Oradro

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

Composition:

Active substance: clarithromycin;

1 vial contains clarithromycin 500 mg;

Excipients: lactobionic acid, sodium hydroxide.

Solvent:

1 ampoule (10 ml) of solvent contains water for injections (10 ml).

Pharmaceutical form. Lyophilisate for solution for infusion.

Main physicochemical characteristics:

Lyophilisate – lyophilized powder of white or almost white color.

Solvent – colorless clear solution.

Finished (reconstituted) solution – slightly opalescent colorless solution.

Pharmacotherapeutic group.

Antibacterials for systemic use. Macrolides. Clarithromycin.

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 biosynthesis. It 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 generally two times lower than those of erythromycin.

Clarithromycin is highly effective in vitro against Legionella pneumophila and Mycoplasma pneumoniae. It exerts bactericidal activity against Helicobacter pylori (H. pylori); the activity of clarithromycin at neutral pH is higher than at acidic pH. In vitro and in vivo data indicate high efficacy of clarithromycin against clinically significant strains of mycobacteria. In vitro studies have shown that strains of Enterobacteriaceae and Pseudomonas, as well as non-lactose-producing gram-negative bacteria, are not susceptible to clarithromycin.

Clarithromycin is active in vitro and in clinical practice against most strains of the following microorganisms

Aerobic gram-positive microorganisms: Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Listeria monocytogenes.

Aerobic gram-negative microorganisms: Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, Neisseria gonorrhoeae, Legionella pneumophila.

Other microorganisms: Mycoplasma pneumoniae, Chlamydia pneumoniae (TWAR).

Mycobacteria: Mycobacterium leprae, Mycobacterium kansasii, Mycobacterium chelonae, Mycobacterium fortuitum, Mycobacterium avium complex (MAC), which includes Mycobacterium avium, Mycobacterium intracellulare.

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

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

Helicobacter: H. pylori.

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

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

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

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

Anaerobic gram-negative microorganisms: Bacteroides melaninogenicus.

Spirochetes: Borrelia burgdorferi, Treponema pallidum.

Campylobacters: Campylobacter jejuni.

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

The primary 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 inhibition zone diameter provide the most 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 interpreted in relation to the 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" suggests 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 regarding absolute breakpoints for susceptibility, resistance, and intermediate susceptibility should be taken into account.

Pharmacokinetics.

Distribution, Biotransformation, and Elimination

Healthy Volunteers

Maximum concentration (Cmax) of clarithromycin ranges from 5.16 μg/mL to 9.40 μg/mL after infusion of 500 mg and 1000 mg of clarithromycin over 1 hour, respectively. Cmax of 14-OH-clarithromycin ranges from 0.66 μg/mL after infusion of 500 mg to 1.06 μg/mL after administration of 1000 mg of clarithromycin over 1 hour. The terminal elimination half-life (t1/2) of clarithromycin from plasma depends on the dose and ranges from 3.8 hours to 4.5 hours after administration of 500 mg and 1000 mg doses over 1 hour, respectively. The t1/2 of 14-OH-clarithromycin in plasma shows moderate dose-dependent increase with increasing doses, ranging from 7.3 hours to 9.3 hours after administration of 500 mg and 1000 mg doses over 1 hour, respectively. The area under the concentration-time curve (AUC) values for clarithromycin increased disproportionately with dose, demonstrating nonlinear AUC dependence, ranging from 22.29 h•μg/mL to 53.26 h•μg/mL after administration of 500 mg and 1000 mg doses over 1 hour, respectively. AUC values for 14-OH-clarithromycin ranged from 8.16 h•μg/mL to 14.76 h•μg/mL after administration of 500 mg and 1000 mg doses over 1 hour, respectively.

With repeated dosing (at 12-hour intervals), steady-state Cmax of clarithromycin increases from 5.5 μg/mL after infusion of 500 mg to 8.6 μg/mL after infusion of 750 mg. Apparent terminal t1/2 is 5.3 hours and 4.8 hours after infusion of 500 mg and 750 mg doses over 1 hour, respectively. Steady-state Cmax of 14-OH-clarithromycin increases from 1.02 μg/mL after infusion of 500 mg to 1.37 μg/mL after infusion of 750 mg. Terminal t1/2 of this metabolite is 7.9 hours and 5.4 hours after infusion of 500 mg and 750 mg doses, respectively. No dose dependency was observed.

Patients

Clarithromycin and its main active 14-OH-metabolite are well distributed into all tissues and body fluids. Tissue concentrations are generally several times higher than plasma concentrations. The highest concentrations are recorded in the liver and lungs. Examples of tissue and plasma concentrations are provided below.

Clinical characteristics.

Indications.

Treatment of infections caused by microorganisms sensitive to clarithromycin, when parenteral therapy is required:

• infections of the upper respiratory tract;
• infections of the lower respiratory tract (see sections "Pharmacodynamics" and "Special precautions" regarding susceptibility testing);
• skin and soft tissue infections (see sections "Pharmacodynamics" and "Special precautions" regarding susceptibility testing);
• disseminated or localized mycobacterial infections caused by Mycobacterium avium or Mycobacterium intracellulare, localized infections caused by Mycobacterium chelonae, Mycobacterium fortuitum or Mycobacterium kansasii, particularly in HIV-infected patients.

Contraindications.

• Hypersensitivity to clarithromycin, other macrolides and/or to excipients of the medicinal product;
• congenital or documented acquired QT interval prolongation or ventricular cardiac arrhythmias in medical history, including torsades de pointes (see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions");
• electrolyte disturbances (hypokalemia or hypomagnesemia, due to the risk of QT interval prolongation);
• severe hepatic impairment and concomitant renal impairment;
• concomitant use with cisapride, pimozide, astemizole, terfenadine and/or domperidone (as this may lead to QT interval prolongation and development of cardiac arrhythmias, 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.

Contraindicated combinations

Cisapride, pimozide, astemizole, terfenadine, domperidone

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

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

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

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 (see section "Contraindications").

Oral midazolam

When midazolam was administered with clarithromycin tablets (500 mg twice daily), the AUC of midazolam increased 7-fold after oral administration of midazolam (see section "Contraindications").

HMG-CoA reductase inhibitors (statins)

Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated, 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.

Caution should be exercised when using clarithromycin concomitantly with other statins. When concomitant use of clarithromycin with statins cannot be avoided, it is recommended to prescribe the lowest registered dose of the statin. It may be possible to use a statin not dependent on CYP3A metabolism (e.g., fluvastatin). Patients should be monitored for signs and symptoms of myopathy.

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 (see sections "Contraindications" and "Special precautions").

Lomitapide

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

Effect of other medicinal products on clarithromycin

Medicinal products that are CYP3A inducers (e.g., rifampicin, phenytoin, carbamazepine, phenobarbital, St. John's wort) may induce the metabolism of clarithromycin. This may lead to subtherapeutic levels of clarithromycin and reduced efficacy. Additionally, monitoring of plasma levels of the CYP3A inducer may be necessary, as they may be increased due to CYP3A inhibition by clarithromycin (see also the prescribing information for 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 concentrations, and therefore 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 risk of cardiac arrhythmias 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 the metabolism of clarithromycin, 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 activity of clarithromycin was reduced by etravirine, while the concentration of the active metabolite 14-OH-clarithromycin 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. Dose adjustment of clarithromycin is not required.

Ritonavir

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

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. Close monitoring of glucose levels is recommended.

CYP3A-related interactions

Concomitant use of clarithromycin, a known CYP3A enzyme inhibitor, with medicinal products primarily metabolized by CYP3A, may lead to increased plasma concentrations of the latter, thereby enhancing or prolonging their therapeutic and adverse effects. Clarithromycin should be used with caution in patients receiving CYP3A substrate medicinal products, 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.

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 is observed with phenytoin, theophylline and valproate, which are metabolized by other cytochrome P450 isoenzymes.

Corticosteroids

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

Direct oral anticoagulants (DOACs)

DOACs dabigatran and edoxaban are substrates of the efflux transporter P-gp. Rivaroxaban and apixaban are metabolized via CYP3A4 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").

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, t1/2 increased by 30%, 89%, and 34%, respectively). When omeprazole was administered alone, the mean gastric 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 have shown a slight but statistically significant (p≤0.05) increase in plasma concentrations of theophylline or carbamazepine when used concomitantly with clarithromycin.

Tolterodine

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

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

When midazolam 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, close patient monitoring is required for timely dose adjustment. With oromucosal administration of midazolam, 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 have documented drug interactions and adverse reactions of the central nervous system (CNS), such as somnolence and confusion, with concomitant use of clarithromycin and triazolam. Patients should be monitored, considering the potential increase in pharmacological effects on the CNS.

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 index, dose reduction is not necessary for patients with normal renal function. The clarithromycin dose should be reduced by 50% for patients with creatinine clearance of 30–60 mL/min and by 75% for patients with creatinine clearance <30 mL/min, using the appropriate formulation of clarithromycin. 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). The interaction may increase plasma concentrations of both clarithromycin and calcium channel blockers. Arterial hypotension, bradyarrhythmia and lactic acidosis have been observed in patients receiving clarithromycin and verapamil concomitantly.

itraconazole

Clarithromycin and itraconazole are substrates and inhibitors of CYP3A; therefore, clarithromycin may increase plasma levels of itraconazole 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 administration of clarithromycin (500 mg twice daily) and saquinavir (soft gelatin capsules, 1200 mg three times daily), both substrates and inhibitors of CYP3A, in 12 healthy volunteers resulted in a 177% and 187% increase in the steady-state AUC and Cmax of saquinavir, respectively, compared to 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/formulations. The results of the drug interaction study using soft gelatin capsules may not reflect the effects observed with hard gelatin capsules of saquinavir. The results of the drug interaction study using saquinavir alone may not reflect the 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

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. Post-marketing surveillance has reported increased plasma digoxin concentrations in patients receiving clarithromycin with digoxin. In some patients, signs of digitalis toxicity, including potentially fatal arrhythmias, have developed. Plasma digoxin concentrations should be closely monitored in patients receiving concomitant clarithromycin and digoxin.

Zidovudine

Concomitant oral administration of clarithromycin tablets and zidovudine in HIV-infected adult patients may lead to decreased steady-state plasma concentrations of zidovudine. Since clarithromycin may interfere with the absorption of oral zidovudine when administered concomitantly, this can largely be avoided by maintaining a 4-hour interval between doses of clarithromycin and zidovudine. Such interaction has not been reported with 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 have documented interactions between CYP3A inhibitors, including clarithromycin, and medicinal products not considered to be metabolized by CYP3A (e.g., phenytoin and valproate). Plasma levels of these medicinal products should be determined when used concomitantly with clarithromycin. Increased plasma levels have been reported.

Oral contraceptives

Patients taking oral contraceptives should be advised that contraceptive failure may occur in case of diarrhea, vomiting or breakthrough bleeding.

Special precautions for use.

The medicinal product should not be used during pregnancy 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 lead to overgrowth of non-susceptible bacteria and fungi. If superinfection develops, appropriate therapy should be initiated.

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

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

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

Risk of hepatobiliary disorders

Hepatic function abnormalities, including elevated liver enzymes, and hepatocellular and/or cholestatic hepatitis, with or without jaundice, have been reported during clarithromycin use. 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 medication. The medicinal product should be discontinued immediately and medical advice sought if signs and symptoms of hepatitis such as anorexia, jaundice, dark urine, pruritus, or abdominal tenderness occur.

Risk of Clostridium difficile (C. difficile)-associated disorders

Pseudomembranous colitis, ranging from moderate to life-threatening severity, has been reported with nearly all antibacterial agents, including macrolides. Clostridium difficile-associated diarrhea (CDAD), ranging from mild to severe colitis with fatal outcomes, has also been reported with nearly all antibacterial agents, including clarithromycin. Antibacterial therapy alters the normal gut flora, which may lead to overgrowth of C. difficile. CDAD should always be considered in any patient presenting with diarrhea following antibacterial use. A careful medical history is essential, as cases of CDAD have been reported up to two months after antibacterial administration. If pseudomembranous colitis occurs, 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 gut motility should be avoided.

QT interval prolongation risk

Prolongation of cardiac repolarization and QT interval, indicating a risk of developing cardiac arrhythmias including torsades de pointes, has been observed with macrolide therapy, including clarithromycin (see section "Adverse reactions"). Since the following conditions 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 with electrolyte imbalances such as hypomagnesemia;
• Patients receiving concomitant medicinal products associated with QT interval prolongation (see section "Interaction with other medicinal products and other forms of interaction").

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

The medicinal product must not be used in patients with hypokalemia (see section "Contraindications").

Concomitant use of the medicinal product with astemizole, cisapride, pimozide, terfenadine, and/or domperidone is contraindicated (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 small, 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

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, the medicinal product should be discontinued immediately and appropriate treatment initiated without delay.

Use in pneumonia

Due to increasing resistance of Streptococcus pneumoniae to macrolides, susceptibility testing is essential when prescribing clarithromycin for 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, each of which may be resistant to macrolides. Therefore, susceptibility testing is important. When beta-lactam antibiotics cannot be used (e.g., due to allergy), alternative agents such as clindamycin may be considered as first-line therapy. To date, macrolides have only a limited role in treating certain skin and soft tissue infections (e.g., those caused by Corynebacterium minutissimum, acne vulgaris, or 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 triazole benzodiazepines

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

Interaction with cytochrome CYP3A4 enzyme inducers

The medicinal product should be used with caution when administered concomitantly with cytochrome CYP3A4 enzyme inducers (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 administered concomitantly 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, the lowest registered dose of the statin should be prescribed. 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 sulfonylureas) and/or insulin may result in pronounced 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 prolonged prothrombin time. Frequent monitoring of INR and prothrombin time is required while patients are receiving both clarithromycin and oral anticoagulants.

Caution is advised when the medicinal product 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").

Precautions related to excipients

The medicinal product contains less than 1 mmol/23 mg of sodium per vial, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding.

Pregnancy

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

Breastfeeding period

Clarithromycin passes into human breast milk in small amounts. It has been estimated that an exclusively breastfed infant receives 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 influence the speed of reactions while driving or operating machinery.

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

Method of Administration and Dosage

Dosage

Adults

The usual dose of the medicinal product is 500 mg twice daily at 12-hour intervals, administered as a prolonged (60 minutes) intravenous infusion after dilution of the drug in the appropriate infusion solution.

Children aged 12 years and older

The dosage for children aged 12 years and older is the same as that for adults.

The medicinal product must not be administered by bolus injection or intramuscular route.

Administration to patients with mycobacterial infection

For adult patients with localized or disseminated mycobacterial infections caused by M. avium, M. intracellulare, M. chelonae, M. fortuitum, or M. kansasii, the recommended dose of clarithromycin is 1 g per day, divided into two equal doses.

Treatment should be continued for 2–5 days depending on the severity of the patient's condition, after which, if possible, transition to oral administration of the medicinal product should be made.

Administration to patients with renal impairment

In patients with renal impairment (creatinine clearance less than 30 mL/min), the dose of clarithromycin should be reduced to half the usual recommended dose.

Method of Administration

The medicinal product is intended for intravenous administration.

Preparation of the infusion solution

1. Prepare the initial solution by adding 10 mL of sterile water for injection to a vial containing 500 mg of clarithromycin. Only sterile water for injection should be used, as other solvents may cause precipitation. Solvents containing preservatives or inorganic salts must not be used.

Note: When diluted as described above, the solution contains an effective antimicrobial preservative; 1 mL of solution contains 50 mg of clarithromycin.

Chemical and physical stability is maintained for 48 hours at 5 °C and for 24 hours at 25 °C. From a microbiological standpoint, the diluted product should be used immediately. If not used immediately, storage under aseptic conditions is required, usually no longer than 24 hours at a temperature of 2 to 8 °C, except when dilution has been performed under controlled and validated aseptic conditions (the responsibility for storage time and conditions lies with the user).

2. Prior to administration, the initial solution (500 mg in 10 mL of water for injection) should be further diluted in at least 250 mL of one of the following diluents: 5% dextrose in lactated Ringer’s solution, 5% dextrose solution, lactated Ringer’s solution, 5% dextrose in 0.3% sodium chloride solution, Normosol-M in 5% dextrose, Normosol-R in 5% dextrose, 5% dextrose in 0.45% sodium chloride solution, or 0.9% sodium chloride solution.

Chemical and physical stability is maintained for 48 hours at 5 °C and for 6 hours at 25 °C. From a microbiological standpoint, the prepared solution should be used immediately. If not used immediately, storage under aseptic conditions is required, usually no longer than 24 hours at a temperature of 2 to 8 °C, except when dilution has been performed under controlled and validated aseptic conditions (the responsibility for storage time and conditions lies with the user).

No medicinal products or reagents should be added to the infusion solution until their impact on the chemical and physical stability of the antibiotic solution has been established.

Children

There is insufficient data on dosage regimens for intravenous administration of clarithromycin in children under 12 years of age; therefore, the use of this medicinal product in this age group is not recommended. For such patients, clarithromycin in the form of granules for oral suspension should be used instead.

The dosage for children aged 12 years and older is the same as that for adults.

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

In case of overdose, administration of the medicinal product should be discontinued and appropriate treatment initiated. Adverse reactions associated with overdose should be managed with elimination procedures and symptomatic therapy. As with other macrolides, hemodialysis or peritoneal dialysis are unlikely to significantly affect plasma levels of clarithromycin.

Adverse Reactions

The most common and frequent adverse reactions associated with clarithromycin treatment in adults and children are abdominal pain, diarrhea, nausea, vomiting, and taste disturbances. These adverse reactions are usually mild and consistent with the known safety profile of macrolide antibiotics. During clinical studies, no significant difference was observed in the frequency of these gastrointestinal adverse reactions between patient groups with or without mycobacterial infections.

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

Infections and infestations:

Uncommon – cellulitis\textsuperscript{1}, candidiasis, gastroenteritis\textsuperscript{2}, infection\textsuperscript{3}, vaginal infection; frequency not known – pseudomembranous colitis, botulism.

Blood and lymphatic system disorders:

Uncommon – leukopenia, neutropenia\textsuperscript{4}, thrombocytosis\textsuperscript{3}, eosinophilia\textsuperscript{4}; frequency not known – agranulocytosis, thrombocytopenia.

Immune system disorders:

Uncommon – anaphylactoid reactions\textsuperscript{1}, 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, nervousness\textsuperscript{3}; frequency not known – psychosis, confusion, depersonalization, 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 – 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 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 – hemorrhage.

Respiratory, thoracic and mediastinal disorders:

Uncommon – asthma\textsuperscript{1}, epistaxis\textsuperscript{2}, pulmonary embolism\textsuperscript{1}.

Gastrointestinal disorders:

Common – diarrhea, vomiting, dyspepsia, nausea, abdominal pain; uncommon – esophagitis\textsuperscript{1}, gastroesophageal 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 – liver 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 generalized exanthematous pustulosis, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS)), acne, Schönlein-Henoch purpura.

Musculoskeletal and connective tissue disorders:

Uncommon – muscle spasms\textsuperscript{3}, skeletal muscle rigidity\textsuperscript{1}, myalgia\textsuperscript{2}; frequency not known – rhabdomyolysis\textsuperscript{**}, myopathy.

Renal and urinary disorders:

Uncommon – increased plasma creatinine\textsuperscript{1}, increased plasma 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 – altered albumin-globulin ratio\textsuperscript{1}, increased plasma alkaline phosphatase\textsuperscript{4}, increased plasma lactate dehydrogenase\textsuperscript{4}; frequency not known – increased INR, prolonged prothrombin time, urine discoloration.

* Since these reactions were 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 experience with clarithromycin use exceeds 1 billion patient-days.

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

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

Children

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 to treat mycobacterial infections, it may not always be possible 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 common adverse reactions were nausea, vomiting, taste disturbances, abdominal pain, diarrhea, rash, abdominal distension, headache, constipation, hearing disturbances, 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 those values that fell outside the significant abnormal range (i.e., the extreme upper or lower limit) for a given test. By this criterion, significant abnormal elevations in plasma ALT and AST levels and abnormal decreases in white blood cell and platelet counts were observed in 2–3% of these patients receiving 1000 mg of clarithromycin daily. A smaller percentage of patients showed elevated blood urea nitrogen levels.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after a medicinal product is authorized is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions via the national pharmacovigilance system.

Shelf life

3 years.

Storage conditions

Store at temperatures not exceeding 25 °C in the original packaging and out of reach of children.

Incompatibilities

For preparation of the initial solution, use only sterile water for injection, as other solvents may cause precipitate formation.

Do not use solvents containing preservatives or inorganic salts.

No medicinal products or reagents should be added to the infusion solution until their impact on the chemical and physical stability of the antibiotic solution has been determined.

Packaging

500 mg in a vial with 10 ml diluent (water for injection) in an ampoule; 1 vial of lyophilized powder for infusion solution and 1 ampoule of diluent in a cardboard box.

Prescription status

Prescription only.

Manufacturer

Mefar Ilac San. A.S.
Mefar Ilac San. A.S.

Manufacturer's address and place of business

Ramazanoglu Mah. Ensar Cad. No: 20, 34906 Kurtkoy – Pendik/Istanbul, Turkey
Ramazanoglu Mah. Ensar Cad. No: 20, 34906 Kurtkoy – Pendik/Istanbul, Turkey.

Marketing Authorization Holder

WORLD MEDICINE, LLC, Ukraine
WORLD MEDICINE, LLC, Ukraine.