Fromilid film-coated tablets 500 mg No. 14

Instructions Fromilid film-coated tablets 500 mg No. 14

Composition

active ingredient: clarithromycin;

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

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

Dosage form

Film-coated tablets.

Main physicochemical properties: oval convex tablets of slightly brownish-yellow color, film-coated.

Pharmacotherapeutic group

Antimicrobials for systemic use. Macrolides, lincosamides and streptogramins. Clarithromycin. ATC code J01F A09.

Pharmacological properties

Pharmacodynamics

Mechanism of action

Clarithromycin is a semisynthetic macrolide antibiotic. The antibacterial effect of clarithromycin is determined by its binding to the 5OS ribosomal subunit of sensitive bacteria and inhibition of protein biosynthesis. This leads to disruption of the normal functioning of the bacterial cell. Due to the diverse structure of human cell ribosomes, it prevents the binding of macrolides to these ribosomes, which is probably the reason for the low toxicity of macrolides to humans. Chloramphenicol and lincosamides in some bacteria compete with macrolides for binding to the peptidyl centers of the ribosome, which leads to an antagonistic effect.

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

The main action of macrolides is bacteriostatic. However, it depends on the amount of macrolide, the number of bacteria present and the stage of the bacterial life cycle at the time of prescribing the antibiotic. Clarithromycin, like other macrolides, can also exhibit bactericidal activity, namely against Streptococcus pyogenes, Streptococcus pneumoniae and Moraxella catarrhalis. Modern studies of macrolides show that the best indicator for predicting the effectiveness of macrolides is the time at which the concentration of this antibiotic in the blood serum exceeds the minimum inhibitory concentration (MIC).

Antibacterial effectiveness

Clarithromycin has bacteriostatic and bactericidal activity against a wide range of clinically significant Gram-positive and Gram-negative bacteria, such as aerobes, anaerobes or obligate anaerobes, other bacteria (mycoplasmas, ureaplasmas, chlamydia, legionella) and atypical mycobacteria.

Table 1. Bacteria susceptible to clarithromycin.

Pharmacokinetics

Absorption

Clarithromycin is well absorbed from the gastrointestinal tract. Bioavailability is approximately 55% after an oral dose. Food may slow absorption but does not significantly affect the bioavailability of clarithromycin. Approximately 20% of clarithromycin is immediately metabolized to the major metabolite, 14-hydroxyclarithromycin, which exhibits the same biological effects as clarithromycin. In healthy subjects, it reaches serum concentrations proportional to the size of the oral dose. Peak serum concentrations are observed in less than 3 hours. After a single oral dose of 250 mg of clarithromycin, mean concentrations range from 0.62 μg/mL to 0.84 μg/mL; after a single oral dose of 500 mg of clarithromycin, they range from 1.77 μg/mL to 1.89 μg/mL. The corresponding concentrations of 14-hydroxyclarithromycin are 0.4 μg/mL to 0.7 μg/mL after a 250 mg dose and 0.67 μg/mL to 0.8 μg/mL after a 500 mg dose. The area under the concentration-time curve (AUC x time) is 4 μg/mL∙h after a 250 mg dose and 11 μg/mL∙h after a 500 mg dose.

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

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

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

Metabolism and excretion

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

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

Effect of age and disease on pharmacokinetics

Children and infants: According to studies, the pharmacokinetics of clarithromycin in children at a dose of 7.5 mg/kg body weight twice daily were similar to those in adults.

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

Effect of disease on pharmacokinetics: Following administration of 200 mg of clarithromycin, there was an increase in peak concentration and AUC and a decrease in clearance of clarithromycin in patients with severe renal impairment compared to healthy subjects. In patients with severe renal impairment, the total clearance of clarithromycin decreased from 26.5% to 3.3% compared to healthy subjects. These results indicate that a dose reduction or a prolonged dosing interval is necessary for patients with severe renal impairment.

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

Indication

Infections caused by microorganisms sensitive to clarithromycin:

– Lower respiratory tract infections (bronchitis, acute lobar pneumonia and primary atypical pneumonia).

– Upper respiratory tract infections, i.e. nasopharynx (tonsillitis, pharyngitis) and sinus infections.

– Skin and soft tissue infections (impetigo, folliculitis, erysipeloid, furunculosis, infected wounds).

– Acute and chronic odontogenic infections.

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

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

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

Clarithromycin is prescribed to adults and children over 12 years of age.

Contraindication

– Hypersensitivity to clarithromycin or other macrolide antibiotics or to any of the ingredients of the drug.

– Concomitant use with the following drugs: astemizole, cisapride, domperidone, pimozide, terfenadine - as this may lead to prolongation of the QT interval and the development of cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation and torsades de pointes (see sections “Special warnings and precautions for use” and “Interaction with other medicinal products and other types of interactions”).

– Congenital or established acquired prolongation of the QT interval or history of ventricular cardiac arrhythmias, including torsade de pointes (see sections “Special warnings and precautions for use” and “Interaction with other medicinal products and other types of interactions”).

– Concomitant use of clarithromycin and ergotamine or dihydroergotamine - as this may lead to ergotoxicity.

– Concomitant use of clarithromycin with lomitapide (see section “Interaction with other medicinal products and other types of interactions”).

– Concomitant use with HMG-CoA reductase inhibitors (statins) that are extensively metabolized by CYP3A4 (lovastatin or simvastatin) – due to an increased risk of myopathy, including rhabdomyolysis (see section “Interaction with other medicinal products and other types of interactions”).

– Concomitant use of clarithromycin and oral midazolam. During treatment with clarithromycin, treatment with these agents should be discontinued (see sections “Special warnings and precautions for use” and “Interaction with other medicinal products and other forms of interaction”).

– Concomitant use of clarithromycin (and other strong CYP3A4 inhibitors) with colchicine in patients with renal or hepatic insufficiency (see sections “Special warnings and precautions for use” and “Interaction with other medicinal products and other forms of interaction”).

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

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

Interaction with other medicinal products and other types of interactions

Clarithromycin does not interact with oral contraceptives.

The use of the following drugs is strictly contraindicated due to the possible development of severe interaction effects:

Astemizole, cisapride, domperidone, pimozide, and terfenadine

Increased serum levels of cisapride have been observed when co-administered with clarithromycin, which may lead to QT prolongation and arrhythmias including ventricular tachycardia, ventricular fibrillation and torsades de pointes. Similar effects have been observed when pimozide and clarithromycin are co-administered (see section 4.3).

Macrolides have been reported to alter the metabolism of terfenadine, leading to increased serum levels of terfenadine, which have sometimes been associated with cardiac arrhythmias such as QT prolongation, ventricular tachycardia, ventricular fibrillation and torsades de pointes (see Contraindications). In a study of 14 volunteers, concomitant administration of terfenadine and clarithromycin resulted in a 2- to 3-fold increase in the acid metabolite of terfenadine and a prolongation of the QT interval, without any clinically apparent effect. Similar effects have been observed with the concomitant administration of astemizole and other macrolides.

Ergotamine/dihydroergotamine

Postmarketing reports indicate that concomitant use of clarithromycin and ergotamine or dihydroergotamine has been associated with the development of signs of acute ergotism, characterized by vasospasm and ischemia of the extremities and other tissues, including the central nervous system. The concomitant use of clarithromycin and ergot alkaloids is contraindicated (see section 4.3).

Oral midazolam

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

HMG-CoA reductase inhibitors (statins)

The combined use of clarithromycin with lovastatin or simvastatin is contraindicated (see section "Contraindications"), since these statins are extensively metabolized by CYP3A4 and concomitant use with clarithromycin increases their plasma concentrations, which in turn increases the risk of myopathy, including rhabdomyolysis. Rhabdomyolysis has been reported in patients receiving concomitant treatment with clarithromycin and these statins. If treatment with clarithromycin cannot be avoided, lovastatin or simvastatin should be discontinued during the course of treatment.

Clarithromycin should be used with caution when co-administered with statins. If concomitant use of clarithromycin with statins cannot be avoided, the lowest approved dose of the statin is recommended. A statin that is not metabolized by CYP3A (e.g., fluvastatin) may be used. Patients should be monitored for signs and symptoms of myopathy.

Lomitapide

Concomitant administration of clarithromycin with lomitapide is contraindicated due to the potential for significant elevations in transaminase levels (see Contraindications).

Effects of other drugs on clarithromycin

Medicinal products that are inducers of CYP3A (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital, St. John's wort) may induce the metabolism of clarithromycin. This may lead to subtherapeutic levels of clarithromycin and reduced efficacy. In addition, monitoring of plasma levels of the CYP3A inducer, which may be increased due to inhibition of CYP3A by clarithromycin, may be necessary (see also the Summary of Product Characteristics of the respective CYP3A4 inducer). Concomitant use of rifabutin and clarithromycin has been shown to increase rifabutin levels and decrease clarithromycin serum levels, with a concomitant increase in the risk of uveitis.

The following drugs are known or suspected to affect clarithromycin blood concentrations and may require dose adjustment or alternative therapy.

Efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine

Potent inducers of cytochrome P450 enzymes, such as efavirenz, nevirapine, rifampicin, rifabutin and rifapentine, may accelerate the metabolism of clarithromycin, reducing its plasma concentration but increasing the concentration of 14-OH-clarithromycin, the microbiologically active metabolite. Since the microbiological activity of clarithromycin and 14-OH-clarithromycin is different against different bacteria, the expected therapeutic effect may not be achieved due to the combined use of clarithromycin and inducers of cytochrome P450 enzymes.

Etravirine

Clarithromycin activity was attenuated by etravirine; however, concentrations of the active metabolite 14-OH-clarithromycin were increased. Since 14-OH-clarithromycin has reduced activity against 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

Ritonavir

The use of ritonavir and clarithromycin resulted in significant inhibition of clarithromycin metabolism. Clarithromycin Cmax increased by 31%, Cmin by 182%, and AUC by 77%. Complete inhibition of 14-OH-clarithromycin formation was observed. Due to the large therapeutic window, no dose reduction of clarithromycin is required in patients with normal renal function. Dosage adjustment is required in patients with renal insufficiency: for CLCR 30–60 ml/min, the dose of clarithromycin should be reduced by 50% to the maximum dose of 1 tablet per day; for CLCR < 30 ml/min, the dose should be reduced by 75%. Doses of clarithromycin exceeding 1 g/day should not be used with ritonavir.

Similar dose adjustments should be made for patients with impaired renal function when ritonavir is used as a pharmacokinetic enhancer with other HIV protease inhibitors, including atazanavir and saquinavir.

Effect of clarithromycin on other medicinal products

CYP3A-related interactions

Concomitant use of clarithromycin, a known inhibitor of the CYP3A enzyme, and a drug that is primarily metabolized by CYP3A may result in increased plasma concentrations of the latter, which in turn may increase or prolong its therapeutic effect and the risk of adverse reactions.

Clarithromycin is contraindicated in patients receiving the CYP3A substrates astemizole, cisapride, domperidone, pimozide, and terfenadine due to the risk of QT prolongation and cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation, and torsades de pointes (see sections 4.3 and 4.4).

The use of clarithromycin with ergot alkaloids, oral midazolam, HMG-CoA reductase inhibitors that are primarily metabolized by CYP3A4 (e.g., lovastatin and simvastatin), colchicine, ticagrelor, ivabradine, and ranolazine is also contraindicated (see Contraindications).

Caution should be exercised when clarithromycin is coadministered with other drugs that are substrates of the CYP3A enzyme, especially if the CYP3A substrate has a narrow safety margin (e.g. carbamazepine) and/or the substrate is extensively metabolized by this enzyme. In such cases, dose adjustment may be necessary and, if possible, serum concentrations of drugs that are primarily metabolized by CYP3A should be closely monitored. Drugs or drug classes known or suspected to be metabolized by the same CYP3A isoenzyme include (but are not limited to): alprazolam, carbamazepine, cilostazol, cyclosporine, disopyramide, ibrutinib, methylprednisolone, midazolam (intravenous), omeprazole, oral anticoagulants (e.g., warfarin, rivaroxaban, apixaban), atypical antipsychotics (e.g., quetiapine), quinidine, rifabutin, sildenafil, sirolimus, tacrolimus, triazolam, and vinblastine.

A similar mechanism of interaction has been observed with phenytoin, theophylline, and valproate, which are metabolized by a different isoenzyme of the cytochrome P450 system.

Direct-acting oral anticoagulants (DAOCs)

The PAPDs dabigatran and edoxaban are substrates of the efflux transporter P-gp (P-glycoprotein). Rivaroxaban and apixaban are metabolized by CYP3A4 and are also substrates of P-gp. Caution should be exercised when clarithromycin is co-administered with these drugs, especially in patients at high risk of bleeding (see Precautions).

Antiarrhythmic drugs

There have been postmarketing reports of torsades de pointes associated with concomitant use of clarithromycin with quinidine or disopyramide. ECG monitoring is recommended for early detection of QT prolongation. Serum concentrations of these drugs should be monitored during clarithromycin therapy.

During post-marketing use, there have been reports of hypoglycemia with the simultaneous use of clarithromycin and disopyramide, therefore, monitoring of blood glucose levels is necessary when these agents are used simultaneously.

Hydroxychloroquine and chloroquine

Clarithromycin should be used with caution in patients receiving these drugs known to prolong the QT interval due to the potential to induce cardiac arrhythmias and serious adverse cardiovascular events.

Oral hypoglycemic agents/insulin

When used concomitantly with certain hypoglycemic agents such as nateglinide and repaglinide, clarithromycin may inhibit the CYP3A enzyme, which may cause hypoglycemia. Close monitoring of glucose levels is recommended.

Omeprazole

The use of clarithromycin (500 mg every 8 hours) in combination with omeprazole (40 mg daily) in healthy adult volunteers resulted in an increase in the equilibrium concentrations of omeprazole. When omeprazole was used alone, the mean pH of gastric juice measured over 24 hours was 5.2, when omeprazole was used together with clarithromycin - 5.7.

Sildenafil, tadalafil and vardenafil

There is a possibility of increased plasma concentrations of phosphodiesterase inhibitors (sildenafil, tadalafil and vardenafil) when co-administered with clarithromycin, which may require a reduction in the dose of phosphodiesterase inhibitors.

Clinical trial results have shown that there is a small but statistically significant increase in theophylline or carbamazepine plasma concentrations when co-administered with clarithromycin.

Tolterodine

Tolterodine is primarily metabolized by the cytochrome P450 isoform 2D6 (CYP2D6). However, in a population of patients lacking CYP2D6, metabolism occurs via CYP3A. In this population, inhibition of CYP3A results in significantly increased serum concentrations of tolterodine. In such patients, a reduction in the dose of tolterodine may be necessary when administered with CYP3A inhibitors such as clarithromycin.

Triazolebenzodiazepines (e.g., alprazolam, midazolam, triazolam)

When midazolam was administered with clarithromycin tablets (500 mg twice daily), the AUC of midazolam increased 2.7-fold after intravenous administration and 7-fold after oral administration of midazolam. The combined use of oral midazolam and clarithromycin should be avoided. When intravenous midazolam is administered with clarithromycin, the patient's condition should be carefully monitored for timely dose adjustment.

The same precautions should be observed when using other benzodiazepines that are metabolized by CYP3A, including triazolam and alprazolam. For benzodiazepines whose elimination is not dependent on CYP3A (temazepam, nitrazepam, lorazepam), the development of clinically significant interactions with clarithromycin is unlikely.

There have been post-marketing reports of drug interactions and the development of central nervous system adverse events (such as drowsiness and confusion) with the concomitant use of clarithromycin and triazolam. The patient should be monitored for the possibility of increased central nervous system pharmacological effects.

Corticosteroids

Caution should be exercised when clarithromycin is coadministered with systemic and inhaled corticosteroids that are primarily metabolized by CYP3A due to the potential for increased systemic exposure to the corticosteroid. Patients should be closely monitored for adverse effects of systemic corticosteroids during concomitant use.

Other types of interactions

Aminoglycosides

Clarithromycin should be used with caution in combination with other ototoxic agents, especially aminoglycosides (see section "Special warnings and 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 coadministered, inhibition of Pgp and CYP3A by clarithromycin may result in increased exposure to colchicine. Patients should be monitored for clinical signs of colchicine toxicity.

Digoxin

In postmarketing experience, increased serum digoxin concentrations have been reported in patients receiving clarithromycin concomitantly with digoxin. Some patients have developed signs of digitalis toxicity, including potentially fatal arrhythmias. Serum digoxin concentrations should be closely monitored in patients receiving clarithromycin concomitantly.

Zidovudine

Concomitant use of clarithromycin immediate-release tablets and zidovudine in HIV-infected patients may result in decreased steady-state serum concentrations of zidovudine. This can be largely avoided by separating the doses of clarithromycin and zidovudine by 4 hours. No such interaction has been reported with clarithromycin suspension and zidovudine or dideoxynazine in children. Interaction studies with clarithromycin extended-release tablets and zidovudine have not been conducted.

Phenytoin and valproate

There have been spontaneous or published reports of interactions between CYP3A inhibitors, including clarithromycin, and drugs not considered to be metabolized by CYP3A (e.g., phenytoin and valproate). It is recommended that serum levels of these drugs be monitored when co-administered with clarithromycin. Increased serum levels have been reported.

Bidirectional drug interactions

Atazanavir

Coadministration of clarithromycin (500 mg twice daily) with atazanavir (400 mg once daily), which are CYP3A substrates and inhibitors, resulted in a 2-fold increase in clarithromycin exposure and a 70% decrease in 14-OH-clarithromycin exposure with a 28% increase in atazanavir AUC. Since clarithromycin has a wide therapeutic range, no dose reduction is necessary in patients with normal renal function. The clarithromycin dose should be reduced by 50% for patients with creatinine clearance 30–60 mL/min and by 75% for patients with creatinine clearance < 30 mL/min. Clarithromycin doses greater than 1000 mg daily should not be administered with protease inhibitors.

Calcium channel blockers

Due to the risk of hypotension, caution should be exercised when administering clarithromycin concomitantly with calcium channel blockers metabolized by CYP3A4 (e.g. verapamil, amlodipine, diltiazem). The interaction may result in increased plasma concentrations of both clarithromycin and the calcium channel blocker.

Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving clarithromycin with verapamil.

Clarithromycin and itraconazole are substrates and inhibitors of CYP3A, and therefore clarithromycin may increase plasma levels of itraconazole and vice versa. When itraconazole is used concomitantly with clarithromycin, patients should be closely monitored for signs or symptoms of increased or prolonged effects.

Saquinavir

The use of clarithromycin (500 mg twice daily) with saquinavir (soft gelatin capsules 1200 mg three times daily), which are substrates and inhibitors of CYP3A, resulted in an increase in steady-state AUC by 177% and Cmax by 187% compared to the use of saquinavir alone. At the same time, the AUC and Cmax of clarithromycin increased by approximately 40% compared to the use of clarithromycin alone. No dose adjustment is necessary if both drugs are used simultaneously for a limited period of time and in the above doses and dosage forms. The results of a drug interaction study with the use of soft gelatin capsules may not correspond to the effects observed with the use of saquinavir in the form of hard gelatin capsules. The results of a drug interaction study with saquinavir alone may not correspond to the effects observed with saquinavir/ritonavir therapy. When saquinavir is used with ritonavir, the possible effects of ritonavir on clarithromycin should be considered.

Application features

The physician should not prescribe clarithromycin to pregnant women without carefully weighing the benefits and risks, especially during the first three months of pregnancy (see section “Use during pregnancy or breastfeeding”).

Prolonged or repeated use of antibiotics may result in overgrowth of nonsusceptible bacteria and fungi. If superinfection occurs, clarithromycin should be discontinued and appropriate therapy initiated.

The drug should be used with caution in patients with severe renal insufficiency (see section "Method of administration and dosage").

Clarithromycin is primarily eliminated by the liver. Therefore, caution should be exercised when prescribing the antibiotic to patients with impaired liver function. Caution should also be exercised when prescribing clarithromycin to patients with moderate to severe renal insufficiency.

Hepatic dysfunction, including elevated liver enzymes, and hepatocellular and/or cholestatic hepatitis with or without jaundice, have been reported with clarithromycin. These hepatic dysfunctions may be severe and are usually reversible. Fatal hepatic failure has occasionally been reported (see Adverse Reactions), and has generally been associated with serious underlying medical conditions and/or concomitant medication. Clarithromycin should be discontinued immediately if signs and symptoms of hepatitis such as anorexia, jaundice, dark urine, pruritus, or abdominal pain occur.

Clostridium difficile-associated diarrhea, ranging from mild to fatal, has been reported with the use of nearly all antibacterial agents, including clarithromycin. The possibility of Clostridium difficile-associated diarrhea should be kept in mind in all patients presenting with diarrhea following antibiotic therapy. In addition, a careful history should be taken, as Clostridium difficile-associated diarrhea has been reported up to 2 months after the use of antibacterial agents. If pseudomembranous colitis occurs, clarithromycin should be discontinued regardless of the indication for which it was prescribed. Microbiological investigation should be performed and appropriate treatment initiated. Drugs that inhibit peristalsis should be avoided.

Colchicine

Colchicine toxicity (including fatal outcomes) has been reported with concomitant use of clarithromycin and colchicine, particularly in the elderly, including patients with renal insufficiency (see section 4.5). Concomitant use of clarithromycin and colchicine is contraindicated (see section 4.3).

Caution should be exercised when clarithromycin is administered concomitantly with triazolebenzodiazepines, e.g. triazolam, intravenous midazolam (see section “Interaction with other medicinal products and other forms of interaction”).

Clarithromycin should be used with caution in combination with other ototoxic agents, especially aminoglycosides. Vestibular and auditory function should be monitored during and after treatment.

Cardiovascular complications

QT prolongation, which reflects an effect on cardiac repolarization, which poses a risk of cardiac arrhythmias and torsades de pointes, has been observed in patients treated with macrolides, including clarithromycin (see section 4.8). Due to the increased risk of QT prolongation and ventricular arrhythmias (including torsades de pointes), clarithromycin is contraindicated in: patients taking astemizole, cisapride, domperidone, pimozide and terfenadine; patients with hypokalemia; patients with a history of QT prolongation or ventricular cardiac arrhythmias (see section 4.8).

– Patients with ischemic heart disease, severe heart failure, conduction disorders or clinically significant bradycardia.

– Patients who are concurrently taking other drugs that prolong the QT interval, except those that are contraindicated.

Epidemiological studies on the risk of adverse cardiovascular events with macrolides have been mixed. Some studies have reported a rare short-term risk of arrhythmia, myocardial infarction, and fatal cardiovascular events associated with macrolides, including clarithromycin. Consideration of these findings when prescribing clarithromycin should be balanced against the benefits of treatment.

Pneumonia

Since Streptococcus pneumoniae may be resistant to macrolides, it is important to perform susceptibility testing when prescribing clarithromycin for the treatment of community-acquired pneumonia. In the case of nosocomial pneumonia, clarithromycin should be used in combination with other appropriate antibiotics.

Mild to moderate skin and soft tissue infections

These infections are most commonly caused by Staphylococcus aureus and Streptococcus pyogenes, both of which may be resistant to macrolides. Susceptibility testing is therefore important. In cases where beta-lactam antibiotics are not suitable (e.g. allergy), other antibiotics such as clindamycin may be used as first-line agents. Macrolides currently have a role only in the treatment of certain skin and soft tissue infections, e.g. infections caused by Corynebacterium minutissimum (erythrasma), acne vulgaris, erysipelas; and in situations where penicillin treatment is not appropriate.

In the event of severe acute hypersensitivity reactions such as anaphylaxis, severe cutaneous adverse reactions (e.g. acute generalized exanthematous pustulosis, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS)), Henoch-Schonlein-Schönlein disease, clarithromycin therapy should be discontinued immediately and appropriate treatment should be initiated immediately.

Clarithromycin should be used with caution when co-administered with inducers of the cytochrome CYP3A4 enzyme (see section “Interaction with other medicinal products and other types of interactions”).

HMG-CoA reductase inhibitors (statins)

The combined use of clarithromycin with lovastatin or simvastatin is contraindicated (see section 4.3). Caution should be exercised when clarithromycin is administered concomitantly with other statins. Rhabdomyolysis has been reported in patients receiving concomitant clarithromycin and statins. Patients should be monitored for signs and symptoms of myopathy. If concomitant use of clarithromycin with statins cannot be avoided, the lowest approved dose of the statin is recommended. A statin that is not metabolized by CYP3A (e.g., fluvastatin) may be used (see section 4.5).

Oral hypoglycemic agents/insulin

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