Meristat-sanovel
Ukraine
Table of Contents
INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT MERISTAT-sanovel (MERISTAT-sanovel)
Composition:
Active substance: clarithromycin;
1 tablet contains clarithromycin 250 mg;
Excipients: microcrystalline cellulose, sodium starch glycolate (type A), povidone, colloidal anhydrous silicon dioxide, talc, magnesium stearate;
coating: sodium saccharin, vanillin, Opadry OY-S-32920 yellow (hypromellose, titanium dioxide (E 171), quinoline yellow (E 104), propylene glycol, hydroxypropylcellulose, polysorbate 80, vanillin, iron oxide yellow (E 172), FD&C blue no. 2), Opadry YS-1R-7006 clear (hypromellose, polyethylene glycol);
or
1 tablet contains clarithromycin 500 mg;
Excipients: microcrystalline cellulose, sodium starch glycolate (type A), povidone, colloidal anhydrous silicon dioxide, talc, magnesium stearate;
coating: sodium saccharin, vanillin, Opadry OY-S-32917 yellow (hypromellose, titanium dioxide (E 171), propylene glycol, hydroxypropylcellulose, polysorbate 80, vanillin, iron oxide yellow (E 172), FD&C yellow no. 5, FD&C blue no. 2), Opadry YS-1R-7006 clear (hypromellose, polyethylene glycol).
Pharmaceutical form. Film-coated tablets.
Main physico-chemical properties: 250 mg tablets – elongated, biconvex film-coated tablets of bright yellow color, with an "S" imprint on one side; 500 mg tablets – elongated, biconvex film-coated tablets of light yellow color, with an "S" imprint on one side.
Pharmacotherapeutic group.
Antibacterials for systemic use. Macrolides. Clarithromycin.
ATC code J01FA09.
Pharmacological properties.
Pharmacodynamics.
Clarithromycin is a semi-synthetic antibiotic of the macrolide group.
The antibacterial action of clarithromycin is determined by its binding to the 50S ribosomal subunit of susceptible bacteria and inhibition of protein biosynthesis. The drug demonstrates high efficacy in vitro against a broad spectrum of aerobic and anaerobic gram-positive and gram-negative microorganisms, including hospital strains. Minimum inhibitory concentrations (MICs) of clarithromycin are usually two times lower than those of erythromycin.
Clarithromycin is highly effective in vitro against Legionella pneumophila and Mycoplasma pneumoniae. It exerts a bactericidal effect against H. pylori. The activity of clarithromycin at neutral pH is higher than at acidic pH. In vitro and in vivo data indicate high efficacy of clarithromycin against clinically significant strains of mycobacteria. In vitro studies have shown that strains of Enterobacteriaceae and Pseudomonas, as well as non-lactose-fermenting gram-negative bacteria, are insensitive to clarithromycin.
Microbiology
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.
Helicobacter: H. pylori.
Other microorganisms: Mycoplasma pneumoniae, Chlamydia pneumoniae (TWAR).
Mycobacteria: Mycobacterium leprae, Mycobacterium kansasii, Mycobacterium chelonae, Mycobacterium fortuitum, Mycobacterium avium complex (MAC), which includes Mycobacterium avium, Mycobacterium intracellulare.
Beta-lactamases produced by microorganisms do not affect the efficacy of clarithromycin.
Most methicillin- and oxacillin-resistant strains of staphylococci are insensitive 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: Clostridium perfringens, Peptococcus niger, Propionibacterium acnes.
Anaerobic gram-negative microorganisms: Bacteroides melaninogenicus.
Spirochetes: Borrelia burgdorferi, Treponema pallidum.
Campylobacters: Campylobacter jejuni.
Clarithromycin exerts bactericidal action against several bacterial strains: Haemophilus influenzae, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Moraxella (Branhamella) catarrhalis, Neisseria gonorrhoeae, H. pylori, and Campylobacter spp.
The main metabolite of clarithromycin in the human body is 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 H. influenzae, against which the metabolite is twice as effective. In vitro and in vivo, the parent compound and its main metabolite exhibit either an additive or synergistic effect against H. influenzae, depending on the microbial strain.
Susceptibility testing
Quantitative methods requiring measurement of inhibition zone diameters provide the most accurate assessment of bacterial susceptibility to antimicrobial agents. In one of the recommended susceptibility testing procedures, disks impregnated with 15 mcg of clarithromycin (Kirby–Bauer diffusion test) are used; the diameter of the inhibition zone for this disk is correlated with MIC values for clarithromycin. MIC is determined by broth or agar dilution methods.
When performing these procedures, a laboratory report stating "susceptible" indicates that the infecting microorganism is likely to respond to therapy. A report stating "resistant" indicates that the infecting microorganism is unlikely to respond to therapy. A report of "intermediate susceptibility" suggests that the therapeutic effect of the drug may be uncertain or that the microorganism may be susceptible if higher doses are administered (intermediate susceptibility is also referred to as moderate susceptibility).
Country- or region-specific data on absolute breakpoints for susceptibility, resistance, and intermediate susceptibility should be taken into account.
Pharmacokinetics.
Clarithromycin is rapidly and well absorbed from the gastrointestinal tract after oral administration in tablet form. The microbiologically active metabolite, 14-hydroxyclarithromycin, is formed via first-pass metabolism. Clarithromycin can be administered independently of food intake, as food does not affect the bioavailability of clarithromycin tablets. Food slightly delays the onset of absorption of clarithromycin and formation of the 14-hydroxy metabolite. The pharmacokinetics of clarithromycin is nonlinear, but steady-state concentrations are achieved within 2 days of drug administration. After administration of 250 mg twice daily, 15–20% of unchanged drug is excreted in urine. At a dose of 500 mg twice daily, urinary excretion is more intensive (approximately 36%).
14-Hydroxyclarithromycin is the main metabolite excreted in urine, accounting for 10–15% of the administered dose. The majority of the remainder is excreted in feces, primarily via bile.
5–10% of the original compound is found in feces.
When 500 mg of clarithromycin is administered three times daily, plasma concentrations of clarithromycin are higher compared to those achieved with a dose of 500 mg twice daily.
Clarithromycin concentrations in tissues are several times higher than in blood. Elevated concentrations have been found in both tonsillar and lung tissues. At therapeutic doses, clarithromycin is approximately 80% bound to plasma proteins.
Clarithromycin penetrates into the gastric mucosa. The concentration of clarithromycin in the gastric mucosa and gastric tissue is higher when clarithromycin is administered concomitantly with omeprazole than with clarithromycin monotherapy.
Clinical characteristics.
Indications.
Treatment of 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).
- Skin and soft tissue infections (impetigo, folliculitis, erysipeloïd, 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.
- Eradication of H. pylori in patients with duodenal ulcer under conditions of suppressed hydrochloric acid secretion (clarithromycin activity against H. pylori at neutral pH is higher than at acidic pH).
Contraindications.
Hypersensitivity to macrolide antibiotics and to any other components of the medicinal product.
Concomitant use of clarithromycin and any of the following drugs: astemizole, cisapride, pimozide, terfenadine (this may lead to QT interval prolongation and development of cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation, and torsades de pointes), ergot alkaloids, such as ergotamine, dihydroergotamine (this may lead to ergot toxicity), HMG-CoA reductase inhibitors (statins) that are extensively metabolized by CYP3A4 (lovastatin or simvastatin)—due to increased risk of myopathy, including rhabdomyolysis (see sections "Interaction with other medicinal products and other types of interactions" and "Special precautions for use").
Concomitant use of clarithromycin and oral midazolam (see section "Interaction with other medicinal products and other types of interactions").
Contraindicated in patients with a history of QT interval prolongation or ventricular cardiac arrhythmias, including torsades de pointes (see sections "Interaction with other medicinal products and other types of interactions" and "Special precautions for use").
Electrolyte disturbances (hypokalemia or hypomagnesemia)—due to the risk of QT interval prolongation.
Severe hepatic insufficiency and concomitant renal insufficiency.
Concomitant use of clarithromycin (and other potent CYP3A4 inhibitors) with colchicine (see sections "Special precautions for use" and "Interaction with other medicinal products and other types of interactions").
Concomitant use of clarithromycin with ticagrelor, ivabradine, or ranolazine.
Concomitant use of clarithromycin with lomitapide (see "Interaction with other medicinal products and other types of interactions").
Interaction with other medicinal products and other types of interactions.
Clarithromycin does not interact with oral contraceptives.
Use of the following medicinal products is strictly contraindicated due to the potential for severe interaction outcomes.
Cisapride, pimozide, astemizole, terfenadine
Elevated serum levels of cisapride, pimozide, and terfenadine have been observed when administered concomitantly with clarithromycin, which may cause QT interval prolongation and the development of arrhythmias, including ventricular tachycardia, ventricular fibrillation, and torsades de pointes. Similar effects have been reported with concomitant use of astemizole and other macrolides. Similar effects have also been observed in patients receiving clarithromycin and pimozide simultaneously (see section "Contraindications").
Macrolides have been reported to alter terfenadine metabolism, leading to increased serum levels of terfenadine, which has sometimes been associated with arrhythmias such as QT interval prolongation, ventricular tachycardia, ventricular fibrillation, and torsades de pointes (see section "Contraindications"). In a study involving 14 volunteers, concomitant administration of clarithromycin and terfenadine resulted in a 2–3-fold increase in serum levels of terfenadine acid metabolite and QT interval prolongation, which did not lead to any clinically apparent effect. Similar effects have been observed with concomitant use of astemizole and other macrolides.
Ergot alkaloids
Post-marketing reports indicate that concomitant use of clarithromycin with ergotamine or dihydroergotamine has been associated with signs of acute ergotism, characterized by vasospasm and ischemia of extremities and other tissues, including the central nervous system (CNS). Concomitant administration of clarithromycin and ergot alkaloids is contraindicated (see section "Contraindications").
Oral midazolam
When midazolam is administered with clarithromycin tablets (500 mg twice daily), the area under the concentration-time curve (AUC) of midazolam increases 7-fold after oral administration of midazolam. 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 extensively metabolized by CYP3A4, and concomitant use with clarithromycin increases their plasma concentration, thereby increasing the risk of myopathy, including rhabdomyolysis. Cases of rhabdomyolysis have been reported in patients receiving clarithromycin concomitantly with these statins. If clarithromycin treatment cannot be avoided, therapy with lovastatin or simvastatin should be discontinued during the course of treatment.
Clarithromycin should be used with caution when administered concomitantly with other statins. In situations where concomitant use of clarithromycin with statins cannot be avoided, it is recommended to use the lowest approved dose of the statin. It may be possible to use a statin that does not depend on CYP3A metabolism (e.g., fluvastatin). 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 elevation of transaminase levels (see "Contraindications").
Effect of other medicinal products on clarithromycin pharmacokinetics
Medicinal products that are CYP3A inducers (e.g., rifampicin, phenytoin, carbamazepine, phenobarbital, St. John's wort preparations) may induce clarithromycin metabolism. This may lead to subtherapeutic clarithromycin levels and reduced efficacy. Additionally, monitoring of plasma levels of the CYP3A inducer may be necessary, as they may be elevated due to CYP3A inhibition by clarithromycin (see also the package leaflet of the respective CYP3A4 inducer). Concomitant use of rifabutin and clarithromycin leads to increased rifabutin levels and decreased clarithromycin serum levels, with an increased risk of uveitis.
Concomitant use of clarithromycin is also contraindicated with ticagrelor, ivabradine, and ranolazine (see section "Contraindications").
Corticosteroids
Caution should be exercised when using clarithromycin concomitantly with systemic or inhaled corticosteroids that are primarily metabolized by CYP3A, due to the potential for increased systemic corticosteroid effects. Patients should be closely monitored for adverse reactions associated with systemic corticosteroids when used concomitantly.
The following medicinal products are known or suspected to affect clarithromycin blood concentration, 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 when clarithromycin is used concomitantly with cytochrome P450 enzyme inducers.
Etravirine
The effect of clarithromycin is reduced by etravirine, although concentrations of the active metabolite 14-OH-clarithromycin are 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 the treatment of MAC.
Fluconazole
Concomitant administration of fluconazole 200 mg daily and clarithromycin 500 mg twice daily in 21 healthy volunteers resulted in a 33% increase in the steady-state minimum concentration (Cmin) of clarithromycin and an 18% increase in AUC. Steady-state concentrations of the active metabolite 14-OH-clarithromycin were not significantly altered with concomitant fluconazole. Dose adjustment of clarithromycin is not required.
Ritonavir
Administration of ritonavir 200 mg every 8 hours and clarithromycin 500 mg every 12 hours resulted in significant inhibition of clarithromycin metabolism. Maximum concentration (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. However, dose adjustment is necessary 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 doses exceeding 1 g/day should not be used concomitantly with ritonavir.
The same dose adjustment should be applied for patients with renal impairment when ritonavir is used as a pharmacokinetic booster with other HIV protease inhibitors, including atazanavir and saquinavir (see below "Bidirectional drug interactions").
Effect of clarithromycin on the pharmacokinetics of other medicinal products
Antiarrhythmic agents
Post-marketing reports exist of torsades de pointes occurring with concomitant use of clarithromycin and quinidine or disopyramide. ECG monitoring is recommended to detect QT interval prolongation promptly. Serum concentrations of these drugs should be monitored during clarithromycin therapy.
Post-marketing reports also describe hypoglycemia with concomitant use of clarithromycin and disopyramide; therefore, blood glucose monitoring is necessary when these medicinal products are used together.
Oral hypoglycemic agents/insulin
When used concomitantly with certain hypoglycemic agents, such as nateglinide and repaglinide, clarithromycin may inhibit the CYP3A enzyme, potentially causing hypoglycemia. Close monitoring of blood glucose levels is recommended.
CYP3A-related interactions
Concomitant use of clarithromycin, a known CYP3A enzyme inhibitor, and 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. Caution is advised when administering clarithromycin to patients receiving drugs that are CYP3A substrates, especially if the CYP3A substrate has a narrow therapeutic range (e.g., carbamazepine) and/or is extensively metabolized by this enzyme. Dose adjustment may be required, and, if possible, careful monitoring of serum concentrations of the CYP3A-metabolized drug is recommended in patients receiving clarithromycin concomitantly.
The following medicinal products or groups of medicinal products are known (or suspected) to be metabolized by the same CYP3A isoenzyme: alprazolam, astemizole, carbamazepine, cilostazol, cisapride, cyclosporine, disopyramide, ergot alkaloids, lovastatin, methylprednisolone, midazolam, omeprazole, oral anticoagulants (e.g., warfarin, rivaroxaban, apixaban), atypical antipsychotics (e.g., quetiapine), pimozide, quinidine, rifabutin, sildenafil, simvastatin, tacrolimus, terfenadine, triazolam, and vinblastine—but this list is not exhaustive. A similar interaction mechanism has been identified with phenytoin, theophylline, and valproate, which are metabolized by another cytochrome P450 isoenzyme.
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").
Omeprazole
Administration of clarithromycin (500 mg every 8 hours) in combination with omeprazole (40 mg daily) in healthy adult volunteers resulted in increased steady-state concentrations of omeprazole (Cmax, AUC0–24, and 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 administration 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. There is a potential for increased plasma concentrations of phosphodiesterase inhibitors (sildenafil, tadalafil, and vardenafil) when used concomitantly with clarithromycin, which may necessitate dose reduction of the phosphodiesterase inhibitors.
Theophylline, carbamazepine
Clinical studies have shown a slight but statistically significant (p≤0.05) increase in plasma concentrations of theophylline or carbamazepine when administered concomitantly with clarithromycin.
Solifenacin
Solifenacin is primarily metabolized by the cytochrome P450 2D6 isoenzyme (CYP2D6). However, in the population of patients lacking CYP2D6, metabolism occurs via CYP3A. In this population, inhibition of CYP3A leads to a significant increase in solifenacin plasma concentrations. In such patients, dose reduction of solifenacin may be necessary when used with CYP3A inhibitors such as clarithromycin.
Triazolobenzodiazepines (e.g., alprazolam, midazolam, triazolam)
When midazolam is administered with clarithromycin tablets (500 mg twice daily), the AUC of midazolam increases 2.7-fold after intravenous administration of midazolam. Combined use of oral midazolam and clarithromycin should be avoided. When midazolam is administered intravenously with clarithromycin, careful monitoring of the patient is required for timely dose adjustment. With oromucosal administration of midazolam, where presystemic elimination of the drug may be bypassed, an interaction similar to that observed with intravenous midazolam (rather than oral) is more likely.
The same precautions should be observed when using other benzodiazepines metabolized by CYP3A, including triazolam and alprazolam. For benzodiazepines whose elimination does not depend on CYP3A (temazepam, nitrazepam, lorazepam), clinically significant interaction with clarithromycin is unlikely.
Post-marketing reports exist of drug interactions and CNS-related adverse effects (drowsiness and confusion) with concomitant use of clarithromycin and triazolam. Patients should be monitored for possible increased pharmacological effects on the CNS.
Other types of interactions
Aminoglycosides
Clarithromycin should be used with caution 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. When clarithromycin and colchicine are used concomitantly, inhibition of Pgp and CYP3A by clarithromycin may lead to increased colchicine exposure. Patients should be monitored for clinical signs of colchicine toxicity. The colchicine dose should be reduced when used concomitantly with clarithromycin in patients with normal renal and hepatic function. Concomitant use of clarithromycin with colchicine in patients with renal or hepatic impairment is contraindicated (see sections "Contraindications" and "Special precautions for use").
Digoxin
Digoxin is considered a Pgp substrate. Clarithromycin is known to inhibit Pgp. Concomitant use may lead to increased digoxin exposure due to Pgp inhibition. Increased serum digoxin concentrations have been reported in patients receiving clarithromycin with digoxin. In some patients, signs of digoxin toxicity developed, including potentially life-threatening arrhythmias. Serum digoxin concentrations should be carefully monitored when used concomitantly 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. Since clarithromycin may interfere with the absorption of oral zidovudine when taken simultaneously, a 4-hour interval between doses of clarithromycin and zidovudine should be maintained. Such an interaction has not been reported with clarithromycin suspension and zidovudine or didanosine in HIV-infected children. This interaction is unlikely when clarithromycin is administered intravenously.
Phenytoin and valproate
Spontaneous or published reports exist of interactions between CYP3A inhibitors, including clarithromycin, and drugs not considered to be metabolized by CYP3A (e.g., phenytoin and valproate). Serum level monitoring of these drugs is recommended when co-administered with clarithromycin. Increased serum levels have been reported.
Bidirectional drug interactions
Atazanavir
Concomitant use of clarithromycin (500 mg twice daily) and atazanavir (400 mg once daily), both substrates and inhibitors of CYP3A, resulted in a doubling of clarithromycin exposure and a 70% reduction in 14-OH-clarithromycin exposure, with a 28% increase in atazanavir AUC. Since clarithromycin has a wide therapeutic index, 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, using the appropriate clarithromycin formulation. 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 when administered concomitantly with calcium channel blockers metabolized by CYP3A4 (e.g., verapamil, amlodipine, diltiazem). Plasma concentrations of both clarithromycin and calcium channel blockers may be increased during interaction. In patients receiving clarithromycin with verapamil, arterial hypotension, bradyarrhythmia, and lactic acidosis have been observed.
Itaconazole
Clarithromycin and itraconazole are both substrates and inhibitors of CYP3A, so 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 pharmacological effect.
Saquinavir
Concomitant administration of clarithromycin (500 mg twice daily) and saquinavir (soft gelatin capsules, 1200 mg three times daily), both substrates and inhibitors of CYP3A, in 12 healthy volunteers resulted in a 177% increase in steady-state AUC and a 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 aforementioned 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 from drug interaction studies using 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 (see above).
Hydroxychloroquine and chloroquine
Clarithromycin should be used with caution in patients receiving medicinal products that prolong the QT interval, due to the potential risk of cardiac arrhythmia and serious cardiovascular adverse reactions.
Special precautions for use
The use of any antimicrobial therapy, including clarithromycin, for the treatment of H. pylori infection may lead to the development of microbial resistance.
Clarithromycin should not be prescribed to pregnant women without careful assessment of the benefit-risk ratio, particularly during the first trimester of pregnancy.
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.
Since clarithromycin is metabolized in the liver and primarily excreted via the liver and kidneys, the drug should be used with particular caution in patients with hepatic impairment, moderate to severe renal impairment, and elderly patients (over 65 years of age).
The drug should be used with caution in patients with severe renal impairment.
During clarithromycin therapy, hepatic function disturbances have been reported, including elevated liver enzymes, and hepatocellular and/or cholestatic hepatitis, with or without jaundice. These hepatic disturbances may be severe but are usually reversible. In some cases, fatal hepatic failure has been reported, primarily associated 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.
Cases of pseudomembranous colitis, ranging from moderate to life-threatening severity, have been reported with nearly all antibacterial agents, including macrolides. Diarrhea caused by Clostridium difficile (CDAD), ranging from mild to pseudomembranous colitis with fatal outcomes, has been reported with nearly all antibacterial agents, including clarithromycin. Clostridium difficile-associated diarrhea should always be considered in all patients presenting with diarrhea after antibiotic use. A careful medical history 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 therapy should be discontinued regardless of the indication for which it was prescribed. Microbiological testing should be performed and appropriate treatment initiated. Medications that inhibit peristalsis should be avoided.
Clarithromycin is primarily eliminated via the liver; therefore, caution is required when administering the drug to patients with hepatic impairment, as well as those with moderate or severe renal impairment.
Colchicine
Colchicine toxicity (including fatal cases) has been reported during concomitant use of clarithromycin and colchicine, particularly in elderly patients and those with renal impairment (see section "Interaction with other medicinal products and other forms of interaction"). Concomitant use of clarithromycin with colchicine is contraindicated (see section "Contraindications").
Concomitant use of clarithromycin with triazolobenzodiazepines, such as triazolam, or intravenous or oromucosal midazolam, should be used with caution (see section "Interaction with other medicinal products and other forms of interaction").
Clarithromycin should be used cautiously with other ototoxic agents, particularly aminoglycosides. Monitoring of vestibular and auditory function should be performed during and after treatment.
QT interval prolongation
Due to the risk of QT interval prolongation, clarithromycin should be used with caution in patients with ischemic heart disease, severe heart failure, hypomagnesemia, bradycardia (< 50 beats/min), or when used concomitantly with other drugs associated with QT interval prolongation (see section "Interaction with other medicinal products and other forms of interaction"). Clarithromycin must not be used in patients with congenital or documented history of QT interval prolongation or with a history of ventricular arrhythmias (see section "Contraindications"). Caution is advised 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 associated with QT interval prolongation (see section "Interaction with other medicinal products and other forms of interaction").
Clarithromycin is contraindicated in patients with hypokalemia or hypomagnesemia (see "Contraindications").
Concomitant use of clarithromycin with astemizole, cisapride, pimozide, and terfenadine is contraindicated (see section "Contraindications").
Epidemiological studies investigating the risk of adverse cardiovascular outcomes with macrolide use have shown variable results. Some observational studies have identified a rare, short-term risk of arrhythmia, myocardial infarction, and cardiovascular mortality associated with macrolide use, including clarithromycin. These findings should be weighed against the benefits of treatment when prescribing clarithromycin.
Pneumonia
Due to possible resistance of Streptococcus pneumoniae to macrolides, it is important to perform susceptibility testing when prescribing clarithromycin for community-acquired pneumonia. For hospital-acquired pneumonia, clarithromycin should be used in combination with other appropriate antibiotics.
Skin and soft tissue infections, mild to moderate
These infections are most commonly caused by Staphylococcus aureus and Streptococcus pyogenes, which may be resistant to macrolides. Therefore, susceptibility testing is important. When beta-lactam antibiotics cannot be used (e.g., due to allergy), other antibiotics such as clindamycin may be considered as first-line therapy. Macrolides have so far played a limited role in the treatment of certain skin and soft tissue infections (e.g., those caused by Corynebacterium minutissimum, acne vulgaris, or erysipelas) and in situations where penicillins cannot be used.
In the event of severe acute hypersensitivity reactions, such as anaphylaxis, severe skin adverse reactions (e.g., acute generalized exanthematous pustulosis, Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS), or Henoch-Schönlein purpura, clarithromycin therapy should be immediately discontinued and appropriate treatment initiated.
Clarithromycin should be used with caution when co-administered with inducers of the CYP3A4 enzyme (see section "Interaction with other medicinal products and other forms of interaction").
Cross-resistance between clarithromycin and other macrolides, as well as with lincomycin and clindamycin, should be considered.
The use of any antimicrobial therapy, including clarithromycin, for the treatment of H. pylori infection may lead to the development of microbial resistance. In a small number of patients, H. pylori may develop resistance to clarithromycin.
HMG-CoA reductase inhibitors (statins)
Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated (see section "Contraindications"). Clarithromycin should be used with caution when administered concurrently with other statins. Cases of rhabdomyolysis have been reported in patients receiving clarithromycin and statins. Monitoring for signs and symptoms of myopathy is necessary. When concomitant use of clarithromycin with statins cannot be avoided, the lowest approved statin dose should be prescribed. Use of a statin not dependent on CYP3A metabolism, such as 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., sulfonylurea derivatives) and/or insulin may cause pronounced hypoglycemia. Close monitoring of blood glucose levels is recommended.
Oral anticoagulants
Concomitant use of clarithromycin with warfarin may increase the risk of serious bleeding, significantly elevated INR (International Normalized Ratio), and prolonged prothrombin time. The INR and prothrombin time should be frequently monitored 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 "Interaction with other medicinal products and other forms of interaction").
The medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., essentially sodium-free.
Use during pregnancy or breastfeeding
Pregnancy
The safety of clarithromycin use during pregnancy has not been established. Based on animal studies and human experience, a potential adverse effect on embryofetal development cannot be excluded. Some observational studies evaluating clarithromycin use during the first and second trimesters have reported an increased risk of miscarriage compared to no antibiotic use or use of other antibiotics during the same period. Epidemiological data on the risk of major congenital malformations associated with macrolide use, including clarithromycin, during pregnancy are conflicting. Therefore, clarithromycin should not be used during pregnancy without careful benefit-risk assessment.
Breastfeeding
Clarithromycin is excreted in human breast milk in small amounts. It has been estimated that an exclusively breastfed infant receives approximately 1.7% of the maternal dose of clarithromycin, adjusted for maternal body weight.
The safety of clarithromycin use during breastfeeding has not been established.
Ability to influence reaction speed when driving or operating machinery
Data on this effect are lacking. However, when driving or operating machinery, the potential occurrence of nervous system adverse reactions such as convulsions, dizziness, vertigo, hallucinations, confusion, and disorientation should be considered.
Method of Administration and Dosage
The recommended dose of clarithromycin for adults and children aged 12 years and older is 250 mg (1 tablet) every 12 hours. In more severe infections, the dose may be increased to 500 mg (2 tablets) every 12 hours. The usual duration of treatment depends on the severity of the infection and ranges from 6 to 14 days.
The medicinal product can be administered independently of food intake, as food does not affect the bioavailability of clarithromycin.
Treatment of odontogenic infections
The recommended dose is 250 mg every 12 hours 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 MAC in AIDS patients should continue as long as medically confirmed clinical and microbiological efficacy is maintained. Clarithromycin may be used in combination with other antimycobacterial agents.
Eradication of H. pylori in patients with duodenal ulcer (adults)
Triple therapy (7–10 days)
Clarithromycin (500 mg) twice daily should be administered together with amoxicillin 1000 mg twice daily and omeprazole 20 mg daily for 7–10 days.
Triple therapy (10 days)
Clarithromycin (500 mg) twice daily, lanzoprazole 30 mg twice daily, and amoxicillin 1000 mg twice daily for 10 days.
Dual therapy (14 days)
Clarithromycin (500 mg) three times daily together with omeprazole 40 mg once daily orally for 14 days, followed by omeprazole 20 mg or 40 mg once daily orally for the next 14 days.
Dual therapy (14 days)
Clarithromycin (500 mg) three times daily together with lanzoprazole 60 mg once daily orally for 14 days. Further acid secretion suppression may be required to reduce ulcer symptoms.
Clarithromycin has also been used in the following therapeutic regimens:
clarithromycin + tinidazole and omeprazole or lanzoprazole;
clarithromycin + metronidazole and omeprazole or lanzoprazole;
clarithromycin + tetracycline, bismuth subcitrate, and ranitidine;
clarithromycin + amoxicillin and lanzoprazole;
clarithromycin + ranitidine bismuth citrate.
Use in elderly patients: same as for adults.
Use in patients with renal impairment: in patients with severe renal impairment (creatinine clearance <30 mL/min), the dose should be reduced by half, e.g., 250 mg once daily or 250 mg twice daily in more severe infections. In such patients, the duration of treatment should not exceed 14 days.
Children
For children under 12 years of age, the drug should be administered in the form of a suspension, as the use of clarithromycin tablets has not been studied in this age group.
Overdose
Symptoms. Available reports indicate that clarithromycin overdose may cause gastrointestinal symptoms. In one patient with a history of bipolar disorder who ingested 8 grams of clarithromycin, altered mental status, paranoid behavior, hypokalemia, and hypoxemia developed.
Treatment. Adverse reactions associated with overdose should be managed by gastric lavage and symptomatic therapy. As with other macrolides, hemodialysis or peritoneal dialysis are unlikely to significantly affect serum clarithromycin levels.
Adverse Reactions
The most common and frequent adverse reactions during clarithromycin treatment in adults and children are abdominal pain, diarrhea, nausea, vomiting, and altered taste. These adverse reactions are generally mild and consistent with the known safety profile of macrolide antibiotics. During clinical studies, no significant difference in the frequency of these adverse reactions was observed between patient groups with or without mycobacterial infections.
The adverse reactions listed below occurred during clinical studies and post-marketing use of various dosage forms and strengths of clarithromycin, including immediate-release formulations. Adverse reactions at least possibly related to clarithromycin are listed by system organ class and frequency: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1,000, <1/100), frequency not known* (reactions reported during post-marketing surveillance; frequency cannot be estimated from available data). Within each group, adverse reactions are listed in order of decreasing severity when severity could be assessed.
Infections and infestations: uncommon – cellulitis1, oral candidiasis, gastroenteritis2, infection3, vaginal infection; frequency not known – pseudomembranous colitis, Whipple's disease.
Blood and lymphatic system disorders: uncommon – leukopenia, neutropenia4, thrombocytosis3, eosinophilia4; frequency not known – agranulocytosis, thrombocytopenia.
Immune system disorders: uncommon – anaphylactoid reactions1, hypersensitivity; frequency not known – anaphylactic reactions, angioedema.
Metabolism and nutrition disorders: uncommon – anorexia, decreased appetite; frequency not known – hypoglycemia.
Psychiatric disorders: common – insomnia; uncommon – anxiety, nervousness3; frequency not known – psychosis, confusion, depersonalization, depression, disorientation, hallucinations, nightmares, mania.
Nervous system disorders: common – dysgeusia (disturbance of taste sensation), headache, altered taste; uncommon – loss of consciousness1, dyskinesia1, dizziness, somnolence, tremor; frequency not known – seizures, ageusia (loss of taste sensation), parosmia, anosmia, paresthesia.
Ear and labyrinth disorders: uncommon – dizziness, vertigo, hearing impairment, tinnitus; frequency not known – hearing loss.
Cardiac disorders: uncommon – cardiac arrest1, atrial fibrillation1, QT interval prolongation, extrasystoles1, palpitations; frequency not known – torsades de pointes, ventricular tachycardia, ventricular fibrillation.
Vascular disorders: common – vasodilation1; frequency not known – hemorrhage.
Respiratory, thoracic and mediastinal disorders: uncommon – asthma1, epistaxis2, pulmonary embolism1.
Gastrointestinal disorders: common – diarrhea, vomiting, dyspepsia, nausea, abdominal pain; uncommon – esophagitis1, gastroesophageal reflux disease2, gastritis, proctalgia2, stomatitis, glossitis, abdominal distension4, constipation, dry mouth, belching, flatulence; frequency not known – acute pancreatitis, tongue discoloration, tooth discoloration.
Hepatobiliary disorders: common – abnormal liver function tests; uncommon – cholestasis4, hepatitis4, increased levels of ALT, AST, GGT4; frequency not known – hepatic failure, cholestatic jaundice, hepatocellular jaundice.
Skin and subcutaneous tissue disorders: common – rash, hyperhidrosis; uncommon – bullous dermatitis1, pruritus, urticaria, maculopapular rash3; frequency not known – severe skin reactions (e.g., acute generalized exanthematous pustulosis, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS)), acne, Henoch-Schönlein purpura.
Musculoskeletal and connective tissue disorders: uncommon – muscle spasms3, skeletal muscle rigidity1, myalgia2; frequency not known – rhabdomyolysis2 (in some reports of rhabdomyolysis, 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: uncommon – increased blood creatinine1, increased blood urea1; frequency not known – renal failure, interstitial nephritis.
General disorders and administration site conditions: very common – phlebitis at injection site1; common – pain, inflammation at injection site1; uncommon – malaise4, fever3, asthenia, chest pain4, chills4, fatigue4.
Investigations: uncommon – altered albumin-globulin ratio1, increased blood alkaline phosphatase4, increased blood lactate dehydrogenase4; frequency not known – increased INR, prolonged prothrombin time, urine discoloration.
* Since these reactions have been reported voluntarily and the patient population size is unknown, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The overall clinical experience with clarithromycin exceeds 1 billion patient-days.
1,2,3,4 These adverse reactions were reported only with the following formulations: 1 – lyophilized powder for solution for infusion, 2 – extended-release tablets, 3 – suspension, 4 – immediate-release tablets.
Arthralgia has been reported. Very rare cases of uveitis have been reported, primarily in patients receiving concomitant rifabutin. Most reactions were reversible.
The frequency, type, and severity of adverse reactions in children are expected to be similar to those in adults.
Patients with Immune System Disorders
In AIDS patients and other patients with immune system disorders receiving 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 drug use from symptoms of the underlying or concomitant diseases.
In adult patients receiving clarithromycin at a daily dose of 1000 mg, the most common adverse effects were nausea, vomiting, altered taste, abdominal pain, diarrhea, rash, abdominal distension, headache, constipation, hearing disturbances, and increased levels of ALT and AST. Dyspnea, insomnia, and dry mouth occurred uncommonly. In these immunocompromised patients, laboratory parameters were evaluated by analyzing values outside the significant abnormal range (i.e., extreme upper or lower limit) for a given test. By this criterion, 2–3% of these patients receiving 1000 mg of clarithromycin daily experienced significantly abnormal elevations in ALT and AST levels and abnormal decreases in white blood cell and platelet counts. A smaller percentage of patients showed increased blood urea nitrogen levels.
Shelf life. 3 years.
Storage conditions.
Store in the original packaging at a temperature not exceeding 25 °C. Keep out of the reach of children.
Packaging. 7 tablets per blister; 2 blisters per cardboard box.
Prescription category. Prescription only.
Manufacturer. Sanovel Ilac Sanai ve Ticaret A.S.
Manufacturer's address and place of business.
Balaban Quarter, Cihangir Sokagi, No. 10, Silivri District, Istanbul 34580, Turkey.