Instructions Fromilid granules for oral suspension 125 mg/5 ml bottle for suspension preparation 60 ml
Composition
active ingredient: clarithromycin;
5 ml of oral suspension (1 syringe) contains 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.
Dosage form
Granules for oral suspension.
Main physicochemical properties: small, heterogeneous granules from white to almost white in color with a banana aroma.
Pharmacotherapeutic group
Antimicrobials for systemic use. Macrolides. ATX code J01F A09.
Pharmacological properties
Pharmacodynamics.
Clarithromycin is a semisynthetic macrolide antibiotic. The antibacterial effect of clarithromycin is determined by its binding to the 5OS ribosomal subunit of sensitive bacteria and inhibition of protein biosynthesis. The drug exhibits high in vitro activity against a wide range of aerobic and anaerobic gram-positive and gram-negative microorganisms, including hospital strains. The minimum inhibitory concentrations (MICs) of clarithromycin are usually two times lower than the MICs of erythromycin.
Clarithromycin in vitro has high activity against Legionella pneumophila and Mycoplasma pneumoniae. It is bactericidal against Helicobacter 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 gram-negative bacteria that do not produce lactose, are insensitive 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 of microorganisms do not affect the effectiveness of clarithromycin.
Most methicillin- and oxacillin-resistant strains of staphylococci are insensitive to clarithromycin.
Clarithromycin is active in vitro against most strains of the following microorganisms, however, clinical efficacy and safety 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: Bacteriodes melaninogenicus.
Spirochetes: Borrelia burgdorferi, Treponema pallidum.
Campylobacter: Campylobacter jejuni.
Clarithromycin has bactericidal activity against several strains of bacteria: Haemophilus influenzae, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Moraxella (Branhamella) catarrhalis, Neisseria gonorrhoeae, Helicobacter pylori and Campylobacter spp.
The main metabolite of clarithromycin in humans 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 the activity of the parent substance, with the exception of Haemophilus influenzae, against which the effectiveness of the metabolite is 2 times higher. In vitro and in vivo, the parent substance and its main metabolite exhibit either an additive or synergistic effect against Haemophilus influenzae, depending on the strain of the microorganism.
Pharmacokinetics.
Clarithromycin is rapidly and well absorbed from the gastrointestinal tract. Microbiologically active 14-OH-clarithromycin is formed during the first pass through the liver. When the drug is taken with food, the onset of absorption and formation of 14-OH-clarithromycin is slightly delayed, but the overall bioavailability is not changed. Although the pharmacokinetics of clarithromycin are nonlinear, stable concentrations are established within 2 consecutive days of administration.
Clarithromycin concentrations in body tissues are several times higher than in serum. Increased concentrations of clarithromycin are observed in tonsillar and lung tissues. Clarithromycin concentrations in middle ear fluid exceed serum concentrations. Clarithromycin, when used in therapeutic doses, 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. Most of the remainder of the dose is excreted in the bile. 5–10% of the active substance is excreted in the feces.
Steady-state concentrations of clarithromycin in patients with hepatic impairment and in healthy volunteers do not differ, except for lower concentrations of 14-OH-clarithromycin in hepatic dysfunction.
In patients with renal impairment receiving a 500 mg dose, pharmacokinetic parameters increased in proportion to the severity of renal impairment.
The age of patients does not affect the pharmacokinetic parameters of clarithromycin.
HIV-infected children receiving clarithromycin at doses of 15–30 mg/kg/day (in 2 divided doses) had higher plasma concentrations of clarithromycin and a longer half-life.
Indication
Infections caused by microorganisms sensitive to clarithromycin:
Upper respiratory tract infections, i.e. nasopharynx (tonsillitis, pharyngitis), and sinus infections.
Lower respiratory tract infections (bronchitis, acute croupous pneumonia and primary atypical pneumonia).
Acute otitis media.
Skin and soft tissue infections (folliculitis, impetigo, erysipelas, 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.
Contraindication
Hypersensitivity to macrolide antibiotics and to other components of the drug.
Concomitant use of astemizole, cisapride, domperidone, pimozide, terfenadine - as this may lead to prolongation of the QT interval and the 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 types of interactions").
Concomitant use of ergot alkaloids, such as ergotamine, dihydroergotamine, as this may lead to ergotoxicity.
Concomitant use of HMG-CoA reductase inhibitors (statins) that are extensively metabolized by CYP3A4 (lovastatin or simvastatin) - due to an increased risk of myopathy, including rhabdomyolysis (see sections "Special warnings and precautions for use" and "Interaction with other medicinal products and other types of interactions").
Concomitant use of clarithromycin with lomitapide (see section “Interaction with other medicinal products and other types of interactions”).
Congenital or established acquired prolongation of the QT interval 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 types of interactions").
Concomitant use of clarithromycin and oral midazolam (see section “Interaction with other medicinal products and other types of interactions”).
Electrolyte disturbances (hypokalemia or hypomagnesemia) - due to the risk of QT prolongation.
Severe hepatic insufficiency with concomitant renal insufficiency (see sections “Special warnings and precautions for use” and “Interaction with other medicinal products and other types of interactions”).
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 types of interactions").
Concomitant use of clarithromycin with ticagrelor, ivabradine, or ranolazine.
Interaction with other medicinal products and other types of interactions
The use of the following drugs with clarithromycin is strictly contraindicated due to the risk of serious interaction effects:
Astemizole, cisapride, domperidone, pimozide, terfenadine
Increased serum levels of cisapride have been observed when co-administered with clarithromycin, which may lead to QT prolongation and cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation, and torsade de pointes. Similar effects have been observed with co-administration of pimozide and clarithromycin (see Contraindications).
Macrolides have been reported to alter the metabolism of terfenadine, leading to increased serum terfenadine levels, which have sometimes been associated with cardiac arrhythmias such as QT prolongation, ventricular tachycardia, ventricular fibrillation and torsade de pointes (see section 4.3). In a study of 14 volunteers, concomitant administration of terfenadine and clarithromycin resulted in a 2- to 3-fold increase in the acid metabolite of terfenadine and a prolongation of the QT interval, without clinically significant effects. Similar effects have been observed with concomitant administration of astemizole and other macrolides.
Ergotamine/dihydroergotamine
According to postmarketing reports, concomitant use of clarithromycin and ergotamine or dihydroergotamine has been associated with the development of signs of acute ergotism: vasospasm, ischemia of the extremities and other tissues, including the central nervous system (CNS). Concomitant administration of clarithromycin and ergot alkaloids is contraindicated (see section 4.3).
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 4.3).
HMG-CoA reductase inhibitors (statins)
Clarithromycin should be used with caution when co-administered with statins. If concomitant use of clarithromycin with statins cannot be avoided, the lowest recommended dose of the statin is recommended. A statin that is not metabolized by CYP3A (e.g. fluvastatin) may be used. Patients should be monitored for signs and symptoms of myopathy.
Lomitapide
Concomitant administration of clarithromycin with lomitapide is contraindicated due to the potential for significant elevations in transaminase levels (see Contraindications).
Effects of other drugs on clarithromycin
Medicinal products that are inducers of CYP3A (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital, St. John's wort) may induce the metabolism of clarithromycin. This may lead to subtherapeutic levels of clarithromycin and reduced efficacy. In addition, it may be necessary to monitor plasma concentrations of the CYP3A inducer, which may be increased due to inhibition of CYP3A by clarithromycin (see also the Summary of Product Characteristics of the respective CYP3A4 inducer). Concomitant use of rifabutin and clarithromycin has been shown to increase serum levels of rifabutin and decrease serum levels of clarithromycin, with a concomitant increase in the risk of uveitis.
The following drugs are known or suspected to affect clarithromycin blood concentrations and may require dose adjustment or alternative therapy.
Efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine
Potent inducers of cytochrome P450 enzymes, such as efavirenz, nevirapine, rifampicin, rifabutin and rifapentine, may accelerate the metabolism of clarithromycin, reducing its plasma concentration but increasing the concentration of 14-OH-clarithromycin, the microbiologically active metabolite. Since the microbiological activity of clarithromycin and 14-OH-clarithromycin differs against different bacteria, the expected therapeutic effect may be reduced by the concomitant use of clarithromycin and enzyme inducers.
Etravirine
Clarithromycin activity was attenuated by etravirine; however, concentrations of the active metabolite 14-OH-clarithromycin were increased. Since 14-OH-clarithromycin has reduced activity against MAC, overall activity against this pathogen may be altered. Therefore, alternative agents should be considered for the treatment of MAC.
Fluconazole
The use of fluconazole 200 mg daily with clarithromycin 500 mg twice daily in 21 volunteers resulted in an average increase in steady-state Cmin of clarithromycin by 33% and AUC by 18%. The steady-state concentrations of the active metabolite 14-OH-clarithromycin were not significantly altered by coadministration with fluconazole. No dose adjustment of clarithromycin is required.
Ritonavir
In a pharmacokinetic study, coadministration of ritonavir 200 mg every 8 hours and clarithromycin 500 mg every 12 hours resulted in significant inhibition of clarithromycin metabolism. Clarithromycin Cmax 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, no dose reduction of clarithromycin is necessary in patients with normal renal function. However, dose adjustment is required in patients with renal impairment: for patients with CLCR 30–60 mL/min, the clarithromycin dose should be reduced by 50%. For patients with severe renal impairment (CLCR < 30 mL/min), the clarithromycin dose should be reduced by 75%. Clarithromycin at doses exceeding 1 g/day should not be used with ritonavir.
Similar dose adjustments should be made in patients with renal impairment when ritonavir is used as a pharmacokinetic enhancer with other HIV protease inhibitors, including atazanavir and saquinavir (see “Bidirectional drug interactions” below).
Effect of clarithromycin on other medicinal products
CYP3A-related interactions
Concomitant use of clarithromycin, a known inhibitor of the CYP3A enzyme, and a drug that is primarily metabolized by CYP3A may result in increased plasma concentrations of the latter, which in turn may enhance or prolong its therapeutic effect and the risk of adverse reactions.
Clarithromycin is contraindicated in patients receiving the CYP3A substrates astemizole, cisapride, domperidone, pimozide, and terfenadine due to the risk of QT prolongation and cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation, and torsades de pointes (see sections 4.3 and 4.4).
Caution should be exercised when clarithromycin is coadministered with other drugs that are substrates of the CYP3A enzyme, especially if the CYP3A substrate has a narrow safety margin (e.g. carbamazepine) and/or the substrate is extensively metabolized by this enzyme. In such cases, dose adjustment may be necessary and, if possible, serum concentrations of drugs that are primarily metabolized by CYP3A should be closely monitored. Drugs or drug classes known or suspected to be metabolized by the same CYP3A isoenzyme include (but are not limited to): 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 mechanism of interaction has been observed with phenytoin, theophylline, and valproate, which are metabolized by a different isoenzyme of the cytochrome P450 system.
Direct-acting oral anticoagulants (DAOCs)
The PAPDs dabigatran and edoxaban are substrates for the efflux transporter P-glycoprotein (P-gp). Rivaroxaban and apixaban are metabolized by CYP3A4 and are also substrates for P-gp. Caution should be exercised when clarithromycin is co-administered with these drugs, especially in patients at high risk of bleeding (see section 4.4).
Antiarrhythmic drugs
There have been postmarketing reports of torsade de pointes occurring with concomitant use of clarithromycin with quinidine or disopyramide. ECG monitoring is recommended for early detection of QT prolongation. Serum concentrations of these drugs should be monitored during clarithromycin therapy.
During post-marketing use, hypoglycemia has been reported with concomitant use of clarithromycin and disopyramide, therefore blood glucose levels should be monitored during concomitant use of these agents.
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 for induction of cardiac arrhythmias and serious adverse cardiovascular events.
Oral hypoglycemic agents/insulin
When used concomitantly with certain hypoglycemic agents such as nateglinide and repaglinide, clarithromycin may inhibit the CYP3A enzyme, which may cause hypoglycemia. Close monitoring of glucose levels is recommended.
Omeprazole
The use of clarithromycin (500 mg every 8 hours) in combination with omeprazole (40 mg daily) in healthy adult volunteers resulted in an increase in steady-state concentrations of omeprazole (Cmax, AUC0-24, t1/2 increased by 30%, 89% and 34%, respectively). When omeprazole was used alone, the mean pH of gastric juice measured over 24 hours was 5.2, when omeprazole was used together with clarithromycin - 5.7.
Sildenafil, tadalafil and vardenafil
Each of these phosphodiesterase inhibitors is metabolized (at least in part) by CYP3A, and CYP3A may be inhibited by concomitant clarithromycin. Concomitant administration of clarithromycin with sildenafil, tadalafil, or vardenafil may result in increased exposure to the phosphodiesterase inhibitor, and a reduction in the dose of sildenafil, tadalafil, or vardenafil should be considered.
Theophylline, carbamazepine
Clinical studies have shown that there is a small but statistically significant (p ≤ 0.05) increase in plasma concentrations of theophylline or carbamazepine when co-administered with clarithromycin. A dose reduction may be necessary.
Tolterodine
Tolterodine is primarily metabolized by the cytochrome P450 2D6 isoform (CYP2D6). However, in patients lacking CYP2D6, metabolism occurs via CYP3A. In this population, inhibition of CYP3A results in significantly increased plasma concentrations of tolterodine. In such patients, a reduction in the dose of tolterodine may be necessary when used with CYP3A inhibitors such as clarithromycin.
Triazolebenzodiazepines (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. The combined use of oral midazolam and clarithromycin should be avoided. When intravenous midazolam is administered with clarithromycin, the patient should be closely monitored for timely dose adjustment.
The same precautions should be taken when using other benzodiazepines that are metabolized by CYP3A, including triazolam and alprazolam. For benzodiazepines whose elimination is not dependent on CYP3A (temazepam, nitrazepam, lorazepam), the development of clinically significant interactions with clarithromycin is unlikely.
There have been postmarketing reports of drug interactions and CNS adverse events (such as drowsiness and confusion) with concomitant use of clarithromycin and triazolam. The patient should be monitored for the potential for increased CNS pharmacological effects.
Caution should be exercised when clarithromycin is coadministered with systemic and inhaled corticosteroids that are primarily metabolized by CYP3A due to the potential for increased systemic exposure to the corticosteroid. Patients should be closely monitored for adverse effects of systemic corticosteroids during concomitant use.
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. When clarithromycin and colchicine are coadministered, inhibition of P-gp and/or CYP3A by clarithromycin may result in increased exposure to colchicine.
Concomitant use of clarithromycin with colchicine is contraindicated (see sections "Contraindications" and "Special warnings and precautions for use").
Digoxin
Digoxin is considered a substrate of P-gp. Clarithromycin is known to inhibit P-gp. Inhibition of P-gp may lead to increased exposure to digoxin when used concomitantly. During post-marketing surveillance, increased serum digoxin concentrations have been reported in patients receiving clarithromycin concomitantly with digoxin. Some patients have developed signs of digitalis toxicity, including potentially fatal arrhythmias. Serum digoxin concentrations should be closely monitored in patients receiving clarithromycin.
Zidovudine
Concomitant administration of clarithromycin tablets and zidovudine in HIV-infected patients may result in decreased steady-state serum concentrations of zidovudine. Clarithromycin may interfere with the absorption of oral zidovudine when co-administered, but this can be largely avoided by separating the doses of clarithromycin and zidovudine by 4 hours. No such interaction has been observed with clarithromycin suspension and zidovudine or dideoxyinosine in HIV-infected children. The interaction is unlikely when clarithromycin is administered intravenously.
Phenytoin and valproate
There have been spontaneous or published reports of interactions between CYP3A inhibitors, including clarithromycin, and drugs not metabolized by CYP3A (e.g., phenytoin and valproate). It is recommended that serum levels of such drugs be monitored when co-administered with clarithromycin. Increased serum levels have been reported.
Bidirectional drug interactions
Atazanavir
Coadministration of clarithromycin (500 mg twice daily) with atazanavir (400 mg once daily), which are CYP3A substrates and inhibitors, resulted in a 2-fold increase in clarithromycin exposure and a 70% decrease in 14-OH-clarithromycin exposure with a 28% increase in atazanavir AUC. Since clarithromycin has a wide therapeutic range, no dose reduction is necessary in patients with normal renal function. The clarithromycin dose should be reduced by 50% for patients with creatinine clearance 30–60 mL/min and by 75% for patients with creatinine clearance < 30 mL/min. Clarithromycin doses above 1000 mg daily should not be administered with protease inhibitors.
Calcium channel blockers
Due to the risk of hypotension, caution should be exercised when clarithromycin is administered concomitantly with calcium channel blockers metabolized by CYP3A4 (such as verapamil, amlodipine, diltiazem). The interaction may result in increased plasma concentrations of both clarithromycin and the calcium channel blocker. Hypotension, bradyarrhythmias, and lactic acidosis have been reported in patients receiving clarithromycin and verapamil.
Itraconazole
Clarithromycin and itraconazole are substrates and inhibitors of CYP3A, and therefore clarithromycin may increase plasma levels of itraconazole and vice versa. When itraconazole is used with clarithromycin, patients should be closely monitored for signs or symptoms of an enhanced or prolonged pharmacological effect.
Saquinavir
Coadministration of clarithromycin (500 mg twice daily) with saquinavir (soft gelatin capsules, 1200 mg three times daily), both substrates and inhibitors of CYP3A, in 12 healthy volunteers resulted in a 177% increase in steady-state AUC and a 187% increase in Cmax compared to saquinavir alone. The AUC and Cmax of clarithromycin were increased by approximately 40% compared to clarithromycin alone. No dose adjustment is necessary when both drugs are coadministered for a limited period of time and at the above-mentioned doses/formulations. The results of a drug interaction study with the soft gelatin capsules may not be consistent with the effects observed with the hard gelatin capsule formulation of saquinavir. The results of drug interaction studies with saquinavir alone may not be consistent with the effects observed with saquinavir/ritonavir therapy. When saquinavir is used with ritonavir, the potential effect of ritonavir on clarithromycin should be considered (see above).
Application features
The drug should be used with caution in patients with moderate or severe renal impairment (see section "Method of administration and dosage").
Prolonged or repeated use of antibiotics may result in overgrowth of non-susceptible bacteria and fungi. If superinfection occurs, appropriate therapy should be initiated.
Clarithromycin is primarily eliminated by the liver. Clarithromycin should be used with caution in patients with moderate to severe hepatic impairment (see Dosage and Administration).
Hepatic dysfunction, including elevated liver enzymes, and hepatocellular and/or cholestatic hepatitis with or without jaundice have been reported with clarithromycin. Hepatic dysfunction may be severe but is usually reversible. Fatal hepatic failure has occasionally been reported (see Adverse Reactions), and has been generally associated with serious underlying medical conditions and/or concomitant medication. Clarithromycin should be discontinued immediately if signs and symptoms of hepatitis such as anorexia, jaundice, dark urine, pruritus, or abdominal pain occur.
Pseudomembranous colitis, ranging from moderate to life-threatening, has been reported with nearly all antibacterial agents, including macrolides. Clostridium difficile-associated diarrhea (CDAD), ranging from moderate to fatal, has been reported with nearly all antibacterial agents, including clarithromycin. Antibacterial therapy disrupts the normal intestinal flora, which may lead to overgrowth of Clostridium difficile. The possibility of Clostridium difficile-associated diarrhea should always be kept in mind in all patients presenting with diarrhea following antibiotic therapy. In addition, a careful history should be taken, as CDAD has been reported up to 2 months after the administration of antibacterial agents. Therefore, clarithromycin should be discontinued regardless of the indication for which it was prescribed. Microbiological investigations should be performed and appropriate treatment initiated. Drugs that inhibit peristalsis should be avoided.
Colchicine
Colchicine toxicity (including fatal outcomes) has been reported with concomitant use of clarithromycin and colchicine, particularly in the elderly, including patients with renal insufficiency (see section 4.5). Concomitant use of clarithromycin and colchicine is contraindicated (see section 4.3).
Caution should be exercised when clarithromycin is administered concomitantly with triazolebenzodiazepines, e.g. triazolam, intravenous midazolam (see section “Interaction with other medicinal products and other forms of interaction”).
Clarithromycin should be used with caution in combination with other ototoxic agents, especially aminoglycosides. Vestibular and auditory function should be monitored during and after treatment.
Cardiovascular complications
QT prolongation, which reflects an effect on cardiac repolarization, which poses a risk of cardiac arrhythmias and torsades de pointes, has been observed in patients treated with macrolides, including clarithromycin (see section 4.8). 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 and terfenadine; patients with hypokalemia; patients with a history of QT prolongation or ventricular cardiac arrhythmias (see section 4.8).
In addition, clarithromycin should be used with caution in the following patient groups.
Patients with ischemic heart disease, severe heart failure, conduction disturbances, or clinically significant bradycardia.
Patients who are concurrently taking other drugs that prolong the QT interval, except those that are contraindicated.
Epidemiological studies on the risk of adverse cardiovascular events with macrolides have been mixed. Some studies have reported a rare short-term risk of arrhythmia, myocardial infarction, and fatal cardiovascular events associated with macrolides, including clarithromycin. Consideration of these findings when prescribing clarithromycin should be balanced against the benefits of treatment.
Pneumonia
Since Streptococcus pneumoniae may be resistant to macrolides, it is important to perform susceptibility testing when prescribing clarithromycin for the treatment of community-acquired pneumonia. In the case of nosocomial pneumonia, clarithromycin should be used in combination with other appropriate antibiotics.
These infections are most commonly caused by Staphylococcus aureus and Streptococcus pyogenes, both of which may be resistant to macrolides. Susceptibility testing is therefore important. In cases where beta-lactam antibiotics cannot be used (e.g., in cases of allergy), other antibiotics, such as clindamycin, may be used as first-line agents. Macrolides currently have a role only in the treatment of some skin and soft tissue infections, such as those caused by Corynebacterium minutissimum, acne vulgaris, erysipelas, and in situations where penicillins cannot be used.
In the event of the development of severe acute hypersensitivity reactions such as anaphylaxis, severe cutaneous adverse reactions (e.g. acute generalized exanthematous pustulosis, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS)), Henoch-Schonlein-Schönlein disease, clarithromycin therapy should be discontinued immediately and appropriate treatment should be initiated immediately.
Clarithromycin should be used with caution when co-administered with inducers of the cytochrome CYP3A4 enzyme (see section “Interaction with other medicinal products and other types of interactions”).
Attention should be paid to the possible cross-resistance between clarithromycin and other macrolides, as well as lincomycin and clindamycin.
HMG-CoA reductase inhibitors (statins)
The combined use of clarithromycin with lovastatin or simvastatin is contraindicated (see section "Contraindications"). Caution should be exercised when clarithromycin is administered concomitantly with other statins. Rhabdomyolysis has been reported in patients receiving concomitant clarithromycin and statins. Patients should be monitored for signs and symptoms of myopathy. If concomitant use of clarithromycin with statins cannot be avoided, the lowest recommended dose of the statin is recommended. A statin that is not metabolized by CYP3A (e.g. fluvastatin) may be used (see section "Interaction with other medicinal products and other forms of interaction").
Oral hypoglycemic agents/insulin
Concomitant use of clarithromycin and oral hypoglycaemic agents (e.g. sulphonylureas) and/or insulin may result in severe hypoglycaemia. Close monitoring of glucose levels is recommended (see section 4.5).
Oral anticoagulants
Concomitant use of clarithromycin with warfarin is associated with a risk of serious bleeding, significant increases in INR (international normalized ratio) and prothrombin time (see section 4.5). INR and prothrombin time should be monitored regularly while patients are receiving concomitant clarithromycin and oral anticoagulants.
Caution should be exercised when clarithromycin is co-administered with direct-acting oral anticoagulants such as dabigatran, rivaroxaban, apixaban and edoxaban, especially in patients at high risk of bleeding (see section 4.5).
Excipients
The medicinal product contains sucrose, therefore patients with rare hereditary forms of fructose intolerance, glucose-galactose malabsorption syndrome or sucrase-isomaltase insufficiency should not use it.
Fromilid®, granules for oral suspension, also contains castor oil, which may cause stomach upset and diarrhea.
Use during pregnancy or breastfeeding
Pregnancy
The safety of clarithromycin during pregnancy or lactation has not been established. Based on the results of animal studies and experience with clarithromycin in humans, the possibility of adverse effects on embryonal development cannot be excluded. Some observational studies evaluating the effects of clarithromycin during the first and second trimesters have shown an increased risk of miscarriage compared with no antibiotic use or the use of other antibiotics during that period.
