Fromilid

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FROMILID® (FROMILID®)

Composition:

Active substance: clarithromycin;

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

Excipients: corn starch, microcrystalline cellulose, colloidal anhydrous silicon dioxide, pregelatinized starch, potassium polycriline, talc, magnesium stearate, hydroxypropylmethylcellulose, propylene glycol, iron oxide yellow pigment (E 172), titanium dioxide (E 171).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: oval, biconvex tablets of slightly brownish-yellow color, coated with a film layer.

Pharmacotherapeutic group. Antimicrobial agents for systemic use. Macrolides, lincosamides and streptogramins. Clarithromycin. ATC code J01FA09.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Clarithromycin is a semisynthetic antibiotic of the macrolide group. The antibacterial activity of clarithromycin is determined by its binding to the 50S ribosomal subunit of susceptible bacteria and inhibition of protein biosynthesis. This leads to disruption of normal bacterial cell function. Due to the different structure of ribosomes in human cells, binding of macrolides to these ribosomes is prevented, which likely explains the low toxicity of macrolides in humans. Chloramphenicol and lincosamides compete with macrolides for binding to the peptidyl sites of the ribosome in certain bacteria, resulting in antagonistic effects.

In addition to clarithromycin, its metabolite 14-hydroxyclarithromycin is also active. It is twice as effective against Haemophilus influenzae as clarithromycin itself.

The primary action of macrolides is bacteriostatic. However, this effect depends on the concentration of the macrolide, the number of bacteria present, and the stage of the bacterial life cycle at the time of antibiotic administration. Clarithromycin, like other macrolides, may also exhibit bactericidal activity against Streptococcus pyogenes, Streptococcus pneumoniae, and Moraxella catarrhalis. Recent studies on macrolides indicate that the best predictor of macrolide efficacy is the duration of time during which the serum concentration of the antibiotic exceeds the minimum inhibitory concentrations (MIC).

Antibacterial efficacy

Clarithromycin exerts bacteriostatic and bactericidal effects against a wide range of clinically significant Gram-positive and Gram-negative bacteria, including aerobes, anaerobes, facultative anaerobes, other bacteria (mycoplasmas, ureaplasmas, chlamydiae, legionellae), and atypical mycobacteria.

Table 1. Bacteria susceptible to clarithromycin.

Aerobic, Gram-positive bacteria	Aerobic, Gram-negative bacteria	Anaerobic bacteria
Streptococcus pyogenes	Haemophilus influenzae	Gram-positive bacteria
Streptococcus pneumoniae	Moraxella catarrhalis	Eubacterium spp.
Methicillin-susceptible Staphylococcus aureus	Legionella pneumophila	Clostridium perfringens
Streptococcus agalactiae	Neisseria gonorrhoeae	Peptococcus spp.
Streptococcus viridans	Helicobacter pylori	Peptostreptococcus spp.
Corynebacterium spp.	Campylobacter jejuni	Propionibacterium acnes
Listeria monocytogenes	Bordetella pertussis
Bacillus spp.	Pasteurella multocida	Gram-negative bacteria
		Bacteroides spp.
		Bacteroides fragilis
		Prevotella melaninogenica
Other microorganisms
Chlamydia pneumoniae Mycobacterium avium complex
Chlamydia trachomatis Mycobacterium fortuitum
Mycoplasma pneumoniae Mycobacterium chelonae
Ureaplasma urealyticum Mycobacterium kansasii
Borrelia burgdorferi Mycobacterium xenopi
Toxoplasma gondii Mycobacterium lepra

Pharmacokinetics.

Absorption

Clarithromycin is well absorbed from the gastrointestinal tract. Bioavailability is approximately 55% following oral administration of the dose. Food may slow absorption, but does not significantly affect the bioavailability of clarithromycin. About 20% of clarithromycin is immediately metabolized to form the main metabolite, 14-hydroxyclarithromycin, which exhibits the same biological effect as clarithromycin. In healthy subjects, serum concentrations are proportional to the size of the oral dose. Peak serum concentrations are reached within less than 3 hours. After a single 250 mg oral dose of clarithromycin, mean concentrations range from 0.62 mcg/mL to 0.84 mcg/mL; after a single 500 mg dose, from 1.77 mcg/mL to 1.89 mcg/mL. Corresponding concentrations of 14-hydroxyclarithromycin are from 0.4 mcg/mL to 0.7 mcg/mL after a 250 mg dose and from 0.67 mcg/mL to 0.8 mcg/mL after a 500 mg dose. Area under the concentration-time curve (AUC × time) values are 4 mcg/mL·h after a 250 mg dose and 11 mcg/mL·h after a 500 mg dose.

Steady-state concentrations are achieved after the fifth dose of 250 mg clarithromycin administered twice daily; peak concentrations of clarithromycin are 1 mcg/mL and of 14-hydroxyclarithromycin are 0.6 mcg/mL.

Tissue Penetration

Clarithromycin penetrates well into body fluids and tissues, where it reaches concentrations up to 10 times higher than in blood plasma. High concentrations have been found in the lungs (8.8 mg/kg), tonsils (1.6 mg/kg), nasal mucosa, skin, saliva, alveoli, sputum, and middle ear fluid. The volume of distribution of clarithromycin in healthy subjects after a single 250 mg and 500 mg dose is 226–266 L/kg and 2.5 L/kg, respectively. The volume of distribution of 14-hydroxyclarithromycin is 304–309 L. Binding of clarithromycin to serum proteins is weak and reversible.

The elimination half-life of clarithromycin is 3–4 hours at a dose of 250 mg every 12 hours and 5–7 hours at a dose of 500 mg every 12 hours.

Metabolism and Excretion

Clarithromycin is metabolized in the liver. At least 7 metabolites have been identified. The most important is 14-hydroxyclarithromycin. Clarithromycin is excreted in the urine either as metabolites or unchanged, and to a lesser extent in feces (4%). Approximately 20% of a 250 mg dose and 30% of a 500 mg dose are excreted unchanged in the urine. 10–15% of the dose is excreted in the urine as 14-hydroxyclarithromycin.

The elimination half-life of clarithromycin is 3–4 hours at a dose of 250 mg every 12 hours and 5–7 hours at a dose of 500 mg every 12 hours.

Effect of Age and Disease on Pharmacokinetics

Children and Infants: Studies have shown that the pharmacokinetics of clarithromycin in children receiving 7.5 mg/kg body weight twice daily are similar to those in adults.

Elderly Patients: There is no need for dose adjustment in elderly patients unless they have severe renal impairment.

Effect of Disease on Pharmacokinetics: After administration of 200 mg clarithromycin, increased maximum concentration and AUC, as well as reduced elimination of clarithromycin, were observed in patients with severe renal impairment compared to healthy subjects. In patients with severe renal impairment, total elimination of clarithromycin decreased from 26.5% to 3.3% compared to healthy subjects. These results indicate that dose reduction or extended dosing intervals are necessary for patients with severe renal impairment.

Steady-state concentrations of clarithromycin in patients with hepatic impairment do not differ from those in healthy subjects, but concentrations of the 14-hydroxy metabolite are lower.

Clinical characteristics.

Indications.

Infections caused by microorganisms sensitive to clarithromycin:

• Lower respiratory tract infections (bronchitis, acute lobar pneumonia, and primary atypical pneumonia).
• Upper respiratory tract infections, i.e., nasopharynx (tonsillitis, pharyngitis), and infections of the paranasal sinuses.
• Skin and soft tissue infections (impetigo, folliculitis, erysipeloid, furunculosis, infected wounds).
• Acute and chronic odontogenic infections.
• Disseminated or localized mycobacterial infections caused by Mycobacterium avium or Mycobacterium intracellulare. Localized infections caused by Mycobacterium chelonae, Mycobacterium fortuitum, or Mycobacterium kansasii.

For eradication of Helicobacter pylori in patients with duodenal ulcer under conditions of inhibited hydrochloric acid secretion (clarithromycin activity against Helicobacter pylori is higher at neutral pH than at acidic pH).

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

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

Contraindications.

• Hypersensitivity to clarithromycin or to other macrolide antibiotics or to any of the excipients 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 diagnosed acquired QT interval prolongation or history of ventricular cardiac arrhythmias, including torsades de pointes (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction").
• 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. Treatment with these agents should be discontinued during clarithromycin therapy (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction").
• Concomitant use of clarithromycin (and other strong CYP3A4 inhibitors) with colchicine in patients with renal or hepatic impairment (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction").
• Electrolyte disturbances (hypokalemia or hypomagnesemia) — due to risk of QT interval prolongation.
• Severe hepatic insufficiency with concomitant renal impairment.
• Concomitant use of clarithromycin with ticagrelor, ivabradine, or ranolazine.

Interaction with other medicinal products and other forms of interaction.

Clarithromycin does not interact with oral contraceptives.

Use of the following drugs is strictly contraindicated due to the potential for severe interaction outcomes

Astemizole, cisapride, domperidone, pimozide, and terfenadine

Increased serum levels of cisapride have been observed when used concomitantly 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, concomitant administration of terfenadine and clarithromycin resulted in a 2–3-fold increase in the serum level of terfenadine acid metabolite and QT interval prolongation, although no clinically evident effect was observed. Similar effects have been reported 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 was administered with clarithromycin tablets (500 mg twice daily), the AUC of midazolam increased 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 therapy cannot be avoided, treatment with lovastatin or simvastatin should be discontinued during the course of therapy.

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

Lomitapide

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

Effect of other medicinal products on clarithromycin

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

The effect of the following medicinal products on clarithromycin blood concentration is known or suspected, and 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 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; however, concentrations of the active metabolite 14-OH-clarithromycin were increased. Since 14-OH-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered. Therefore, alternative agents to clarithromycin should be considered for MAC treatment.

Fluconazole

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

Ritonavir

Concomitant use of ritonavir and clarithromycin resulted in significant inhibition of clarithromycin metabolism. Cmax of clarithromycin increased by 31%, Cmin by 182%, and AUC by 77%. Complete inhibition of 14-OH-clarithromycin formation was observed. Due to the wide therapeutic window, dose reduction of clarithromycin is not required in patients with normal renal function. For patients with renal impairment, dose adjustment is required: for CLCR 30–60 mL/min, the clarithromycin dose should be reduced by 50% to a maximum of 1 tablet per day; for CLCR < 30 mL/min, the dose should be reduced by 75%. Clarithromycin doses exceeding 1 g/day should not be used concomitantly 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.

Effect of clarithromycin on 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 concentration 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 using clarithromycin concomitantly 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 (intravenous), 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 cytochrome P450 isoenzymes.

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 using clarithromycin concomitantly with these agents, especially in patients at high risk of bleeding (see "Special precautions for use").

Antiarrhythmic agents

Post-marketing reports describe cases of torsades de pointes occurring with concomitant use of clarithromycin and quinidine or disopyramide. ECG monitoring is recommended for timely detection of QT interval prolongation. Serum concentrations of these agents should be monitored during clarithromycin therapy.

Post-marketing reports also describe hypoglycemia with concomitant use of clarithromycin and disopyramide; therefore, glucose monitoring is required when these agents are used together.

Hydroxychloroquine and chloroquine

Clarithromycin should be used with caution in patients receiving these agents, which are known to prolong the QT interval, due to the potential to induce cardiac arrhythmias and serious cardiovascular 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 glucose levels is recommended.

Omeprazole

Concomitant use of clarithromycin (500 mg every 8 hours) with omeprazole (40 mg daily) in healthy adult volunteers led to increased steady-state concentrations of omeprazole. When omeprazole was used alone, the mean gastric juice pH measured over 24 hours was 5.2; with concomitant use of omeprazole and clarithromycin, it was 5.7.

Sildenafil, tadalafil, and vardenafil

There is a potential for increased plasma concentrations of phosphodiesterase inhibitors (sildenafil, tadalafil, vardenafil) when used concomitantly with clarithromycin, which may require dose reduction of the phosphodiesterase inhibitors.

Theophylline, carbamazepine

Clinical studies have shown a slight but statistically significant increase in plasma concentrations of theophylline or carbamazepine when used concomitantly with clarithromycin.

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, inhibition of CYP3A leads to a significant increase in serum concentrations of tolterodine. 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 and 7-fold after oral administration of midazolam. Combined 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 does not depend on CYP3A (temazepam, nitrazepam, lorazepam), clinically significant interaction with clarithromycin is unlikely.

Post-marketing reports describe drug interactions and adverse effects on the central nervous system (such as somnolence and confusion) with concomitant use of clarithromycin and triazolam. Patients should be monitored, considering the potential for increased 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 of patients for adverse effects of systemic corticosteroids is required when used concomitantly.

Other types of interactions

Aminoglycosides

Clarithromycin should be used cautiously when administered 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. Patients should be monitored for clinical signs of colchicine toxicity.

Digoxin

Post-marketing reports describe increased serum digoxin concentrations in patients receiving clarithromycin concomitantly with digoxin. In some patients, signs of digitalis toxicity developed, including potentially life-threatening arrhythmias. Serum digoxin concentrations should be closely monitored when digoxin is 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. 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. Studies on interaction between extended-release clarithromycin tablets and zidovudine have not been conducted.

Phenytoin and valproate

Spontaneous or published reports describe 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 used concomitantly with clarithromycin. Increased serum levels have been reported.

Bidirectional drug interactions

Atazanavir

Concomitant use of clarithromycin (500 mg twice daily) with atazanavir (400 mg once daily), both substrates and inhibitors of CYP3A, resulted in a doubling of clarithromycin exposure and a 70% reduction in 14-OH-clarithromycin exposure, with a 28% increase in atazanavir AUC. Since clarithromycin has a wide therapeutic 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 concomitantly with protease inhibitors.

Calcium channel blockers

Due to the risk of arterial hypotension, clarithromycin should be used cautiously 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 concomitantly with verapamil, arterial hypotension, bradyarrhythmias, 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 effect.

Saquinavir

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

Special precautions for use.

The physician should not prescribe clarithromycin to pregnant women without carefully weighing the benefits against the risks, especially during the first three months of pregnancy (see section "Use in pregnancy or lactation").

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

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

Clarithromycin is primarily eliminated via the liver. Therefore, the antibiotic should be prescribed with caution in patients with hepatic impairment. Caution should also be exercised when prescribing clarithromycin to patients with moderate to severe renal impairment.

During clarithromycin therapy, 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 and are usually reversible. Rarely, fatal hepatic failure has been reported (see section "Adverse reactions"), which was primarily associated with serious underlying diseases and/or concomitant medication. Clarithromycin therapy should be immediately discontinued if signs and symptoms of hepatitis such as anorexia, jaundice, dark urine, pruritus, or abdominal pain occur.

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 any patient presenting with diarrhea following antibiotic use. Furthermore, careful history taking is essential, as cases of Clostridium difficile-associated diarrhea have been reported even up to two months after antibiotic administration. If pseudomembranous colitis develops, clarithromycin treatment must be discontinued regardless of the indication for which it was prescribed. Microbiological testing should be performed and appropriate treatment initiated. Antiperistaltic agents should be avoided.

Colchicine

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

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

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

Cardiovascular complications

QT interval prolongation, reflecting effects on cardiac repolarization and increasing the risk of cardiac arrhythmias and 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 patients taking astemizole, cisapride, domperidone, pimozide, or terfenadine; in patients with hypokalemia; and in patients with a history of QT prolongation 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 who are concurrently taking other drugs known to prolong the QT interval, except those that are contraindicated.

Epidemiological study results regarding the risk of adverse cardiovascular outcomes associated with macrolide use are varied. Some observational studies have identified a rare short-term risk of arrhythmia, myocardial infarction, and fatal cardiovascular events associated with macrolide use, including clarithromycin. Consideration of these findings when prescribing clarithromycin should be balanced against the benefits of treatment.

Pneumonia

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

Skin and soft tissue infections of mild to moderate severity

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

In the event of severe acute hypersensitivity reactions such as anaphylaxis or severe skin adverse reactions (e.g., acute generalized exanthematous pustulosis, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS)), or Henoch-Schönlein purpura, clarithromycin therapy should be immediately discontinued and appropriate treatment initiated without delay.

Clarithromycin should be used with caution when co-administered with inducers of the cytochrome P450 enzyme CYP3A4 (see section "Interaction with other medicinal products and other forms of interaction").

HMG-CoA reductase inhibitors (statins)

Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated (see section "Contraindications"). Clarithromycin should be prescribed with caution when used concomitantly with other statins. Cases of rhabdomyolysis have been reported in patients receiving clarithromycin together with statins. Patients should be monitored for signs and symptoms of myopathy. If concomitant use of clarithromycin with statins cannot be avoided, it is recommended to prescribe the lowest registered dose of the statin. Use of a statin not metabolized by CYP3A (e.g., fluvastatin) may be considered (see section "Interaction with other medicinal products and other forms of interaction").

Oral hypoglycemic agents/insulin

Concomitant use of clarithromycin with oral hypoglycemic agents (e.g., sulfonylureas) and/or insulin may result in pronounced hypoglycemia. Close monitoring of blood glucose levels is recommended (see section "Interaction with other medicinal products and other forms of interaction").

Oral anticoagulants

When clarithromycin is used concomitantly with warfarin, there is a risk of serious bleeding, significant increase in INR (international normalized ratio), and prolonged 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 clarithromycin is used concomitantly with direct oral anticoagulants such as dabigatran, rivaroxaban, apixaban, and edoxaban, particularly in patients at high risk of bleeding (see section "Interaction with other medicinal products and other forms of interaction").

Use in pregnancy or lactation.

Pregnancy

The safety of clarithromycin use during pregnancy or lactation has not been established. Based on animal studies and human experience with clarithromycin, a potential adverse effect on embryonic development cannot be excluded. Some observational studies assessing the impact of clarithromycin 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. Available 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.

Lactation

Clarithromycin is excreted in small amounts into human breast milk. It has been estimated that an exclusively breastfed infant would receive approximately 1.7% of the maternal dose of clarithromycin (adjusted for weight).

Therefore, clarithromycin is contraindicated in women who are breastfeeding.

Fertility

Fertility studies in rats revealed no evidence of harmful effects.

Ability to affect reaction speed when driving or operating machinery.

Data on the effect are lacking. However, possible adverse reactions affecting the nervous system such as convulsions, dizziness, vertigo, hallucinations, confusion, and disorientation, which may impair psychomotor performance, should be taken into account.

Method of Administration and Dosage

Administer orally, without chewing, swallowing with a small amount of water, regardless of food intake.

Adults and children aged 12 years and older

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

Treatment of odontogenic infections

250 mg twice daily for 5 days.

Use in patients with mycobacterial infection

The initial dose for adults is 500 mg twice daily. If there is no clinical or bacteriological improvement within 3–4 weeks of treatment, the clarithromycin dose may be increased to 1000 mg twice daily.

Treatment of disseminated infections caused by the Mycobacterium avium complex in AIDS patients should continue as long as clinically and microbiologically confirmed efficacy is maintained. Clarithromycin must be used in combination with other antimicrobial agents.

The duration of treatment for other nontuberculous mycobacterial infections is determined individually by the physician.

Eradication of Helicobacter pylori in patients with duodenal ulcer (adults):

Triple therapy (7–10 days)

500 mg clarithromycin twice daily concomitantly with amoxicillin 1000 mg twice daily and omeprazole 20 mg once daily for 7–10 days.

Triple therapy (10 days)

500 mg clarithromycin twice daily, 30 mg lansoprazole twice daily, and 1000 mg amoxicillin twice daily for 0 days.

Double therapy (14 days)

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

Double therapy (14 days)

500 mg clarithromycin three times daily with lansoprazole 60 mg once daily for 14 days. Additional acid suppression may be required to reduce ulcer symptoms.

Claritromycin may also be used in the following therapeutic regimens:

clarithromycin + tinidazole and omeprazole or lansoprazole;

clarithromycin + metronidazole and omeprazole or lansoprazole;

clarithromycin + tetracycline and bismuth subcitrate or ranitidine;

clarithromycin + amoxicillin and lansoprazole;

clarithromycin + ranitidine bismuth citrate.

Use in elderly patients: same as for adults.

Use in patients with renal impairment: dose adjustment is usually not required, except in patients with severe renal impairment (creatinine clearance < 30 mL/min). If dose adjustment is necessary, the daily dose should be halved, i.e., administer 250 mg once daily or 250 mg twice daily in cases of more severe infections. In such patients, the duration of treatment should not exceed 14 days.

Children

Clinical trials of clarithromycin suspension have been conducted in children aged 6 months to 12 years. Therefore, children under 12 years of age should receive the drug in the form of a suspension.

Overdose

Symptoms: vomiting, abdominal pain, headache, and dizziness. In one patient with a history of bipolar disorder, ingestion of 8 g of clarithromycin resulted in psychiatric disturbances, paranoid behavior, hypokalemia, and hypoxemia.

Treatment: gastric lavage and symptomatic therapy. As with other macrolides, hemodialysis is unlikely to significantly affect serum clarithromycin levels.

Adverse reactions.

Summary of safety profile

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

Table of adverse reactions

The table below lists adverse reactions observed during clinical trials and post-marketing use of clarithromycin immediate-release, oral suspension granules, and extended-release tablets.

Reactions considered at least possibly related to clarithromycin are listed by system organ class and frequency: common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), and frequency not known (reactions reported during post-marketing experience; frequency cannot be estimated from available data).

System Organ Class	Adverse Reactions
	Common	Uncommon	Unknown
Infections and infestations		Cellulitis1, oral candidiasis, gastroenteritis2, infection3, vaginal infection	Pseudomembranous colitis, shigellosis, erythrasma
Blood and lymphatic system disorders		Leukopenia, neutropenia4, thrombocytosis3, eosinophilia4	Agranulocytosis, thrombocytopenia
Immune system disorders		Anaphylactoid reactions1, hypersensitivity	Anaphylactic reactions, angioedema
Metabolism and nutrition disorders		Anorexia, decreased appetite
Psychiatric disorders	Insomnia	Anxiety, nervousness3	Psychosis, confusion, depersonalization, depression, disorientation, hallucinations, nightmares, mania
Central nervous system disorders	Dysgeusia, headache	Loss of consciousness1, dyskinesia1, dizziness, somnolence, tremor	Seizures, ageusia (loss of taste sensation), parosmia, anosmia, paresthesia
Ear and labyrinth disorders		Dizziness, hearing impairment, tinnitus	Hearing loss
Cardiac disorders		Cardiac arrest1, atrial fibrillation1, QT interval prolongation, extrasystoles1, palpitations	Torsades de pointes, ventricular tachycardia
Vascular disorders	Vasodilation1		Ecchymosis
Respiratory, thoracic and mediastinal disorders		Nosebleed2, asthma1, pulmonary embolism1
Gastrointestinal disorders	Diarrhea, vomiting, dyspepsia, nausea, abdominal pain	Esophagitis1, gastroesophageal reflux disease2, gastritis, proctalgia2, stomatitis, glossitis, abdominal distension4, constipation, dry mouth, belching, flatulence	Acute pancreatitis, change in tongue color, change in tooth color
Hepatobiliary disorders	Abnormal liver function tests	Cholestasis4, hepatitis4, increased ALT, AST, GGT4	Liver failure, cholestatic jaundice, hepatocellular jaundice
Skin and subcutaneous tissue disorders	Rash, hyperhidrosis	Bullous dermatitis1, pruritus, urticaria, maculopapular rash3	Severe skin adverse reactions (e.g., acute generalized exanthematous pustulosis, Stevens-Johnson syndrome4, toxic epidermal necrolysis4, DRESS syndrome, acne, Henoch-Schönlein purpura
Musculoskeletal and connective tissue disorders		Muscle spasms3, skeletal muscle rigidity1, myalgia2	Rhabdomyolysis2 (in some reports, rhabdomyolysis occurred when clarithromycin was used concomitantly with other medicinal products known to be associated with rhabdomyolysis (such as statins, fibrates, colchicine or allopurinol)), myopathy
Renal and urinary disorders		Increased blood creatinine1, increased blood urea1	Renal failure, interstitial nephritis
General disorders and administration site conditions	Phlebitis at injection site1, pain, inflammation at injection site1	Malaise4, fever3, asthenia, chest pain4, chills4, fatigue4
Laboratory investigations		Increased alkaline phosphatase in blood4, increased lactate dehydrogenase in blood4, change in albumin/globulin ratio1	Increased INR, prolonged prothrombin time, change in urine color

1,2,3,4 The following adverse reactions have been reported only with the use of the medicinal product in the following forms: 1 – lyophilisate powder for infusion solution, 2 – prolonged-release tablets, 3 – suspension, 4 – immediate-release tablets.

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

Other patient groups

Patients with impaired immune system.

In patients with AIDS and other patients with impaired immune system who received high doses of clarithromycin for longer than recommended for the treatment of mycobacterial infections, it may not always be possible to distinguish adverse reactions related to the medicinal product 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 disturbance, abdominal pain, diarrhea, rash, abdominal distension, 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 of suspected adverse reactions after marketing authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients or their legal representatives should report any suspected adverse reactions and lack of efficacy of the medicinal product to the State Expert Center of the Ministry of Health of Ukraine via the following link: https://aisf.dec.gov.ua.

Shelf life. 5 years.

Storage conditions. Store at temperatures not exceeding 25 °C in a dry place. Keep out of reach of children.

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

Prescription status. Prescription only.

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

Manufacturer's address and location of operations.

Smarjeska cesta 6, 8501 Novo mesto, Slovenia.