Fromilid uno

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT Fromilid® uno (Fromilid® uno)

Composition:

Active substance: clarithromycin;

1 tablet contains 500 mg of clarithromycin;

Excipients: sodium alginate, calcium sodium alginate, lactose monohydrate, povidone, polysorbate 80, colloidal anhydrous silicon dioxide, magnesium stearate, talc, hypromellose, iron oxide yellow (E 172), titanium dioxide (E 171), propylene glycol.

Pharmaceutical form. Modified-release tablets.

Main physico-chemical properties: oval, biconvex, film-coated tablets, brownish-yellow in colour, with the letter "U" embossed on one side.

Pharmacotherapeutic group. Antibacterials for systemic use.

Macrolides, lincosamides and streptogramins. Clarithromycin. ATC code J01FA09.

Pharmacological Properties

Pharmacodynamics

Clarithromycin is a semi-synthetic antibiotic of the macrolide group. Its antibacterial activity is due to binding to the 5OS ribosomal subunit of susceptible bacteria and inhibition of protein biosynthesis. Modified-release tablets have a uniform crystalline base that ensures prolonged release of the active substance as it passes through the gastrointestinal tract.

The drug demonstrates high efficacy in vitro against a broad spectrum of aerobic and anaerobic Gram-positive and Gram-negative microorganisms, including hospital strains. Minimum inhibitory concentrations (MICs) of clarithromycin are usually twice lower than those of erythromycin.

Clarithromycin is highly effective in vitro against Legionella pneumophila and Mycoplasma pneumoniae. It has bactericidal activity against H. pylori; the activity of clarithromycin is higher at neutral pH than at acidic pH. Clarithromycin is effective against clinically significant strains of mycobacteria. In vitro studies have shown that strains of Enterobacteriaceae and Pseudomonas, as well as non-lactose fermenting Gram-negative bacteria, are resistant to clarithromycin.

Microbiology

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

Gram-positive bacteria: Staphylococcus aureus (methicillin-sensitive); Streptococcus pyogenes; Streptococcus pneumoniae; Streptococcus agalactiae; Listeria monocytogenes.

Gram-negative bacteria: Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, Neisseria gonorrhoeae; Legionella pneumophila, Bordetella pertussis, Helicobacter pylori; Campylobacter jejuni.

Mycoplasma: Mycoplasma pneumoniae; Ureaplasma urealyticum.

Other organisms: Chlamydia trachomatis; Mycobacterium avium; Mycobacterium leprae; Chlamydia pneumoniae.

Anaerobes: Macrolide-sensitive Bacteroides fragilis; Clostridium perfringens; Peptococcus species; Peptostreptococcus species; Propionibacterium acnes.

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

The main metabolite of clarithromycin in the human body is the microbiologically active 14-hydroxyclarithromycin. This metabolite is less active than the parent compound against most organisms, including Mycobacterium spp. An exception is Haemophilus influenzae, where the 14-hydroxy metabolite is twice as active as the parent compound.

Pharmacokinetics

The pharmacokinetics of prolonged-release clarithromycin tablets were compared with those of immediate-release tablets of 250 and 500 mg. The extent of absorption was equivalent when equivalent doses were administered. Absolute bioavailability is approximately 50%. With repeated administration, no accumulation occurs, and the pattern of metabolism in the human body does not change.

Healthy subjects

After oral administration of 500 mg once daily of modified-release clarithromycin tablets taken with food, steady-state maximum plasma concentrations (Cmax) of clarithromycin and 14-hydroxyclarithromycin were 1.3 and 0.48 mcg/mL, respectively. The elimination half-lives of the drug and its metabolite were 5.3 and 7.7 hours, respectively. After administration of 1000 mg of prolonged-release clarithromycin per day (2 tablets of 500 mg), steady-state maximum concentrations of clarithromycin and 14-hydroxyclarithromycin averaged 2.4 mcg/mL and 0.67 mcg/mL, respectively. The elimination half-lives of the drug and its main metabolite were 5.8 and 8.9 hours, respectively. Tmax was reached at 6 hours for both 500 mg and 1000 mg daily doses. Steady-state concentrations of clarithromycin and 14-hydroxyclarithromycin do not increase proportionally with dose, and the elimination half-lives of clarithromycin and its main metabolite increase with higher doses. The nonlinear pharmacokinetics of clarithromycin is associated with reduced formation of 14-hydroxylated and N-demethylated metabolites when higher doses are administered. Approximately 40% of the dose is excreted in urine and 30% via the intestine.

Patients

Clarithromycin and its metabolite are widely distributed in body tissues and fluids. After oral administration, the concentration of clarithromycin in cerebrospinal fluid remains low (1–2% of serum levels with a normal blood-brain barrier). Clarithromycin concentrations in tissues are usually several times higher than in serum.

Hepatic impairment

In patients with moderate to severe hepatic impairment but preserved renal function, dosage adjustment of clarithromycin is not required.

Renal impairment

In patients with impaired renal function, minimum and maximum plasma concentrations, elimination half-life, and area under the concentration-time curve (AUC) of clarithromycin and 14-hydroxyclarithromycin increase. Elimination constant and urinary excretion decrease. The extent of these changes depends on the degree of renal impairment—the more severe the impairment, the more pronounced the changes in parameters.

Elderly patients

In elderly patients, blood levels of clarithromycin and 14-hydroxyclarithromycin were higher and elimination was slower compared to younger individuals. Changes in pharmacokinetics in elderly patients are primarily related to impaired renal function rather than age itself.

Clinical characteristics.

Indications

For the treatment of infections caused by microorganisms sensitive to clarithromycin:

• Lower respiratory tract infections (bronchitis, pneumonia, etc.).
• Upper respiratory tract infections (sinusitis, pharyngitis, etc.).
• Skin and soft tissue infections (folliculitis, impetigo, etc.).

Clarithromycin is indicated for adults and children aged 12 years and older.

Attention should be paid to official recommendations regarding the appropriate use of antibacterial agents.

Contraindications

• Hypersensitivity to clarithromycin or to other macrolide antibiotics or to any component of the medicinal product.
• Concomitant use with the following drugs: astemizole, cisapride, domperidone, pimozide, terfenadine — as this may lead to QT interval prolongation and development of cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation, and torsades de pointes (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction").
• Congenital or 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 for use").
• Concomitant use of clarithromycin with ergotamine or dihydroergotamine — as this may lead to ergot toxicity.
• Concomitant use of clarithromycin with lomitapide (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) — due to increased risk of myopathy, including rhabdomyolysis (see section "Interaction with other medicinal products and other forms of interaction").
• Concomitant use of clarithromycin and oral midazolam (see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions for use").
• Electrolyte disturbances (hypokalemia or hypomagnesemia) — due to the risk of QT interval prolongation.
• Severe hepatic insufficiency and concomitant renal insufficiency.
• Concomitant use of clarithromycin (and other strong CYP3A4 inhibitors) with colchicine in patients with renal or hepatic impairment (see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions for use").
• Concomitant use of clarithromycin with ticagrelor, ivabradine, or ranolazine.
• Creatinine clearance less than 30 mL/min — as this dosage form does not allow reducing the dose below 500 mg per day.

Interaction with other medicinal products and other forms of interaction

Clarithromycin does not interact with oral contraceptives.

The following medicinal products are strictly contraindicated due to the potential for severe interaction consequences

Astemizole, cisapride, domperidone, pimozide, and terfenadine

Elevated serum levels of cisapride have been observed when co-administered with clarithromycin, which may cause QT interval prolongation and arrhythmias, including ventricular tachycardia, ventricular fibrillation, and torsades de pointes. Similar effects have been reported with concomitant use of pimozide and clarithromycin (see section "Contraindications").

Macrolides have been reported to alter the metabolism of terfenadine, leading to increased serum levels of terfenadine, which has sometimes been associated with cardiac arrhythmias such as QT interval prolongation, ventricular tachycardia, ventricular fibrillation, and torsades de pointes (see section "Contraindications"). In a study involving 14 volunteers, co-administration of terfenadine and clarithromycin resulted in a 2- to 3-fold increase in the serum level of the acidic metabolite of terfenadine and QT interval prolongation, although this did not lead to clinically significant effects. Similar effects have been observed with concomitant use of astemizole and other macrolides.

Ergotamine/dihydroergotamine

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. 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 AUC of midazolam increases 7-fold after oral administration of midazolam. Concomitant use of oral midazolam and clarithromycin is contraindicated (see "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 their concomitant use with clarithromycin increases their plasma concentration, thereby increasing the risk of myopathy, including rhabdomyolysis. Cases of rhabdomyolysis have been reported in patients receiving clarithromycin concomitantly with these statins. If clarithromycin treatment cannot be avoided, therapy with lovastatin or simvastatin should be discontinued during the course of treatment.

Clarithromycin should be used with caution when administered concomitantly with other statins. In situations where concomitant use of clarithromycin with statins cannot be avoided, it is recommended to use the lowest registered dose of the statin. Use of a statin not dependent on CYP3A metabolism (e.g., fluvastatin) may be considered. Monitoring for signs and symptoms of myopathy is necessary.

Lomitapide

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

Effects of other medicinal products on the pharmacokinetics of 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 result in subtherapeutic levels of clarithromycin and reduced efficacy. Additionally, monitoring of plasma levels of the CYP3A inducer may be necessary, as levels may be increased due to CYP3A inhibition by clarithromycin (see also the instructions for medical use of the respective CYP3A4 inducer). Concomitant use of rifabutin and clarithromycin has led to increased rifabutin levels and decreased clarithromycin serum levels, with an increased risk of uveitis.

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

Efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine

Potent inducers of cytochrome P450 enzymes, such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine, may accelerate the metabolism of clarithromycin, reducing its plasma concentration but increasing the concentration of 14-hydroxyclarithromycin — a microbiologically active metabolite. Since the microbiological activity of clarithromycin and 14-hydroxyclarithromycin 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 is diminished by etravirine; however, concentrations of the active metabolite 14-hydroxyclarithromycin are increased. Since 14-hydroxyclarithromycin 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

Steady-state concentrations of the active metabolite 14-hydroxyclarithromycin were not significantly altered when co-administered with fluconazole. No dose adjustment of clarithromycin is required.

Ritonavir

Administration of 200 mg ritonavir every 8 hours and 500 mg clarithromycin 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 use of ritonavir. Complete inhibition of 14-hydroxyclarithromycin formation was observed. Due to the wide therapeutic window, dose reduction of clarithromycin is not required for patients with normal renal function. For patients with renal impairment, dose adjustment is necessary: for CLCR 30–60 mL/min, the clarithromycin dose should be reduced by 50%; for CLCR < 30 mL/min, it should be reduced by 75%. Doses of clarithromycin exceeding 1 g/day should not be used with ritonavir.

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

Effects of clarithromycin on the pharmacokinetics of other medicinal products.

CYP3A-related interactions

Concomitant use of clarithromycin, a known inhibitor of the CYP3A enzyme, with a drug primarily metabolized by CYP3A, may lead to increased plasma concentrations of the latter, thereby potentially enhancing or prolonging its therapeutic effect and increasing the risk of adverse reactions.

Use of clarithromycin is contraindicated in patients receiving CYP3A substrates astemizole, cisapride, domperidone, pimozide, and terfenadine, due to the risk of QT interval prolongation and cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation, and torsades de pointes (see sections "Contraindications" and "Special precautions for use").

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").

Caution is required when co-administering clarithromycin with other drugs that are CYP3A substrates, especially if the CYP3A substrate has a narrow safety margin (e.g., carbamazepine) and/or is extensively metabolized by this enzyme. In such cases, dose adjustment may be necessary, and, if possible, serum concentrations of drugs predominantly metabolized by CYP3A should be closely monitored. Medicinal products or classes of medicinal products known or suspected to be metabolized by the same CYP3A isoenzyme include (list not exhaustive): alprazolam, carbamazepine, cilostazol, cyclosporine, disopyramide, ibrutinib, methylprednisolone, midazolam, omeprazole, oral anticoagulants (e.g., warfarin, rivaroxaban, apixaban), atypical antipsychotics (e.g., quetiapine), quinidine, rifabutin, sildenafil, sirolimus, tacrolimus, triazolam, and vinblastine.

A similar interaction mechanism has been observed with phenytoin, theophylline, and valproate, which are metabolized by other isoenzymes of the cytochrome P450 system.

Direct oral anticoagulants (DOACs)

DOACs dabigatran and edoxaban are substrates of the efflux transporter P-gp (P-glycoprotein). Rivaroxaban and apixaban are metabolized via CYP3A4 and are also P-gp substrates. Caution is advised when co-administering clarithromycin with these agents, especially in patients at high risk of bleeding (see "Special precautions for use").

Antiarrhythmic agents

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

Hypoglycemia has been reported with concomitant use of clarithromycin and disopyramide; therefore, glucose monitoring is necessary when these agents are used together.

Hydroxychloroquine and chloroquine

Clarithromycin should be used with caution in patients receiving these medicinal products, which are known to prolong the QT interval, due to the potential risk of inducing cardiac arrhythmias and serious cardiovascular adverse events.

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 blood glucose levels is recommended.

Omeprazole

Administration of clarithromycin (500 mg every 8 hours) in combination with omeprazole (40 mg daily) in healthy adult volunteers resulted in increased steady-state concentrations of omeprazole (Cmax, AUC0-24, t1/2 increased by 30%, 89%, and 34%, respectively). When omeprazole was administered alone, the mean gastric juice pH value measured over 24 hours was 5.2; with concomitant use of omeprazole and clarithromycin, it was 5.7.

Sildenafil, tadalafil, and vardenafil

Concomitant use of clarithromycin with sildenafil, tadalafil, or vardenafil, which are at least partially metabolized by CYP3A, is likely to increase exposure to the phosphodiesterase inhibitor, potentially requiring dose reduction of the phosphodiesterase inhibitors.

Theophylline, carbamazepine

Clinical studies have shown a slight but statistically significant (p ≤ 0.05) increase in plasma concentrations of theophylline or carbamazepine when used concomitantly with clarithromycin. Dose reduction may be necessary.

Tolterodine

Tolterodine is primarily metabolized by the CYP2D6 isoenzyme of cytochrome P450 (CYP2D6). However, in patients lacking CYP2D6, metabolism occurs via CYP3A. In this population, CYP3A inhibition leads to a significant increase in tolterodine plasma concentrations. Dose reduction of tolterodine may be necessary when used 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 increases 2.7-fold after intravenous administration and 7-fold after oral administration. Concomitant use of oral midazolam and clarithromycin should be avoided. With intravenous midazolam and clarithromycin, close patient monitoring is required for timely dose adjustment.

The same precautions should be observed when using other benzodiazepines metabolized by CYP3A, including triazolam and alprazolam. For benzodiazepines whose elimination is independent of CYP3A (temazepam, nitrazepam, lorazepam), clinically significant interaction with clarithromycin is unlikely.

Post-marketing reports exist of drug interactions and adverse central nervous system effects (such as somnolence and confusion) with concomitant use of clarithromycin and triazolam. Patients should be monitored, considering the potential for enhanced pharmacological effects on the central nervous system.

Corticosteroids

Caution is advised when using clarithromycin concomitantly with systemic and inhaled corticosteroids that are primarily metabolized by CYP3A, due to the potential for increased systemic exposure to corticosteroids. Close monitoring for adverse effects of systemic corticosteroids is recommended when used together.

Other types of interactions

Aminoglycosides

Caution is recommended when using clarithromycin concomitantly with other ototoxic agents, especially aminoglycosides (see section "Special precautions for use").

Colchicine

Colchicine is a substrate of CYP3A and P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. Concomitant use of clarithromycin and colchicine may lead to increased colchicine exposure due to inhibition of Pgp and CYP3A by clarithromycin. Concomitant use of clarithromycin with colchicine in patients with renal or hepatic impairment is contraindicated (see sections "Contraindications" and "Special precautions for use").

Digoxin

Digoxin is considered a substrate of P-glycoprotein (Pgp). Clarithromycin is known to inhibit Pgp. Concomitant use may lead to increased digoxin exposure due to Pgp inhibition. Increased serum digoxin concentrations have been reported in patients taking clarithromycin with digoxin. In some patients, signs of digoxin toxicity, including potentially fatal arrhythmias, have developed. Serum digoxin concentrations should be closely monitored when used with clarithromycin.

Zidovudine

Concomitant use of immediate-release clarithromycin tablets and zidovudine in HIV-infected patients may lead to decreased steady-state serum concentrations of zidovudine. Clarithromycin may interfere with the absorption of oral zidovudine when taken simultaneously; 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 children. This interaction is unlikely with intravenous clarithromycin administration.

Phenytoin and valproate

Spontaneous or published reports exist of interactions between CYP3A inhibitors, including clarithromycin, and drugs not considered to be metabolized by CYP3A (e.g., phenytoin and valproate). Monitoring of serum levels of these drugs is recommended when co-administered with clarithromycin. Increased serum levels have been reported.

Bidirectional drug interactions

Atazanavir

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

Calcium channel blockers

Due to the risk of arterial hypotension, clarithromycin should be used with caution when administered concomitantly with calcium channel blockers metabolized by CYP3A4 (e.g., verapamil, amlodipine, diltiazem). Plasma concentrations of both clarithromycin and calcium channel blockers may increase during interaction.

In patients receiving clarithromycin with verapamil, arterial hypotension, bradyarrhythmias, and lactic acidosis have been observed.

• Itraconazole*

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

Saquinavir

Concomitant use of clarithromycin with saquinavir (soft gelatin capsules three times daily), both substrates and inhibitors of CYP3A, resulted in a 177% increase in saquinavir AUC at steady state and a 187% increase in Cmax 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 and at the above-mentioned doses and dosage forms. Results from drug interaction studies using soft gelatin capsules may not reflect effects observed with hard gelatin capsules. Results from saquinavir interaction studies alone may not reflect effects observed with saquinavir/ritonavir therapy. If saquinavir is used with ritonavir, the potential effect of ritonavir on clarithromycin should be considered (see above).

Special precautions for use.

Clarithromycin should not be prescribed to pregnant women without careful assessment of the benefit-risk ratio, especially during the first trimester of pregnancy (see section "Use during pregnancy or breastfeeding").

Prolonged or repeated use of antibiotics may lead to overgrowth of non-susceptible bacteria and fungi. If superinfection occurs, clarithromycin should be discontinued and appropriate therapy initiated.

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

Claritromycin is primarily eliminated via the liver. Therefore, the antibiotic should be administered with caution in patients with hepatic dysfunction. Caution is also required when prescribing clarithromycin to patients with moderate to severe renal impairment (see section "Dosage and administration").

During treatment with clarithromycin, 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 (see section "Adverse reactions"), primarily associated with serious underlying diseases and/or concomitant medication. Clarithromycin therapy should be immediately discontinued if signs or symptoms of hepatitis occur, such as anorexia, jaundice, dark urine, pruritus, or abdominal pain.

Diarrhea ranging from mild to severe pseudomembranous colitis, including fatal cases caused by Clostridium difficile (CDAD), has been reported with nearly all antibacterial agents, including clarithromycin. Clostridium difficile-associated diarrhea should always be considered in patients presenting with diarrhea after antibiotic use. A careful medical history is essential, as cases of Clostridium difficile infection have been reported up to 2 months after antibiotic administration. If pseudomembranous colitis develops, clarithromycin treatment must be discontinued regardless of the initial indication. Microbiological testing should be performed and appropriate therapy initiated. Agents that inhibit intestinal motility should be avoided.

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

The drug is eliminated by both the liver and kidneys. Caution is required when administering the drug to patients with hepatic impairment or moderate to severe renal impairment.

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. Concomitant administration of clarithromycin and colchicine is contraindicated in patients with renal or hepatic impairment (see section "Contraindications").

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

Claritromycin should be used cautiously in combination with other ototoxic agents, especially aminoglycosides. Monitoring of vestibular and auditory function during and after treatment is recommended.

Cardiovascular complications

QT interval prolongation, reflecting effects on cardiac repolarization and increasing the risk of cardiac arrhythmias including torsades de pointes, has been observed in patients treated with macrolides, including clarithromycin (see section "Adverse reactions"). Due to the increased risk of QT prolongation and ventricular arrhythmias (including torsades de pointes), clarithromycin is contraindicated in the following: patients taking astemizole, cisapride, domperidone, pimozide, or terfenadine; patients with hypokalemia; and patients with a history of prolonged QT interval or ventricular arrhythmias (see section "Contraindications").

In addition, clarithromycin should be used with caution in the following patient groups:

• Patients with ischemic heart disease, severe heart failure, conduction disorders, or clinically significant bradycardia.
• Patients concurrently taking other drugs known to prolong the QT interval, except those contraindicated.

Epidemiological data on the cardiovascular risks associated with macrolide use are inconsistent. Some observational studies have identified a rare, short-term risk of arrhythmias, myocardial infarction, and fatal cardiovascular events associated with macrolide use, including clarithromycin. When prescribing clarithromycin, the potential benefits of treatment should be carefully weighed against these risks.

Pneumonia

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

Skin and soft tissue infections of mild to moderate severity

These infections are commonly caused by Staphylococcus aureus and Streptococcus pyogenes, both of which may be macrolide-resistant. Therefore, susceptibility testing is essential. In cases where beta-lactam antibiotics cannot be used (e.g., due to allergy), alternative agents such as clindamycin may be considered first-line. Currently, macrolides play a limited role in treating certain skin and soft tissue infections, such as those caused by Corynebacterium minutissimum (erythrasma), acne vulgaris, and trench foot, or in situations where penicillin therapy is contraindicated.

In the event of severe acute hypersensitivity reactions, such as anaphylaxis, Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS, or Henoch-Schönlein purpura, clarithromycin therapy should be immediately discontinued and appropriate treatment initiated.

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

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

Use of any antimicrobial therapy, including clarithromycin, for Helicobacter pylori infection may lead to the development of microbial resistance.

HMG-CoA reductase inhibitors (statins)

Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated (see section "Contraindications"). Caution is required when co-administering clarithromycin with other statins. Cases of rhabdomyolysis have been reported with concomitant use of clarithromycin and statins. Patients should be monitored for signs and symptoms of myopathy. If concomitant use cannot be avoided, the lowest registered dose of the statin should be prescribed. Consider using a statin not metabolized by CYP3A (e.g., fluvastatin).

Oral hypoglycemic agents/insulin

Concomitant use of clarithromycin with oral hypoglycemic agents (such as sulfonylureas) and/or insulin may cause marked hypoglycemia. Close monitoring of blood glucose levels is recommended (see section "Interaction with other medicinal products and other forms of interaction").

Oral anticoagulants

Concomitant use of clarithromycin with warfarin increases the risk of serious bleeding, with significant elevation of the INR (International Normalized Ratio) and prothrombin time (see section "Interaction with other medicinal products and other forms of interaction"). Frequent monitoring of INR and prothrombin time is required while patients are receiving both clarithromycin and oral anticoagulants.

Caution is advised when using clarithromycin concomitantly with direct oral anticoagulants such as dabigatran, rivaroxaban, apixaban, and edoxaban, especially in patients at high risk of bleeding (see section "Special precautions for use").

Excipients

The medicinal product contains lactose; therefore, it should not be administered to patients with rare hereditary conditions of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

Use during pregnancy or breastfeeding.

Pregnancy

The safety of clarithromycin use during pregnancy or breastfeeding has not been established. Based on animal studies and human experience, a potential adverse effect on embryonal development cannot be excluded. Some observational studies assessing clarithromycin use during the first and second trimesters have shown an increased risk of miscarriage compared to no antibiotic use or use of other antibiotics during the same period. Epidemiological data on the risk of major congenital malformations associated with macrolide use, including clarithromycin, during pregnancy are conflicting.

Clarithromycin should be prescribed only if the expected benefit to the mother outweighs the potential risk to the fetus, particularly during the first three months of pregnancy.

Breastfeeding

Claritromycin is excreted in small amounts in human breast milk. An exclusively breastfed infant is estimated to receive approximately 1.7% of the maternal dose (adjusted for weight).

Therefore, clarithromycin is contraindicated in breastfeeding women.

Fertility

Fertility studies in rats revealed no evidence of harmful effects.

Ability to influence reaction speed when driving or operating machinery.

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

Method of administration and dosage.

Take orally during meals, without chewing, with water.

The recommended dose of clarithromycin for adults and children aged 12 years and older is 500 mg (1 tablet) every 24 hours. In severe infections, the dose may be increased to 1000 mg (2 tablets) every 24 hours.

The usual duration of treatment is 5 to 14 days, except for community-acquired pneumonia and sinusitis, which require 6 to 14 days of therapy.

Use in patients with renal impairment: This formulation should not be used in patients with severe renal impairment (creatinine clearance < 30 mL/min), as it does not allow for adequate dose reduction. Such patients should receive immediate-release clarithromycin tablets (Fromilid®, 250 mg or 500 mg tablets). For patients with moderate renal impairment (creatinine clearance 30–60 mL/min), the dose should be reduced by 50% to a maximum dose of clarithromycin – 1 prolonged-release tablet per day.

Children.

The use of clarithromycin tablets in children under 12 years of age has not been studied. Such patients should receive clarithromycin as an oral suspension.

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, disturbances in mental status, paranoid behavior, hypokalemia, and hypoxemia developed.

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

Adverse reactions

The most common and frequent adverse reactions associated with clarithromycin therapy in both adults and children were abdominal pain, diarrhea, nausea, vomiting, and taste disturbance. These adverse reactions were generally mild in intensity and consistent with the known safety profile of macrolide antibiotics (see section "Adverse reactions"). During clinical studies, no significant difference was observed in the frequency of these gastrointestinal adverse reactions between patient populations with mycobacterial infections and those without such infections.

Caution is advised when co-administering clarithromycin with triazolam due to the risk of central nervous system adverse effects (e.g., somnolence and confusion).

Adverse effects that may occur during clarithromycin therapy are classified by organ systems:

1,2,3,4 These adverse reactions were reported only when the drug was used in the following forms: 1 – lyophilized powder for infusion solution, 2 – prolonged-release tablets, 3 – suspension, 4 – immediate-release tablets.

Description of selected adverse reactions*

Arthralgia, angioneurotic edema, anaphylactic reactions, and paresthesia have been reported.

Very rare cases of uveitis have been reported, primarily in patients who were concurrently taking rifabutin. Most cases were reversible.

Cases of colchicine toxicity have been reported, especially in elderly patients (see sections "Contraindications" and "Special precautions").

*Frequency unknown, as these reactions were reported spontaneously and the size of the patient population is undefined. It is not always possible to establish the frequency of adverse reactions or a causal relationship to the use of the drug. General data on clarithromycin use — over 1 billion patient-days.

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

Other patient groups

Patients with immune system disorders.

In AIDS patients and other patients with immune system disorders who received high doses of clarithromycin for longer than recommended for the treatment of mycobacterial infections, it is not always possible to distinguish adverse reactions related to the drug from symptoms of the underlying or concomitant diseases.

In adult patients who received clarithromycin at daily doses of 1000 mg and 2000 mg, the most common adverse effects were nausea, vomiting, taste perversion, abdominal pain, diarrhea, rash, bloating, headache, constipation, and hearing disturbances. According to this criterion, significant abnormal elevations in ALT and AST levels and abnormal decreases in white blood cell and platelet counts occurred in 2–3% of these patients. A smaller percentage of patients experienced increased blood urea nitrogen levels.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after drug authorization is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of drug efficacy to the State Expert Center of the Ministry of Health of Ukraine via the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

Store at temperatures not exceeding 25°C in the original packaging to protect from moisture. Keep out of reach of children.

Packaging.

5 tablets in a blister; 1 blister in a cardboard box.

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

Prescription status. Prescription only.

Manufacturer. KRKA, d.d., Novo mesto, Slovenia/KRKA, d.d., Novo mesto, Slovenia.

Manufacturer's address and site of operations.

Smarjeska cesta 6, 8501 Novo mesto, Slovenia/Smarjeska cesta 6, 8501 Novo mesto, Slovenia.