Meristat-sanovel long
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MERISTAT-sanovel LONG
Composition:
Active substance: clarithromycin;
1 tablet contains 500 mg of clarithromycin;
Excipients: vanillin; hydroxypropylmethylcellulose; lactose monohydrate; magnesium stearate; sodium saccharin; talc;
coating: Opadry Yellow OY-S-32917 (hydroxypropylmethylcellulose, titanium dioxide (E 171), propylene glycol, hydroxypropylcellulose, polysorbate 80, vanillin, colorant FD&C Yellow No. 2 (tartrazine) (E 102), iron oxide yellow (E 172), FD&C Blue No. 2 (indigocarmine) (E 132)).
Pharmaceutical form. Modified-release tablets.
Main physicochemical properties: oval tablets coated with a yellow film, with an imprint «S» on one side.
Pharmacotherapeutic group.
Antibacterial agents for systemic use. Macrolides.
ATC code J01FA09.
Pharmacological Properties.
Pharmacodynamics.
Clarithromycin is a semi-synthetic antibiotic of the macrolide group. The antibacterial action of clarithromycin is due to its binding to the 50S ribosomal subunit of susceptible bacteria and inhibition of protein biosynthesis. The modified-release tablet formulation ensures prolonged release of the active substance.
The drug demonstrates high efficacy in vitro against a broad spectrum of aerobic and anaerobic Gram-positive and Gram-negative microorganisms, including hospital strains. It acts primarily as bacteriostatic, but exhibits bactericidal activity against certain microorganisms. The minimal inhibitory concentrations (MICs) of clarithromycin are generally twice as low as those of erythromycin.
Clarithromycin is highly active in vitro against Legionella pneumophila and Mycoplasma pneumoniae. In vitro studies have shown that Enterobacteriaceae and Pseudomonas strains, as well as other non-lactose fermenting Gram-negative bacteria, are not susceptible 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.
Beta-lactamases produced by microorganisms do not affect the efficacy of clarithromycin.
Most methicillin- and oxacillin-resistant Staphylococcus strains are not susceptible to clarithromycin.
Helicobacter: H. pylori.
Clarithromycin is active in vitro against most strains of the following microorganisms; however, the 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.
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 activity against several bacterial strains: Haemophilus influenzae, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Moraxella (Branhamella) catarrhalis, Neisseria gonorrhoeae, H. pylori, and Campylobacter spp.
The primary metabolite of clarithromycin in the human body is microbiologically active 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 substance, 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 additive or synergistic effects 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. One of the recommended procedures for susceptibility testing uses disks impregnated with 15 µg of clarithromycin (Kirby-Bauer diffusion method); the zone diameter for this disk is interpreted in relation to the MIC values for clarithromycin. MIC is determined by broth or agar dilution methods.
When performing these tests, 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 indicating "intermediate susceptibility" suggests that the therapeutic effect of the drug may be uncertain or that the microorganism may respond only to higher doses (intermediate susceptibility is also referred to as moderate susceptibility).
Country- or region-specific data on the absolute breakpoints for susceptibility, resistance, and intermediate susceptibility must be taken into account.
Breakpoints
The European Committee on Antimicrobial Susceptibility Testing (EUCAST) has established the following breakpoints.
| Breakpoint values (MIC, mg/l) |
||
| Microorganism |
Susceptible (≤) |
Resistant (>) |
| Staphylococcus spp. |
1 mg/l |
2 mg/l |
| Streptococcus A, B, C and G |
0.25 mg/l |
0.5 mg/l |
| Streptococcus pneumoniae |
0.25 mg/l |
0.5 mg/l |
| Viridans group streptococcus |
NS |
NS |
| Haemophilus spp. |
1 mg/l |
32 mg/l |
| Moraxella catarrhalis |
0.25 mg/l |
0.5 mg/l1 |
| Helicobacter pylori |
0.25 mg/l1 |
0.5 mg/l |
| 1Breakpoint values are based on epidemiological cut-off values (ECOFFs) that distinguish wild-type isolates from isolates with reduced susceptibility. “NS” means insufficient evidence that the specified organism is an appropriate target for treatment with the drug. |
||
Pharmacokinetics.
The absorption of clarithromycin after administration of modified-release tablets corresponds to the absorption after administration of conventional tablets. Bioavailability is approximately 50%. Gastric acid does not affect the stability or absorption of clarithromycin. Food promotes increased absorption; therefore, modified-release tablets should be taken during meals.
Approximately 20% of the drug is metabolized after absorption, forming 14-OH-clarithromycin.
Patients. Clarithromycin and its 14-OH-metabolite are widely distributed in body tissues and fluids. After oral administration, the concentration of clarithromycin in cerebrospinal fluid remains low (1–2% of serum levels with a normally functioning blood-brain barrier). Tissue concentrations of clarithromycin are usually several times higher than serum concentrations.
Clarithromycin is metabolized in the liver via the cytochrome P450 system and is excreted in urine (approximately 40%) and feces (approximately 30%). The elimination half-life (t1/2) of clarithromycin and its main metabolite is approximately 5.8 and 8.9 hours, respectively.
Hepatic impairment. Dose adjustment of clarithromycin is not required in patients with moderate or severe hepatic impairment who have preserved renal function.
Renal impairment. In patients with impaired renal function, the minimum (Cmin) and maximum (Cmax) plasma concentrations, the half-life (t1/2), and the area under the concentration-time curve (AUC) of clarithromycin and 14-OH-clarithromycin increase. The elimination rate constant and urinary excretion decrease. The extent of these changes depends on the degree of renal impairment: the more severe the impairment, the greater the changes in these parameters.
Elderly patients. In elderly patients, blood levels of clarithromycin and 14-OH-clarithromycin were higher and elimination was slower compared to younger patients. Changes in pharmacokinetics in elderly patients are primarily related to impaired renal function rather than age itself.
Clinical characteristics.
Indications.
Treatment of infections caused by microorganisms sensitive to clarithromycin in adults and children aged 12 years and older:
- lower respiratory tract infections (bronchitis, pneumonia);
- upper respiratory tract infections (sinusitis, pharyngitis);
- skin and soft tissue infections (folliculitis, impetigo).
Contraindications.
- Hypersensitivity to clarithromycin or to other macrolide antibiotics, or to any excipient of the medicinal product.
- Concomitant use with 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.
- Concomitant use of clarithromycin and oral midazolam (see section "Interaction with other medicinal products and other types of interactions").
- History of QT interval prolongation or ventricular cardiac arrhythmias, including torsades de pointes.
- Electrolyte disturbances (hypokalemia or hypomagnesemia) — due to risk of QT interval prolongation.
- Severe hepatic insufficiency and concomitant renal insufficiency.
- Concomitant use of clarithromycin and other strong CYP3A4 inhibitors with colchicine in patients with renal or hepatic impairment (see sections "Interaction with other medicinal products and other types of interactions" and "Special precautions for use").
- 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").
- Creatinine clearance less than 30 mL/min (this formulation does not allow dose reduction below 500 mg per day).
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 consequences
Increased serum levels of cisapride, pimozide, and terfenadine have been observed when used concomitantly with clarithromycin, which may cause QT interval prolongation and arrhythmias, including ventricular tachycardia, ventricular fibrillation, and torsades de pointes. Similar effects have been reported with concomitant use of astemizole and other macrolides.
Macrolides have been reported to alter the metabolism of terfenadine, leading to increased terfenadine serum levels, 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 the serum concentration of terfenadine's acid metabolite and QT interval prolongation, although no clinically evident effect was observed. Similar effects were noted 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 oral 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 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 and the aforementioned statins. If clarithromycin treatment cannot be avoided, therapy with lovastatin or simvastatin should be discontinued during the course of treatment.
Clarithromycin should be used with caution when administered concomitantly with other statins. In situations where concomitant use of clarithromycin with statins cannot be avoided, it is recommended to use the lowest registered dose of the statin. Use of a statin not dependent on CYP3A metabolism (e.g., fluvastatin) may be considered. Monitoring of patients for signs and symptoms of myopathy is necessary.
Ergotamine/dihydroergotamine. Concomitant use of clarithromycin and ergotamine or dihydroergotamine has been associated with signs of acute ergotism, characterized by vasospasm and ischemia of extremities and other tissues, including the CNS.
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 the pharmacokinetics of clarithromycin
Inducers of CYP3A4 (rifampicin, phenytoin, carbamazepine, phenobarbital, St. John's wort) may enhance the metabolism of clarithromycin. This may result in subtherapeutic concentrations of clarithromycin and reduced efficacy. Additionally, plasma concentrations of the CYP3A4 inducer should be monitored, as they may increase due to CYP3A4 inhibition by clarithromycin (see also the instructions for medical use of the respective CYP3A4 inducer). Concomitant use of rifabutin and clarithromycin has led to increased rifabutin concentrations and decreased clarithromycin concentrations in serum, along with an increased risk of uveitis.
The effect of the following medicinal products on clarithromycin plasma concentration is known or suspected, and therefore dose adjustment or alternative therapy may be required.
Concomitant use of clarithromycin is also contraindicated with ticagrelor, ivabradine, and ranolazine (see section "Contraindications").
Glucocorticoids
Caution should be exercised when using clarithromycin concomitantly with systemic or inhaled glucocorticoids that are primarily metabolized by CYP3A, due to the potential for increased systemic effects of glucocorticoids. Patients should be closely monitored for adverse reactions associated with systemic glucocorticoids when used concomitantly.
The following medicinal products are known or suspected to affect clarithromycin blood concentration, and therefore dose adjustment or alternative therapy may be required.
Efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine – potent inducers of cytochrome P450 enzymes that may accelerate the metabolism of clarithromycin, reducing its plasma concentration, but simultaneously increasing the concentration of the active metabolite 14-OH-clarithromycin. Since the microbiological activity of clarithromycin and 14-OH-clarithromycin varies against different bacteria, the expected therapeutic effect may not be achieved with concomitant use of clarithromycin and cytochrome P450 enzyme inducers.
Etravirine. The effect of clarithromycin was reduced by etravirine, although the concentration of the active metabolite 14-OH-clarithromycin increased. Since the latter 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 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 fluconazole use. Dose adjustment of clarithromycin is not required when used concomitantly with fluconazole.
Ritonavir. 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 required in patients with normal renal function. For patients with renal impairment, dose adjustment is necessary: in patients with creatinine clearance of 30–60 mL/min, the clarithromycin dose should be reduced by 50% to a maximum of 500 mg (1 tablet) per day; in patients with creatinine clearance <30 mL/min, the clarithromycin dose should be reduced by 75%. Immediate-release clarithromycin tablets may be used in these patients. Doses of clarithromycin exceeding 1 g/day should not be used with ritonavir. The same dose adjustment should be applied for patients with renal dysfunction when ritonavir is used 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. Isolated reports of torsades de pointes have been reported with concomitant use of clarithromycin and quinidine or disopyramide. ECG monitoring is recommended to detect QT interval prolongation promptly. During clarithromycin therapy, serum concentrations of these drugs should be monitored. Post-marketing reports have noted 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. Careful monitoring of blood glucose levels is recommended.
CYP3A-related interactions. Concomitant use of clarithromycin, a known inhibitor of the CYP3A enzyme, with a drug primarily metabolized by CYP3A, may lead to increased plasma concentrations of the latter, thereby enhancing or prolonging its therapeutic effect and increasing the risk of adverse reactions. Caution is advised when using clarithromycin in patients receiving therapy with CYP3A substrate drugs, especially if the CYP3A substrate has a narrow therapeutic range (e.g., carbamazepine) and/or is extensively metabolized by this enzyme.
Dose adjustment and careful monitoring of serum concentrations of the CYP3A-metabolized drug may be required for patients receiving clarithromycin concomitantly.
The following medicinal products or groups of 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, sirolimus, terfenadine, triazolam, and vinblastine — but this list is not exhaustive.
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 should be exercised when using clarithromycin concomitantly with these agents, especially in patients at high risk of bleeding (see "Special precautions for use").
Phenytoin, valproate. A similar interaction mechanism has been observed with phenytoin and valproate, which are metabolized by another cytochrome P450 isoenzyme. Increased serum concentrations of these drugs have been reported with concomitant use of clarithromycin.
Cyclosporine, tacrolimus, and sirolimus. More than a two-fold increase in Cmin of cyclosporine and tacrolimus has been observed with concomitant use of clarithromycin. A similar effect should be expected for sirolimus concentrations; therefore, continuous monitoring of plasma concentrations of cyclosporine, tacrolimus, and sirolimus is recommended for appropriate dose adjustment.
Omeprazole. Administration of clarithromycin (500 mg every 8 hours) in combination with omeprazole (40 mg daily) 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 pH measured over 24 hours was 5.2; with concomitant use of omeprazole and clarithromycin, it was 5.7.
Oral hypoglycemic agents/insulin. Concomitant use of clarithromycin with oral hypoglycemic agents (such as nateglinide, pioglitazone, repaglinide, rosiglitazone) and/or insulin may cause pronounced hypoglycemia due to inhibition of the CYP3A enzyme. Continuous monitoring of blood glucose levels is recommended.
Oral anticoagulants. There is a risk of serious bleeding, significant increase in INR and prothrombin time when clarithromycin is used concomitantly with oral anticoagulants (warfarin); therefore, frequent monitoring of these parameters is necessary.
Sildenafil, tadalafil, and vardenafil. There is a possibility of increased plasma concentrations of these phosphodiesterase inhibitors when used concomitantly with clarithromycin, which may require dose reduction of the phosphodiesterase inhibitors.
Theophylline, carbamazepine. Clinical studies have shown a slight but statistically significant (p≤0.05) increase in plasma concentrations of theophylline or carbamazepine when used concomitantly with clarithromycin.
Solifenacin. Solifenacin is primarily metabolized by the CYP2D6 isoenzyme of cytochrome P450 (CYP2D6). However, in patients lacking CYP2D6, metabolism occurs via CYP3A. In this population, inhibition of CYP3A leads to a significant increase in solifenacin plasma concentrations. Dose reduction of solifenacin may be necessary when used with clarithromycin.
Triazolobenzodiazepines (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 of midazolam. Combined use of oral midazolam and clarithromycin should be avoided. With intravenous administration of midazolam and 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.
There have been isolated reports of drug interaction and CNS adverse effects (drowsiness and confusion) with concomitant use of clarithromycin and triazolam. Patients should be monitored, considering the possible enhancement of 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). Concomitant use of clarithromycin and colchicine may lead to increased colchicine effects due to inhibition of Pgp and/or CYP3A by clarithromycin. Monitoring of patients for early detection of clinical signs of colchicine toxicity is necessary.
Digoxin. Digoxin is considered a substrate of Pgp. Clarithromycin is known to inhibit Pgp. Concomitant use may lead to increased digoxin exposure due to Pgp inhibition. Post-marketing observations have reported increased serum digoxin concentrations in patients receiving clarithromycin with digoxin. In some patients, signs of digoxin toxicity, including potentially fatal arrhythmias, developed. Serum digoxin concentrations should be carefully monitored in patients receiving digoxin with clarithromycin.
Zidovudine. Concomitant use of clarithromycin and zidovudine in HIV-infected patients may lead to decreased steady-state plasma concentrations of zidovudine. This can be avoided by ensuring an interval of at least 4 hours between administration of clarithromycin and zidovudine. No such interaction has been reported with use of clarithromycin suspension and zidovudine or didanosine in children. This interaction is unlikely with intravenous administration of clarithromycin.
Verapamil
Cases of arterial hypotension, bradyarrhythmia, and lactic acidosis have been reported with concomitant use of clarithromycin and verapamil.
Bidirectional drug interactions may also occur between clarithromycin and atazanavir, itraconazole, saquinavir.
Increased plasma concentrations of clarithromycin are possible with concomitant use of antacids or ranitidine. Dose adjustment is not required.
Particular caution is required when clarithromycin is prescribed concomitantly with ototoxic agents, especially aminoglycosides. Vestibular and auditory function should be checked during and after completion of combination therapy.
Phenytoin and valproate
There have been spontaneous or published reports of interaction between CYP3A inhibitors, including clarithromycin, and medicinal products not considered to be metabolized by CYP3A (e.g., phenytoin and valproate). Serum levels of these medicinal products should be determined when prescribed concomitantly with clarithromycin. Increased serum levels have been reported.
Bidirectional drug interactions
Atazanavir
Administration of clarithromycin (500 mg twice daily) with atazanavir (400 mg once daily), both substrates and inhibitors of CYP3A, resulted in a doubling of clarithromycin exposure and a 70% reduction in 14-OH-clarithromycin exposure, with a 28% increase in atazanavir AUC. Since clarithromycin has a wide therapeutic range, dose reduction is not necessary in patients with normal renal function. The clarithromycin dose should be reduced by 50% in patients with creatinine clearance of 30–60 mL/min and by 75% in patients with creatinine clearance <30 mL/min. Clarithromycin doses higher than 1000 mg daily should not be used with protease inhibitors.
Calcium channel blockers
Due to the risk of arterial hypotension, clarithromycin should be used with caution when administered concomitantly with calcium channel blockers metabolized by CYP3A4 (e.g., verapamil, amlodipine, diltiazem). Plasma concentrations of both clarithromycin and calcium channel blockers may increase with interaction. Arterial hypotension, bradyarrhythmia, and lactic acidosis have been observed in patients receiving clarithromycin with verapamil.
Itraconazole
Clarithromycin and itraconazole are both substrates and inhibitors of CYP3A, and thus clarithromycin may increase itraconazole plasma levels and vice versa. When itraconazole is used with clarithromycin, patients should be closely monitored for signs or symptoms of enhanced or prolonged pharmacological effect.
Saquinavir
Administration of clarithromycin (500 mg twice daily) with saquinavir (soft gelatin capsules, 1200 mg three times daily), both substrates and inhibitors of CYP3A, leads to increased AUC and Cmax at steady state 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/formulations. Results of drug interaction studies using soft gelatin capsules may not correspond to effects observed with hard gelatin capsules of saquinavir. Results of drug interaction studies using saquinavir alone may not correspond to effects observed with saquinavir/ritonavir therapy. When saquinavir is used with ritonavir, possible 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.
Clarithromycin may be prescribed to pregnant women only when the expected benefit to the mother outweighs the potential risk to the fetus, particularly during the first trimester (see section "Use during pregnancy or breastfeeding").
Prolonged or repeated use of antibiotics may lead to overgrowth of resistant bacteria and fungi. If superinfection occurs, clarithromycin should be discontinued and appropriate therapy initiated.
The drug is eliminated via the liver and kidneys. Caution should be exercised when administering the drug to patients with renal or hepatic impairment. The drug should also be used with caution in patients with moderate to severe renal dysfunction. Particular caution is required when administering the drug to patients with severe renal impairment. Cases of hepatic dysfunction, including elevated liver enzymes, hepatocellular and/or cholestatic hepatitis with or without jaundice, have been reported during clarithromycin treatment. These effects are usually reversible, but isolated cases of fatal liver failure have been reported, typically associated with severe underlying diseases and/or concomitant medications. The drug should be discontinued immediately upon the appearance of symptoms of hepatitis such as anorexia, jaundice, dark urine, pruritus, or abdominal pain.
Pseudomembranous colitis, ranging from moderate to life-threatening severity, has been reported with nearly all antibacterial agents, including macrolides. In cases of severe diarrhea characteristic of pseudomembranous colitis (most often caused by Clostridium difficile [CDAD]), discontinuation of the drug and initiation of appropriate measures are recommended. Antiperistaltic agents are contraindicated. Antibacterial therapy disrupts the normal intestinal flora, potentially leading to overgrowth of Clostridium difficile. The possibility of Clostridium difficile-associated diarrhea should always be considered in any patient presenting with diarrhea following antibiotic use. A careful medical history is essential, as cases of Clostridium difficile-associated diarrhea have been reported up to two months after antibiotic administration.
Therefore, in the event of persistent diarrhea during clarithromycin therapy, discontinuation of treatment should be considered regardless of the initial indication. Diagnostic testing for causative microorganisms should be performed, and appropriate therapy initiated. Antiperistaltic agents should be avoided.
Exacerbation of myasthenia symptoms has been reported in patients receiving clarithromycin.
Colchicine
Colchicine toxicity (including fatal outcomes) has been reported when colchicine is used concomitantly with clarithromycin, particularly in elderly patients and those with renal impairment.
Clarithromycin should be used with caution when co-administered with cytochrome CYP3A4 inducers and triazolobenzodiazepines (triazolam, midazolam) (see section "Interaction with other medicinal products and other forms of interaction").
Cardiovascular complications
Due to the risk of QT interval prolongation, clarithromycin should be used with caution in patients with coronary artery disease, severe heart failure, hypomagnesemia, or bradycardia (heart rate less than 50 bpm). Concomitant use with other drugs that prolong the QT interval is contraindicated. Given that the following conditions may increase the risk of ventricular arrhythmias (including torsades de pointes), clarithromycin should be used cautiously in the following patient groups:
- Patients with ischemic heart disease, severe heart failure, conduction disorders, or clinically significant bradycardia.
- Patients 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").
Clarithromycin must not be used in patients with congenital or documented acquired QT interval prolongation or a history of ventricular arrhythmia (see section "Contraindications").
Epidemiological studies investigating the risk of adverse cardiovascular outcomes associated with macrolide use have yielded inconsistent results. Some observational studies have reported 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 therapeutic benefits when prescribing clarithromycin.
Pneumonia
Since Streptococcus pneumoniae may be resistant to macrolides, susceptibility testing is essential when prescribing clarithromycin for community-acquired pneumonia. For hospital-acquired pneumonia, the drug should be used in combination with other antibiotics.
Skin and soft tissue infections of mild to moderate severity
These infections are most commonly caused by Staphylococcus aureus and Streptococcus pyogenes, both of which may exhibit macrolide resistance. Therefore, susceptibility testing is important. When beta-lactam antibiotics cannot be used (e.g., due to allergy), alternative agents such as clindamycin may be considered first-line. Currently, macrolides play a limited role in treating certain skin and soft tissue infections, such as those caused by Corynebacterium minutissimum, acne vulgaris, and erysipelas, or in situations where penicillins are contraindicated.
In the event of severe acute hypersensitivity reactions such as anaphylaxis, or severe skin adverse reactions (e.g., acute generalized exanthematous pustulosis, Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS), or Henoch-Schönlein purpura, treatment with the drug should be immediately discontinued and appropriate therapy initiated. Clarithromycin should be used with caution when co-administered with cytochrome CYP3A4 inducers (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.
HMG-CoA reductase inhibitors (statins)
Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated (see section "Contraindications"). Clarithromycin should be used cautiously with other statins. Cases of rhabdomyolysis have been reported with concomitant use of clarithromycin and statins. Patients should be monitored for symptoms of myopathy. When concomitant use of clarithromycin with statins cannot be avoided, the lowest approved statin dose is recommended. A statin not metabolized by CYP3A, 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 (such as sulfonylureas) and/or insulin may cause pronounced hypoglycemia. Close monitoring of blood glucose levels is recommended.
Oral anticoagulants
Concomitant use of clarithromycin with warfarin increases the risk of serious bleeding and significant elevation of the INR (International Normalized Ratio) and prothrombin time. Frequent monitoring of INR and prothrombin time is required while patients are receiving both clarithromycin and oral anticoagulants.
Caution is advised when clarithromycin is used concomitantly with direct oral anticoagulants such as dabigatran, rivaroxaban, apixaban, and edoxaban, especially in patients at high risk of bleeding (see section "Interaction with other medicinal products and other forms of interaction").
Excipients
The product contains lactose. Patients with rare hereditary conditions of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this medicine.
The product contains sodium – less than 1 mmol (23 mg) per dose, which should be considered in patients on a sodium-restricted diet.
The colorant FD&C Yellow No. 2 (tartrazine) (E 102) contained in the medicinal product may cause allergic reactions.
The use of any antimicrobial therapy, including clarithromycin, for the treatment of H. pylori infection may lead to the development of resistance.
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 assessment of the benefit-risk ratio.
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 clarithromycin dose, adjusted for body weight.
The safety of clarithromycin use during breastfeeding has not been established.
Fertility. No significant effects on fertility were observed in animal studies at daily doses of the drug.
Ability to affect reaction speed when driving or operating machinery.
Data on this effect are lacking. However, when driving or operating machinery, the possibility of central nervous system adverse reactions such as seizures, 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 500 mg once daily taken with food. In more severe infections, the dose may be increased to 1000 mg (2 tablets) once daily. Tablets should be swallowed whole, without chewing, and taken with a glass of water.
The usual duration of treatment is 5–14 days, except for the treatment of community-acquired pneumonia and sinusitis, which require 6–14 days of therapy.
Patients with Renal Impairment
This formulation should not be used in patients with severe renal impairment (creatinine clearance <30 mL/min) because it does not allow adequate dose reduction. Such patients should receive clarithromycin in another pharmaceutical formulation.
For patients with moderate renal impairment (creatinine clearance 30–60 mL/min), the dose should be reduced by 50%, up to a maximum of one modified-release tablet per day.
Elderly Patients
Dose adjustment is not required (except in cases of impaired renal function).
Children
The use of clarithromycin tablets in children under 12 years of age has not been studied. For children in this age group, the drug may be administered in the form of a suspension.
Overdose
Symptoms: gastrointestinal disturbances (nausea, vomiting, diarrhea, fluid and electrolyte imbalances), headache, disturbances of consciousness, changes in mental status, paranoid behavior, hypokalemia, and hypoxemia. In one patient with a history of bipolar disorder who ingested 8 grams of clarithromycin, disturbances in mental status, paranoid behavior, hypokalemia, and hypoxemia developed. Cases of crystalluria have been reported, sometimes leading to renal failure.
Treatment: gastric lavage is recommended within the first 2 hours after overdose. Therapy is symptomatic. Hemodialysis or peritoneal dialysis do not significantly alter serum levels of clarithromycin.
Side effects.
The most common and frequent adverse reactions associated with clarithromycin treatment in adults and children are abdominal pain, diarrhea, nausea, vomiting, and altered taste. These adverse reactions are usually mild and consistent with the known safety profile of macrolide antibiotics. During clinical studies, no significant difference was observed in the frequency of these gastrointestinal adverse reactions between patient groups with or without mycobacterial infections.
The adverse reactions listed below were reported during clinical trials and post-marketing use of various dosage forms and strengths of clarithromycin, including extended-release tablets. Adverse reactions considered at least possibly related to clarithromycin are categorized by organ system and frequency of occurrence: 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 category, adverse reactions are listed in order of decreasing severity, where severity could be assessed.
Gastrointestinal disorders:
Common – diarrhea, nausea, vomiting, dyspepsia, abdominal pain;
Uncommon – esophagitis\textsuperscript{1}, gastroesophageal reflux disease\textsuperscript{2}, gastroesophageal reflux, gastritis, proctalgia\textsuperscript{2}, stomatitis, glossitis, abdominal distension\textsuperscript{4}, constipation, dry mouth, eructation, flatulence;
Frequency not known – acute pancreatitis, discoloration of tongue, teeth.
Cardiac disorders:
Uncommon – cardiac arrest\textsuperscript{1}, atrial fibrillation\textsuperscript{1}, QT interval prolongation, extrasystoles\textsuperscript{1}, palpitations;
Frequency not known – ventricular tachycardia of the torsades de pointes type, ventricular tachycardia, ventricular tachycardia, hemorrhage, ventricular fibrillation.
Blood and lymphatic system disorders:
Uncommon – leukopenia, neutropenia\textsuperscript{4}, thrombocytosis\textsuperscript{3}, eosinophilia\textsuperscript{4};
Frequency not known – agranulocytosis, thrombocytopenia.
Vascular disorders:
Common – vasodilatation\textsuperscript{1};
Frequency not known – hemorrhage.
Immune system disorders:
Uncommon – anaphylactoid reactions\textsuperscript{1}, hypersensitivity;
Frequency not known – anaphylactic reactions, angioedema.
Nervous system disorders:
Common – dysgeusia (disturbance of taste sensation), headache;
Uncommon – loss of consciousness\textsuperscript{1}, dyskinesia\textsuperscript{1}, dizziness, somnolence, tremor;
Frequency not known – seizures, ageusia (loss of taste sensation), parosmia, anosmia, paresthesia.
Psychiatric disorders:
Common – insomnia;
Uncommon – anxiety, nervousness\textsuperscript{3};
Frequency not known – psychosis, confusion, depersonalization, depression, disorientation, hallucinations, nightmares, mania.
Infections and infestations:
Uncommon – cellulitis\textsuperscript{1}, candidiasis, gastroenteritis\textsuperscript{2}, infection\textsuperscript{3}, vaginal infection;
Frequency not known – pseudomembranous colitis, botulism.
Metabolism and nutrition disorders:
Uncommon – anorexia, decreased appetite;
Frequency not known – hypoglycemia.
Ear and labyrinth disorders:
Uncommon – vertigo, decreased hearing acuity, tinnitus;
Frequency not known – hearing loss.
Respiratory, thoracic and mediastinal disorders:
Uncommon – asthma\textsuperscript{1}, epistaxis\textsuperscript{2}, pulmonary embolism\textsuperscript{1}.
Hepatobiliary disorders:
Common – abnormal liver function tests;
Uncommon – cholestasis\textsuperscript{4}, hepatitis\textsuperscript{4}, increased levels of ALT, AST, GGT\textsuperscript{4};
Frequency not known – hepatic failure, hepatocellular jaundice.
Skin and subcutaneous tissue disorders:
Common – rash;
Uncommon – bullous dermatitis\textsuperscript{1}, hyperhidrosis, pruritus, urticaria, maculopapular rash\textsuperscript{3};
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 spasms\textsuperscript{3}, skeletal muscle rigidity\textsuperscript{1}, myalgia\textsuperscript{2};
Frequency not known – rhabdomyolysis\textsuperscript{2**}, myopathy.
Renal and urinary disorders:
Uncommon – increased blood creatinine\textsuperscript{1}, increased blood urea\textsuperscript{1};
Frequency not known – renal failure, interstitial nephritis.
General disorders and administration site conditions:
Very common – phlebitis at injection site\textsuperscript{1};
Common – pain at injection site\textsuperscript{1}, inflammation at injection site\textsuperscript{1};
Uncommon – malaise\textsuperscript{4}, pyrexia\textsuperscript{3}, asthenia, chest pain\textsuperscript{4}, chills\textsuperscript{4}, fatigue\textsuperscript{4}.
Other: asthenia; isolated reports of paresthesia, angioedema, uveitis (mostly in patients concurrently receiving rifabutin). Cases of colchicine toxicity have been reported when clarithromycin was co-administered with colchicine.
Laboratory findings:
Altered albumin-globulin ratio\textsuperscript{1}, increased alkaline phosphatase levels in blood\textsuperscript{4}, increased lactate dehydrogenase levels in blood\textsuperscript{4};
Frequency not known – increased INR, prolonged prothrombin time, change in urine color.
* Frequency not known: these reactions have been reported voluntarily from a population of uncertain size, making it impossible to reliably estimate their frequency or establish a causal relationship to drug exposure. The overall clinical experience with clarithromycin exceeds 1 billion patient-days.
** In some reports of rhabdomyolysis, clarithromycin was co-administered with other drugs known to be associated with rhabdomyolysis (e.g., statins, fibrates, colchicine, or allopurinol).
\textsuperscript{1},\textsuperscript{2},\textsuperscript{3},\textsuperscript{4} These adverse reactions were reported only with the following dosage forms: \textsuperscript{1} – lyophilized powder for solution for infusion, \textsuperscript{2} – extended-release tablets, \textsuperscript{3} – suspension, \textsuperscript{4} – immediate-release tablets.
Very rarely, there have been reports of detection of clarithromycin immediate-release tablets in feces, many of which occurred in patients with anatomical (including ileostomy or colostomy) or functional gastrointestinal disorders associated with shortened gastrointestinal transit time. In several reports, tablet remnants were observed in the context of diarrhea.
Patients in whom tablet residues are observed in feces and who do not show clinical improvement during treatment should be advised to switch to another dosage form of clarithromycin (e.g., suspension) or to another antibiotic.
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 patients with AIDS and other immunocompromised patients receiving high-dose, long-term clarithromycin for treatment of mycobacterial infections, it was often difficult to distinguish adverse reactions related to drug administration 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 elevated serum ALT and AST levels. Dyspnea, insomnia, and dry mouth occurred less frequently.
In these immunocompromised patients, laboratory parameters were evaluated by assessing values outside the range of marked abnormality (i.e., extreme upper or lower limits) for a given test. By this criterion, 2–3% of patients receiving 1000 mg of clarithromycin daily showed markedly 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. 4 years.
Storage conditions.
Store in the original packaging, protected from light, in a place inaccessible to children, at a temperature not exceeding 25 °C.
Packaging.
7 tablets in a blister; 1 or 2 blisters per cardboard box.
Prescription status. Prescription only.
Manufacturer.
Sanovel Ilac Sanayi ve Ticaret A.S., Turkey.
Manufacturer's address and place of business.
Balaban Mahallesi, Cihaner Sokagi, No 10, Istanbul, 34580 Silivri, Turkey.