients

Dosage adjustment is not required in this patient group.

Children

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

Overdose

Symptoms

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

Treatment

Adverse reactions associated with overdose should be managed by gastric lavage and symptomatic therapy. As with other macrolides, hemodialysis or peritoneal dialysis are unlikely to significantly affect clarithromycin plasma 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 altered taste. These adverse reactions are usually mild in intensity and consistent with the known safety profile of macrolide antibiotics. During clinical trials, no significant difference was observed in the frequency of these gastrointestinal adverse reactions between patient groups with or without mycobacterial infections.

Below are adverse reactions reported during clinical studies and post-marketing use of various dosage forms and strengths of clarithromycin, including immediate-release tablets. The adverse reactions considered at least possibly related to clarithromycin are listed by system organ class and frequency of occurrence: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), frequency not known (reactions reported during post-marketing surveillance for which frequency cannot be estimated from available data*). Within each group, adverse reactions are listed in descending order of severity when severity could be assessed.

Infections and infestations:

Uncommon – cellulitis¹, candidiasis, gastroenteritis², infection³, vaginal infection; frequency not known – pseudomembranous colitis, Behçet's inflammation.

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.

Metabolism and nutrition disorders:

Uncommon – anorexia, decreased appetite; frequency not known – hypoglycemia.

Psychiatric disorders:

Common – insomnia; uncommon – anxiety, nervousness³; frequency not known – psychosis, confusion, depersonalization, depression, disorientation, hallucinations, nightmares, mania.

Nervous system disorders:

Common – dysgeusia (disturbance of taste sensation), headache; uncommon – loss of consciousness¹, dyskinesia¹, dizziness, somnolence, tremor; frequency not known – seizures, ageusia (loss of taste sensation), parosmia, anosmia, paresthesia.

Ear and labyrinth disorders:

Uncommon – vertigo, hearing impairment, tinnitus; frequency not known – hearing loss.

Cardiac disorders:

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

Vascular disorders:

Common – vasodilation¹; frequency not known – hemorrhage.

Respiratory, thoracic and mediastinal disorders:

Uncommon – asthma¹, epistaxis², pulmonary embolism¹.

Gastrointestinal disorders:

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

Hepatobiliary disorders:

Common – abnormal liver function tests; uncommon – cholestasis⁴, hepatitis⁴, increased levels of ALT, AST, GGT⁴; frequency not known – hepatic failure, hepatocellular jaundice.

Skin and subcutaneous tissue disorders:

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

Musculoskeletal and connective tissue disorders:

Uncommon – muscle spasms³, skeletal muscle rigidity¹, myalgia²; frequency not known – rhabdomyolysis^2**, myopathy.

Renal and urinary disorders:

Uncommon – increased plasma creatinine¹, increased plasma urea¹; frequency not known – renal failure, interstitial nephritis.

General disorders and administration site conditions:

Very common – phlebitis at injection site¹; common – pain at injection site¹, inflammation at injection site¹; uncommon – malaise⁴, fever³, asthenia, chest pain⁴, chills⁴, fatigue⁴.

Investigations:

Uncommon – altered albumin-globulin ratio¹, increased plasma alkaline phosphatase⁴, increased plasma lactate dehydrogenase⁴; frequency not known – increased INR, prolonged prothrombin time, change in urine color.

* Since these reactions have been reported voluntarily and the number of patients is unknown, it is not always possible to reliably estimate their frequency or establish a causal relationship to clarithromycin use. The overall clinical experience with clarithromycin exceeds 1 billion patient-days.

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

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

Children

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

Patients with Immune System Disorders

In patients with AIDS and other patients with impaired immune systems who received high doses of clarithromycin for prolonged periods to treat mycobacterial infections, it may be difficult to distinguish adverse reactions associated with clarithromycin from symptoms of the underlying or concomitant diseases.

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

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives are encouraged to report all 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 25 °C, protected from light and kept out of reach of children.

Packaging.

Tablets, film-coated, 250 mg:

7 or 14 tablets in a blister; 2 blisters of 7 tablets or 1 blister of 14 tablets in a cardboard box.

Tablets, film-coated, 500 mg:

7 tablets in a blister; 2 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

UORLД MEDICINE ILAC SAN. VE TIC. A.S. /
WORLD MEDICINE ILAC SAN. VE TIC. A.S.

Manufacturer's address and location of operations.

15 Temmuz Mahallesi Cami Yolu Caddesi No:50 Gunesli Bagcilar/Istanbul, Turkey.

Marketing Authorization Holder.

WORLD MEDICINE, LLC, Ukraine.