Fromilid

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

Composition:

active substance: clarithromycin;

5 ml of oral suspension (1 syringe) contain 125 mg of clarithromycin;

excipients: carbomer, povidone, hypromellose phthalate (HP 55), talc, castor oil, xanthan gum, banana flavor, potassium sorbate, citric acid, colloidal anhydrous silicon dioxide, titanium dioxide (E 171), sucrose.

Pharmaceutical form. Granules for oral suspension.

Main physicochemical properties: small, heterogeneous granules of white to almost white color with a banana odor.

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

Pharmacological Properties

Pharmacodynamics

Clarithromycin is a semi-synthetic antibiotic of the macrolide group. Its antibacterial activity is determined by binding to the 50S ribosomal subunit of susceptible bacteria and inhibition of protein biosynthesis. 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 generally two times lower than those of erythromycin.

Clarithromycin is highly active in vitro against Legionella pneumophila and Mycoplasma pneumoniae. It exerts bactericidal activity against Helicobacter pylori, with clarithromycin activity being 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.

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.

Helicobacter: Helicobacter pylori.

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

Most methicillin- and oxacillin-resistant strains of staphylococci are resistant to clarithromycin.

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.

Other microorganisms: Chlamydia trachomatis.

Anaerobic gram-positive microorganisms: Bacteroides melaninogenicus.

Spirochetes: Borrelia burgdorferi, Treponema pallidum.

Camphylobacters: Campylobacter jejuni.

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

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

Pharmacokinetics

Clarithromycin is rapidly and well absorbed from the gastrointestinal tract. The microbiologically active 14-OH-clarithromycin is formed during first-pass metabolism in the liver. When administered with food, the onset of absorption and formation of 14-OH-clarithromycin is slightly delayed, but overall bioavailability remains unchanged. Although the pharmacokinetics of clarithromycin is nonlinear, steady-state concentrations are achieved within 2 consecutive days of dosing.

Tissue concentrations of clarithromycin are several times higher than serum concentrations. Elevated concentrations of clarithromycin are observed in tonsillar and lung tissues. Concentrations in middle ear fluid exceed those in serum. At therapeutic doses, clarithromycin is approximately 80% bound to plasma proteins. 14-OH-clarithromycin is the main metabolite excreted by the kidneys and accounts for approximately 10–15% of the administered dose. The majority of the remaining dose is excreted via bile. 5–10% of the active substance is excreted in feces.

Steady-state concentrations of clarithromycin in patients with impaired liver function do not differ significantly from those in healthy volunteers, except for lower concentrations of 14-OH-clarithromycin in hepatic dysfunction.

In patients with impaired renal function receiving a 500 mg dose, pharmacokinetic parameters increased proportionally to the degree of renal impairment.

Patient age does not affect the pharmacokinetic parameters of clarithromycin.

In HIV-infected children receiving clarithromycin at doses of 15–30 mg/kg/day (in two divided doses), higher plasma concentrations of clarithromycin and a longer elimination half-life were observed.

Clinical Characteristics.

Indications.

Infections caused by microorganisms sensitive to clarithromycin:

Infections of the upper respiratory tract, i.e., nasopharynx (tonsillitis, pharyngitis), and infections of the paranasal sinuses.

Infections of the lower respiratory tract (bronchitis, acute lobar pneumonia, and primary atypical pneumonia).

Acute otitis media.

Infections of the skin and soft tissues (folliculitis, impetigo, ecthyma, furunculosis, infected wounds).

Disseminated or localized mycobacterial infections caused by Mycobacterium avium or Mycobacterium intracellulare. Localized infections caused by Mycobacterium chelonae, Mycobacterium fortuitum, or Mycobacterium kansasii.

Contraindications.

Hypersensitivity to macrolide antibiotics and to other components of the medicinal product.

Concomitant use of astemizole, cisapride, domperidone, pimozide, terfenadine — as this may lead to QT interval prolongation and development of cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation, and torsade de pointes (see sections "Special Warnings and Precautions for Use" and "Interaction with Other Medicinal Products and Other Forms of Interaction").

Concomitant use of ergot alkaloids, e.g., ergotamine, dihydroergotamine — as this may lead to ergot toxicity.

Concomitant use of HMG-CoA reductase inhibitors (statins) that are predominantly metabolized by CYP3A4 (lovastatin or simvastatin) — due to increased risk of myopathy, including rhabdomyolysis (see sections "Special Warnings and Precautions for Use" and "Interaction with Other Medicinal Products and Other Forms of Interaction").

Concomitant use of clarithromycin with lomitapide (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

Congenital or documented acquired QT interval prolongation or history of ventricular cardiac arrhythmias, including torsade de pointes (see sections "Special Warnings and Precautions for Use" and "Interaction with Other Medicinal Products and Other Forms of Interaction").

Concomitant use of clarithromycin and oral midazolam (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

Electrolyte disturbances (hypokalemia or hypomagnesemia) — due to the risk of QT interval prolongation.

Severe hepatic insufficiency with concomitant renal insufficiency (see sections "Special Warnings and 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 (see sections "Special Warnings and Precautions for Use" and "Interaction with Other Medicinal Products and Other Forms of Interaction").

Concomitant use of clarithromycin with ticagrelor, ivabradine, or ranolazine.

Interaction with Other Medicinal Products and Other Forms of Interaction.

Concomitant use of the following drugs with clarithromycin is strictly contraindicated due to the risk of severe interaction consequences

Astemizole, cisapride, domperidone, pimozide, terfenadine

Increased serum levels of cisapride have been observed when used concomitantly with clarithromycin, which may cause QT interval prolongation and cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation, and torsade de pointes. Similar effects have been reported with concomitant use of pimozide and clarithromycin (see section "Contraindications").

Macrolides have been reported to alter terfenadine metabolism, 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 torsade de pointes (see section "Contraindications"). In a study involving 14 volunteers, concomitant use of terfenadine and clarithromycin resulted in a 2- to 3-fold increase in serum levels of terfenadine acid metabolite and QT interval prolongation, without clinically apparent effects. Similar effects have been observed with concomitant use of astemizole and other macrolides.

Ergotamine/dihydroergotamine

According to post-marketing reports, concomitant use of clarithromycin and ergotamine or dihydroergotamine has been associated with signs of acute ergotism: vasospasm, ischemia of limbs and other tissues, including the central nervous system (CNS). Concomitant administration of clarithromycin and ergot alkaloids is contraindicated (see section "Contraindications").

Oral midazolam

When midazolam was administered with clarithromycin tablets (500 mg twice daily), the AUC of midazolam increased 7-fold. Concomitant use of oral midazolam and clarithromycin is contraindicated (see section "Contraindications").

HMG-CoA reductase inhibitors (statins)

Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated (see section "Contraindications"), as these statins are predominantly metabolized by CYP3A4, and clarithromycin increases their plasma concentration, thereby increasing the risk of myopathy, including rhabdomyolysis. Cases of rhabdomyolysis have been reported in patients receiving concomitant clarithromycin and 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 statins. If concomitant use of clarithromycin with statins cannot be avoided, it is recommended to use the lowest recommended 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 necessary.

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 clarithromycin metabolism. This may lead to subtherapeutic levels of clarithromycin and reduced efficacy. Additionally, monitoring of plasma concentrations 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 serum, with an 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 be reduced with concomitant use of clarithromycin and enzyme inducers.

Etravirine

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

Fluconazole

Administration of fluconazole 200 mg daily together with clarithromycin 500 mg twice daily in 21 volunteers led to an average 33% increase in steady-state 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 use of fluconazole. Dose adjustment of clarithromycin is not required.

Ritonavir

In a pharmacokinetic study, 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%. Complete inhibition of 14-OH-clarithromycin formation was observed. Due to the wide therapeutic window, dose reduction of clarithromycin is not necessary for patients with normal renal function. However, dose adjustment is required for patients with renal insufficiency: for patients with CLCR 30–60 mL/min, the clarithromycin dose should be reduced by 50%. For patients with severe renal insufficiency (CLCR < 30 mL/min), the clarithromycin 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 to patients with impaired renal function when ritonavir is used as a pharmacokinetic booster with other HIV protease inhibitors, including atazanavir and saquinavir (see below "Bidirectional Drug Interactions").

Effect of clarithromycin on other medicinal products

CYP3A-related interactions

Concomitant use of clarithromycin, a known CYP3A enzyme inhibitor, and a drug primarily metabolized by CYP3A may lead to increased plasma concentrations of the latter, which in turn may enhance or prolong its therapeutic effect and increase 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 Warnings and Precautions for Use").

Also contraindicated is the use of clarithromycin 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 another isoenzyme of the cytochrome P450 system.

Direct oral anticoagulants (DOACs)

DOACs dabigatran and edoxaban are substrates of the P-glycoprotein (P-gp) efflux transporter. Rivaroxaban and apixaban are metabolized via CYP3A4 and are also P-gp substrates. Caution should be exercised when using clarithromycin concomitantly with these agents, especially in patients at high risk of bleeding (see section "Special Warnings and Precautions for Use").

Antiarrhythmic agents

Post-marketing reports have described cases of torsade de pointes occurring with concomitant use of clarithromycin and quinidine or disopyramide. ECG monitoring is recommended for early detection of QT interval prolongation. During clarithromycin therapy, serum concentrations of these drugs should be monitored.

Post-marketing use has reported hypoglycemia 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 hydroxychloroquine or chloroquine, which are known to prolong the QT interval, due to the potential risk of inducing 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

Administration of clarithromycin (500 mg every 8 hours) in combination with omeprazole (40 mg daily) in healthy adult volunteers led to 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 measured over 24 hours was 5.2; with concomitant use of omeprazole and clarithromycin, it was 5.7.

Sildenafil, tadalafil, and vardenafil

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

Theophylline, carbamazepine

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 cytochrome P450 2D6 isoenzyme (CYP2D6). However, in patients lacking CYP2D6, metabolism occurs via CYP3A. In this population, inhibition of CYP3A leads to significantly increased plasma concentrations of tolterodine. Dose reduction of tolterodine may be necessary in such patients 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. Combined use of oral midazolam and clarithromycin should be avoided. With intravenous administration of midazolam and clarithromycin, close monitoring of the patient is required for timely dose adjustment.

The same precautions should be taken 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 described drug interactions and CNS adverse effects (such as drowsiness and confusion) with concomitant use of clarithromycin and triazolam. Patients should be monitored, considering the possibility of increased pharmacological effects on the CNS.

Corticosteroids

Caution should be exercised when using clarithromycin concomitantly with systemic and inhaled corticosteroids, which 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

Colchicine

Colchicine is a substrate of CYP3A and P-gp. Clarithromycin and other macrolides are known to inhibit CYP3A and P-gp. Concomitant use of clarithromycin and colchicine may lead to increased colchicine exposure due to inhibition of P-gp and/or CYP3A by clarithromycin.

Concomitant use of clarithromycin with colchicine is contraindicated (see sections "Contraindications" and "Special Warnings and Precautions for Use").

Digoxin

Digoxin is considered a P-gp substrate. Clarithromycin is known to inhibit P-gp. Concomitant use may lead to increased digoxin exposure due to P-gp inhibition. Post-marketing reports have described increased serum digoxin concentrations in patients receiving clarithromycin concomitantly with digoxin. In some patients, signs of digoxin toxicity, including potentially life-threatening arrhythmias, developed. Serum digoxin concentrations should be closely monitored when used with clarithromycin.

Zidovudine

Concomitant use of 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, but this can largely be avoided by maintaining a 4-hour interval between doses of clarithromycin and zidovudine. This interaction was not observed with use of clarithromycin suspension and zidovudine or didanosine in HIV-infected children. The interaction is unlikely when clarithromycin is administered intravenously.

Phenytoin and valproate

There are spontaneous or published reports of interactions between CYP3A inhibitors, including clarithromycin, and drugs not metabolized by CYP3A (e.g., phenytoin and valproate). Monitoring of serum levels of such 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, led to a doubling of clarithromycin exposure and a 70% reduction in 14-OH-clarithromycin exposure, with a 28% increase in atazanavir AUC. Since clarithromycin has a wide therapeutic range, dose reduction is not necessary for patients with normal renal function. The clarithromycin dose should be reduced by 50% for patients with creatinine clearance of 30–60 mL/min and by 75% for patients with creatinine clearance < 30 mL/min. 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). 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, thus clarithromycin may increase plasma levels of itraconazole and vice versa. When itraconazole is used concomitantly with clarithromycin, patients should be closely monitored for signs or symptoms of enhanced or prolonged pharmacological effect.

Saquinavir

Concomitant use of clarithromycin (500 mg twice daily) and saquinavir (soft gelatin capsules, 1200 mg three times daily), both substrates and inhibitors of CYP3A, in 12 healthy volunteers led to a 177% increase in saquinavir steady-state AUC and an 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 drugs are used concomitantly for a limited period and at the aforementioned doses/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 with saquinavir/ritonavir therapy. When 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, particularly during the first trimester of pregnancy (see section "Use during pregnancy or breastfeeding").

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

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

Clarithromycin is primarily eliminated via the liver. Caution should be exercised when administering clarithromycin to patients with moderate to severe hepatic impairment (see section "Dosage and administration").

Hepatic function abnormalities, including elevated liver enzymes, and hepatocellular and/or cholestatic hepatitis, with or without jaundice, have been reported during clarithromycin therapy. Hepatic dysfunction may be severe but is usually reversible. Rare cases of fatal hepatic failure have been reported (see section "Side effects"), primarily in patients with serious underlying diseases and/or concomitant medications. Clarithromycin therapy should be discontinued immediately if signs or symptoms of hepatitis occur, such as anorexia, jaundice, dark urine, pruritus, or abdominal pain.

Pseudomembranous colitis, ranging from mild to life-threatening, has been reported with nearly all antibacterial agents, including macrolides. Cases of Clostridium difficile-associated diarrhea (CDAD), ranging from mild to fatal colitis, have been reported with nearly all antibacterial agents, including clarithromycin. Antibacterial therapy may disrupt the normal intestinal flora, leading to overgrowth of Clostridium difficile. CDAD should always be considered in any patient presenting with diarrhea following antibiotic use. A careful medical history is essential, as CDAD has been reported even up to two months after antibacterial therapy. Therefore, clarithromycin treatment should be discontinued regardless of the initial indication. Microbiological testing should be performed and appropriate therapy initiated. Antiperistaltic agents should be avoided.

Colchicine

Colchicine toxicity (including fatal outcomes) has been reported with concomitant use of clarithromycin and colchicine, particularly in elderly patients and those with renal impairment (see section "Interaction with other medicinal products and other forms of interaction"). The concomitant use of clarithromycin with colch游戏副本

Dosage and Administration

Nontuberculous infections

For the treatment of nontuberculous infections, the recommended dose for infants and children aged 6 months to 12 years is 7.5 mg/kg twice daily, up to a maximum of 500 mg twice daily. The duration of treatment is usually 5–10 days, depending on the type of pathogen and severity of the disease. The suspension can be administered regardless of food intake (it may be taken with milk).

It is recommended to give the child a small amount of liquid after administration of the suspension. The oral suspension contains small granules which should not be chewed by the child, as their contents have a bitter taste. An oral dosing syringe is provided for administering the dose. One full syringe contains 5 mL of suspension, which corresponds to 125 mg. After each use, the syringe should be rinsed with water.

Dosage of the medicinal product for children with nontuberculous infection according to body weight.

*For children with body weight below 8 kg, the dose should be calculated per kilogram of body weight (7.5 mg/kg twice daily).

Patients with renal impairment

In children with creatinine clearance below 30 mL/min, the dose of the drug should be reduced by 50% to 7.5 mg/kg daily. Treatment should not last longer than 14 days.

Mycobacterial infections

For the treatment of mycobacterial infections in children, the recommended dose of clarithromycin as a suspension is 7.5 to 15 mg/kg twice daily, depending on the physician's individual clinical assessment of the patient's condition and severity of the disease; however, the maximum dose should not be exceeded—500 mg twice daily.

Treatment should be continued as long as clinical efficacy is observed (additional therapy in combination with other antimycobacterial drugs may be required). The dosage of the drug recommended for the treatment of children with mycobacterial infections depends on the child's body weight.

Dosage of the medicinal product for children with mycobacterial infection depends on body weight.

*For children with body weight below 8 kg, the dose should be calculated per kilogram of body weight (7.5–15 mg/kg/day).

**It is recommended to use the medicinal product Fromilid® with a dosage strength of 250 mg/5 ml.

Preparation of suspension

To prepare 60 ml of suspension, 42 ml of purified or boiled and cooled water is required. Shake the bottle to disperse the granules. Add approximately half of the required volume of water and shake thoroughly until the granules dissolve. Then add the remaining water up to the mark on the bottle and shake well.

Avoid vigorous and/or prolonged shaking. The bottle should be shaken before each administration to re-suspend the suspension.

Children.

Clinical studies on the use of clarithromycin in suspension form have been conducted in children aged from 6 months to 12 years; therefore, clarithromycin in suspension form can be prescribed to children aged from 6 months to 12 years.

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 altered mental status, paranoid behavior, hypokalemia, and hypoxemia.

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

Adverse reactions

The most common and frequently reported 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 trials.

The table below lists adverse reactions reported 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 — < 1/10), uncommon (≥ 1/1000 — < 1/100), and frequency not known (reactions reported during post-marketing experience; frequency cannot be estimated based on available data).

1,2,3,4The following 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.

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 longer than recommended for the treatment of mycobacterial infections, it may not always be 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, 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 were observed in 2–3% of these patients. A smaller percentage of patients showed increased blood urea nitrogen levels.

If serious adverse effects occur, treatment should be discontinued.

Reporting of suspected adverse reactions

Reporting of adverse reactions after drug registration is of great importance. It enables ongoing monitoring of the benefit-risk balance of the drug. 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. 2 years.

The prepared suspension should be used within 14 days when stored at a temperature not exceeding 25 °C. Store in the original packaging to protect from light.

Storage conditions.

Store at a temperature not exceeding 30 °C. Keep out of reach of children.

Packaging.

Granules for oral suspension 60 mL (125 mg/5 mL), in a glass bottle with a plastic cap, oral suspension dosing syringe, in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

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

Manufacturer's address and location of business operations.

Smarjeska cesta 6, 8501 Novo mesto, Slovenia.