Fromilid uno, 500 mg 7 pcs

Pharmacodynamics

Clarithromycin is a semi-synthetic antibiotic of macrolide group and has antibacterial effect by interacting with 50S ribosomal subunit and inhibiting protein synthesis of bacteria sensitive to it.

Clarithromycin has demonstrated high activity under in vitro conditions against both standard laboratory strains of bacteria and those isolated from patients in clinical practice. It shows high activity against many aerobic and anaerobic gram-positive and gram-negative microorganisms. Minimum inhibitory concentrations (MIC) of clarithromycin for most pathogens are lower than MIC of erythromycin, on average, by one log2 dilution.

Clarithromycin is highly active against Legionella pneumophila, Mycoplasma pneumoniae under in vitro conditions. It has a bactericidal effect against Helicobacter pylori; this activity of clarithromycin is higher at neutral pH than at acidic pH.

In addition, in vitro and in vivo data indicate that clarithromycin is active against clinically relevant mycobacterial species. Enterobacteriaceae and Pseudomonas spp. as well as other non-lactose-fermenting Gram-negative bacteria are not sensitive to clarithromycin.

The activity of clarithromycin against most strains of the microorganisms listed below has been demonstrated both in vitro and in clinical practice for the diseases listed under “Indications”.

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) – complex including: Mycobacterium avium, Mycobacterium intracellulare.

The production of beta-lactamase has no effect on clarithromycin activity. Most staphylococcal strains resistant to methicillin and oxacillin are also resistant to clarithromycin.

Helicobacter pylori. Sensitivity of Helicobacter pylori to clarithromycin was studied in Helicobacter pylori isolates isolated from 104 patients before the start of therapy with the drug. Clarithromycin-resistant Helicobacter pylori strains were isolated in 4 patients, moderately resistant strains were isolated in 2 patients, and the remaining 98 patients had Helicobacter pylori isolates sensitive to clarithromycin.

Clarithromycin has action in vitro and against most strains of the following microorganisms (however, the safety and efficacy of clarithromycin in clinical practice has not been confirmed by clinical studies, and the practical value remains unclear):

Aerobic gram-positive microorganisms: Streptococcus agalactiae, Streptococci (groupsC, 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.

Campylobacter: Campilobacter jejuni.

The main metabolite of clarithromycin in humans is the microbiologically active metabolite 14-hydroxyclarithromycin (14-OH-clarithromycin).

The microbiological activity of the metabolite is the same as that of the parent substance, or 2 times weaker against most microorganisms. The exception is Haemophilus influenzae, against which the effectiveness of the metabolite is twice as high. The parent compound and its main metabolite have either additive or synergistic effect against Haemophilus influenzae under in vitro and in vivo conditions depending on the bacterial strain.

Pharmacokinetics

Absorption. The drug is rapidly absorbed in the gastrointestinal tract. Absolute bioavailability is about 50%. When taking repeated doses of the drug, cumulation was practically not found, and the character of metabolism in human body did not change.

Distribution, metabolism and excretion

In vitro. Clarithromycin binds to blood plasma proteins by 70% at concentrations from 0.45 to 4.5 µg/ml. At a concentration of 45 µg/ml, the binding decreases to 41%, probably as a result of saturation of the binding sites.

This is observed only at concentrations many times greater than the therapeutic concentration.

Healthy. In patients taking 500 mg of clarithromycin once daily after a meal, the Cmax of clarithromycin and 14-OH-clarithromycin in plasma was 1.3 and 0.48 µg/mL, respectively. T1/2 of clarithromycin and the metabolite were 5.3 and 7.7 h, respectively. When a single dose of clarithromycin in the dosage form – sustained release film-coated tablets, 1000 mg (2 × 500 mg), the Cmax of clarithromycin and its hydroxylated metabolite in blood plasma was 2.4 and 0.67 µg/ml, respectively. T1/2 of clarithromycin when administered at a dose of 1000 mg was 5.8 h, while the same indicator for 14-OH-clarithromycin was 8.9 h. Tmax with oral administration of both 500 and 1000 mg of clarithromycin was approximately 6 h. The Cmax of 14-OH-clarithromycin did not increase in proportion to the oral dose of clarithromycin, while the T1/2 of both clarithromycin and its hydroxylated metabolite tended to lengthen with increasing dose. This nonlinear pharmacokinetics of clarithromycin combined with decreased formation of 14-hydroxylated and N-demethylated products at high doses indicates a nonlinear metabolism of clarithromycin that becomes more pronounced at higher doses.

The kidneys excrete approximately 40% of the oral dose of clarithromycin; the intestines excrete approximately 30%.

Patients. Clarithromycin and its metabolite (14-OH clarithromycin) are rapidly absorbed into tissues and body fluids. There is limited evidence that the concentration of clarithromycin in cerebrospinal fluid when ingested is negligible (i.e., only 1-2% of the serum concentration with normal blood-brain barrier permeability). Concentrations in tissues are usually several times higher than in serum.

Liver function impairment. No dose adjustment of clarithromycin is required in patients with moderate to severe hepatic impairment but with preserved renal function. Plasma Css and systemic clearance of clarithromycin do not differ between patients in this group and healthy patients. Css of 14-OH clarithromycin is lower in patients with liver dysfunction than in healthy patients.

Renal dysfunction. Impaired renal function increases plasma Cmax and Cmin of clarithromycin, T1/2, AUC of clarithromycin and its metabolite (14-OH clarithromycin). The elimination constant and renal excretion decreases. The degree of change in these parameters depends on the degree of renal impairment.

In elderly patients. In elderly patients, plasma concentrations of clarithromycin and its metabolite (14-OH clarithromycin) were higher and excretion slower than in the younger group. However, after adjustment for renal creatinine clearance, there were no differences in the two groups. Thus, the main influence on the pharmacokinetic parameters of clarithromycin is renal function, not age.

Indications

Infectious and inflammatory diseases caused by microorganisms sensitive to the drug:

– lower respiratory tract infections (bronchitis, pneumonia);

– infections of the upper respiratory tract and ENT organs (tonsillitis, pharyngitis, sinusitis, acute otitis media);

– infections of the skin and soft tissues (including folliculitis, inflammation of the subcutaneous tissue, erysipelas).

Pharmacological effect

Pharmacological action – antibacterial.
Pharmacodynamics

Clarithromycin is a semisynthetic antibiotic of the macrolide group and has an antibacterial effect by interacting with the 50S ribosomal subunit and inhibiting the protein synthesis of bacteria sensitive to it.

Clarithromycin demonstrated high activity in vitro against both standard laboratory strains of bacteria and those isolated from patients during clinical practice. Shows high activity against many aerobic and anaerobic gram-positive and gram-negative microorganisms. The minimum inhibitory concentrations (MICs) of clarithromycin for most pathogens are less than the MICs of erythromycin, on average, by one log2 dilution.

Clarithromycin is highly active in vitro against Legionella pneumophila and Mycoplasma pneumoniae. It has a bactericidal effect against Helicobacter pylori; this activity of clarithromycin is higher at neutral pH than at acidic pH.

In addition, in vitro and in vivo data indicate that clarithromycin is active against clinically relevant mycobacterial species. Enterobacteriaceae and Pseudomonas spp. like other non-lactose-fermenting gram-negative bacteria, they are not sensitive to clarithromycin.

The activity of clarithromycin against most of the strains of microorganisms listed below has been proven both in vitro and in clinical practice for the diseases listed in the “Indications” section.

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) – a complex including: Mycobacterium avium, Mycobacterium intracellulare.

The production of beta-lactamase does not affect the activity of clarithromycin. Most strains of staphylococci resistant to methicillin and oxacillin are also resistant to clarithromycin.

Helicobacter pylori. The sensitivity of Helicobacter pylori to clarithromycin was studied on Helicobacter pylori isolates isolated from 104 patients before the start of drug therapy. Helicobacter pylori strains resistant to clarithromycin were isolated in 4 patients, moderately resistant strains were isolated in 2 patients, and Helicobacter pylori isolates were sensitive to clarithromycin in the remaining 98 patients.

Clarithromycin is effective in vitro and against most strains of the following microorganisms (however, the safety and effectiveness of clarithromycin in clinical practice has not been confirmed by clinical studies, and the practical significance remains unclear):

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.

Campylobacter: Campilobacter jejuni.

The main metabolite of clarithromycin in the human body is the microbiologically active metabolite 14-hydroxyclarithromycin (14-OH-clarithromycin).

The microbiological activity of the metabolite is the same as that of the parent substance, or 2 times weaker against most microorganisms. The exception is Haemophilus influenzae, for which the effectiveness of the metabolite is twice as high. The parent compound and its major metabolite have either additive or synergistic effects against Haemophilus influenzae in vitro and in vivo, depending on the bacterial strain.

Pharmacokinetics

Suction. The drug is quickly absorbed into the gastrointestinal tract. Absolute bioavailability is about 50%. When taking repeated doses of the drug, practically no accumulation was detected, and the nature of metabolism in the human body did not change.

Distribution, metabolism and excretion

In vitro. Clarithromycin binds to plasma proteins by 70% at concentrations from 0.45 to 4.5 μg/ml. At a concentration of 45 μg/ml, binding decreases to 41%, probably as a result of saturation of binding sites.

This is observed only at concentrations many times higher than the therapeutic concentration.

Healthy. In patients taking 500 mg of clarithromycin once a day after meals, the Cmax of clarithromycin and 14-OH-clarithromycin in blood plasma was 1.3 and 0.48 mcg/ml, respectively. T1/2 of clarithromycin and metabolite were 5.3 and 7.7 hours, respectively. When taking a single dose of clarithromycin in the dosage form – extended-release film-coated tablets, 1000 mg (2×500 mg), the Cmax of clarithromycin and its hydroxylated metabolite in blood plasma was 2.4 and 0.67 μg/ml, respectively. T1/2 of clarithromycin when administered at a dose of 1000 mg was 5.8 hours, while the same figure for 14-OH-clarithromycin was 8.9 hours. Tmax when administered orally with both 500 and 1000 mg of clarithromycin was approximately 6 hours. Cmax of 14-OH-clarithromycin did not increase in proportion to the oral dose of clarithromycin, while while T1/2 of both clarithromycin and its hydroxylated metabolite tended to lengthen with increasing dose. This nonlinear pharmacokinetics of clarithromycin, coupled with a decrease in the formation of 14-hydroxylated and N-demethylated products at high dosages, indicates a nonlinear metabolism of clarithromycin, which becomes more pronounced at high dosages.

Approximately 40% of an oral dose of clarithromycin is excreted by the kidneys; intestines – approximately 30%.

Patients. Clarithromycin and its metabolite (14-OH-clarithromycin) quickly penetrate into tissues and body fluids. There is limited data indicating that the concentration of clarithromycin in the cerebrospinal fluid after oral administration is negligible (i.e., only 1-2% of the serum concentration when the blood-brain barrier is normally permeable). Concentrations in tissues are usually several times higher than in serum.

Liver dysfunction. In patients with moderate to severe liver dysfunction, but with preserved renal function, no dose adjustment of clarithromycin is required. Css in blood plasma and systemic clearance of clarithromycin do not differ between patients in this group and healthy patients. Css of 14-OH-clarithromycin in patients with impaired liver function is lower than in healthy patients.

Renal dysfunction. If renal function is impaired, the Cmax and Cmin of clarithromycin in the blood plasma, T1/2, and AUC of clarithromycin and its metabolite (14-OH-clarithromycin) increase. The elimination constant and renal excretion decrease. The degree of changes in these parameters depends on the degree of renal dysfunction.

Elderly patients. In elderly patients, the concentration of clarithromycin and its metabolite (14-OH-clarithromycin) in the blood plasma was higher, and elimination was slower than in the group of young people. However, after adjustment for renal creatinine clearance, there was no difference in both groups. Thus, the main influence on the pharmacokinetic parameters of clarithromycin is renal function, and not age.

Special instructions

Long-term use of antibiotics can lead to the formation of colonies with an increased number of insensitive bacteria and fungi. In case of superinfection, appropriate therapy must be prescribed.

Hepatic dysfunction (increased plasma liver enzyme activity, hepatocellular and/or cholestatic hepatitis with or without jaundice) has been reported with the use of clarithromycin.

Liver dysfunction can be severe but is usually reversible. There have been cases of fatal liver failure, mainly associated with the presence of serious concomitant diseases and/or concomitant use of other drugs. If signs and symptoms of hepatitis appear, such as anorexia, jaundice, dark urine, itching, abdominal tenderness, clarithromycin therapy should be stopped immediately.

In the presence of chronic liver diseases, it is necessary to regularly monitor the activity of liver enzymes in the blood serum.

When treated with almost all antibacterial agents, incl. clarithromycin, cases of pseudomembranous colitis have been described, the severity of which can range from mild to life-threatening. Antibacterial drugs can change the normal intestinal microflora, which can lead to the growth of Clostridium difficile.

Pseudomembranous colitis caused by Clostridium difficile should be suspected in all patients who develop diarrhea after using antibacterial agents. After a course of antibiotic therapy, careful medical monitoring of the patient is necessary. Cases of the development of pseudomembranous colitis 2 months after the use of antibiotics have been described.

Prolongation of the QT interval. A long period of myocardial repolarization and the QT interval, which increases the risk of developing cardiac arrhythmia and torsade de pointes, have been observed with the use of macrolides, including clarithromycin. The use of clarithromycin may increase the risk of developing ventricular arrhythmias (including torsade de pointes), therefore clarithromycin should be used with caution:

– in patients with coronary artery disease, severe heart failure, cardiac conduction disorders, clinically significant bradycardia;

– in patients with fluid and electrolyte disorders such as hypomagnesemia. Clarithromycin should not be given to patients with hypokalemia;

– when used simultaneously with other drugs associated with prolongation of the QT interval (see “Interaction”).

It is possible to develop cross-resistance to clarithromycin and other macrolide antibiotics, as well as lincomycin and clindamycin.

Given the increasing resistance of Streptococcus pneumoniae to macrolides, it is important to perform susceptibility testing when prescribing clarithromycin to patients with community-acquired pneumonia. For hospital-acquired pneumonia, clarithromycin should be used in combination with appropriate antibiotics.

Mild to moderate skin and soft tissue infections are most often caused by Staphylococcus aureus and Streptococcus pyogenes. Moreover, both pathogens can be resistant to macrolides. Therefore, it is important to conduct an antibiotic susceptibility test.

Macrolides can be used for infections caused by Corynebacterium minutissimum (erythrasma), acne vulgaris and erysipelas, as well as in situations where penicillin cannot be used.

If acute hypersensitivity reactions such as anaphylactic reaction, Stevens-Johnson syndrome, toxic epidermal necrolysis and drug rash with eosinophilia and systemic symptoms (DRESS syndrome) occur, clarithromycin should be stopped immediately and appropriate therapy should be initiated.

In case of simultaneous use with warfarin or other indirect anticoagulants, it is necessary to monitor the INR and PT (see “Interaction”).

Impact on the ability to drive vehicles and machinery. There are no data regarding the effect of clarithromycin on the ability to drive a car or use machinery. Be aware of the potential for dizziness, vertigo, confusion, and disorientation that may occur while using this drug.

Care should be taken when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Active ingredient

Clarithromycin

Composition

1 extended-release film-coated tablet contains:

Core:

Active ingredient:

Clarithromycin 500.00 mg

Excipients: sodium alginate – 80 mg; sodium calcium alginate – 90 mg; lactose monohydrate – 225 mg; povidone – 30 mg; polysorbate 80 – 30 mg; colloidal silicon dioxide – 5 mg; magnesium stearate – 10 mg; talc – 30 mg,

film shell: hypromellose – 14.45 mg; talc – 1.33 mg; iron dye yellow oxide (E172) – 0.5 mg; titanium dioxide – 2.64 mg; propylene glycol – 1.08 mg..

Pregnancy

The safety of clarithromycin during pregnancy and breastfeeding has not been established.

The use of clarithromycin during pregnancy (especially in the first trimester) is possible only when there is no alternative therapy and the potential benefit to the mother outweighs the potential risk to the fetus.

Clarithromycin is excreted in breast milk. If it is necessary to take it during breastfeeding, breastfeeding should be discontinued.

Contraindications

– hypersensitivity to the components of the drug and other macrolides;

– severe renal failure (creatinine Cl less than 30 ml/min);

– simultaneous use of clarithromycin with the following drugs: astemizole, cisapride, pimozide, terfenadine (see “Interaction”);

– simultaneous use of clarithromycin with ergot alkaloids, for example ergotamine, dihydroergotamine (see “Interaction”);

– simultaneous use of clarithromycin with midazolam for oral administration (see “Interaction”);

– simultaneous use of clarithromycin with HMG-CoA reductase inhibitors (statins), which are largely metabolized by the CYP3A4 isoenzyme (lovastatin, simvastatin), due to an increased risk of myopathy, including rhabdomyolysis (see “Interaction”);

– simultaneous use of clarithromycin with colchicine;

– simultaneous use with ticagrelor or ranolazine;

– prolongation of the QT interval on the ECG (congenital or documented prolongation of the QT interval) in the anamnesis, ventricular arrhythmia or ventricular tachycardia of the “pirouette” type in the anamnesis;

– hypokalemia (risk of prolongation of the QT interval on the ECG);

– severe liver failure occurring simultaneously with renal failure;

– a history of cholestatic jaundice/hepatitis that developed during the use of clarithromycin (see “Special Instructions”);

– porphyria;

– lactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome;

– breastfeeding period;

– age up to 18 years (according to indications: tonsillitis, acute otitis media), up to 12 years (according to other indications).

With caution: moderate renal failure; moderate to severe liver failure; simultaneous use of clarithromycin with benzodiazepines, such as alprazolam, triazolam, midazolam for intravenous use (see “Interaction”); simultaneous use with drugs that are metabolized by the CYP3A isoenzyme, for example, carbamazepine, cilostazol, cyclosporine, disopyramide, methylprednisolone, omeprazole, indirect anticoagulants (for example, warfarin), quinidine, rifabutin, sildenafil, tacrolimus, vinblastine (see “Interaction”); simultaneous use with drugs that induce the CYP3A4 isoenzyme, for example rifampicin, phenytoin, carbamazepine, phenobarbital, St. John’s wort (see “Interaction”); simultaneous use with CCBs that are metabolized by the CYP3A4 isoenzyme (for example, verapamil, amlodipine, diltiazem); simultaneous use with other ototoxic drugs, especially aminoglycosides; simultaneous use with statins that do not depend on the metabolism of the CYP3A4 isoenzyme (for example, fluvastatin); patients with coronary heart disease (CHD), severe heart failure, hypomagnesemia, severe bradycardia (less than 50 beats/min), as well as patients simultaneously taking class IA (quinidine, procainamide) and class III antiarrhythmic drugs (dofetilide, amiodarone, sotalol); pregnancy.

Side Effects

Classification of the frequency of side effects of the World Health Organization (WHO): very often – ≥1/10; often – from ≥ 1/100 to < 1/10; uncommon - from ≥1/1000 to <1/100; rarely - from ≥1/10000 to <1/1000; very rarely - <1/10000; frequency unknown—cannot be estimated from available data. Within each group, adverse effects are presented in order of decreasing severity.

Allergic reactions: often – skin rash; uncommon – anaphylactoid reaction1, hypersensitivity, bullous1 dermatitis, pruritus, urticaria, maculopapular rash3; frequency unknown – anaphylactic reaction, angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS syndrome).

From the nervous system: often – headache, insomnia; uncommon – loss of consciousness1, dyskinesia1, dizziness, drowsiness, tremor, anxiety, increased excitability3; frequency unknown – convulsions, psychotic disorders, confusion, depersonalization, depression, disorientation, hallucinations, dream disturbances (nightmare dreams), paresthesia, mania.

From the skin: often – intense sweating; frequency unknown – acne, hemorrhages.

From the urinary system: frequency unknown – renal failure, interstitial nephritis.

From the side of metabolism and nutrition: infrequently – anorexia, loss of appetite.

From the musculoskeletal system: infrequently – muscle spasm, musculoskeletal stiffness, myalgia; frequency unknown – rhabdomyolysis2.5, myopathy.

From the digestive system: often – diarrhea, vomiting, dyspepsia, nausea, abdominal pain; uncommon – esophagitis1, gastroesophageal reflux disease2, gastritis, proctalgia2, stomatitis, glossitis, bloating4, constipation, dry oral mucosa, belching, flatulence, cholestasis4, hepatitis, including cholestatic or hepatocellular4; frequency unknown – acute pancreatitis, discoloration of the tongue and teeth, liver failure, cholestatic jaundice.

From the respiratory system: infrequently – bronchial asthma1, nosebleeds2, pulmonary embolism1.

From the senses: often – dysgeusia (perversion of taste); infrequently – vertigo, hearing loss, ringing in the ears; frequency unknown – deafness, ageusia (loss of taste), parosmia, anosmia.

From the cardiovascular system: often – vasodilation1; uncommon – sudden cardiac arrest1, atrial fibrillation1, prolongation of the QT interval on the ECG, extrasystole1, atrial flutter; frequency unknown – ventricular tachycardia, incl. pirouette type, ventricular fibrillation.

Laboratory indicators: often – deviation of laboratory indicators of liver function; infrequently – increased concentration of creatinine1, increased concentration of urea1 in blood plasma, change in the albumin/globulin ratio1, leukopenia, neutropenia4, eosinophilia4, thrombocythemia3, increased activity of AJIT, ACT, GGT4, ALP4, LDH4 in blood plasma; frequency unknown – agranulocytosis, thrombocytopenia, increased INR value, prolongation of PT, change in urine color, increased concentration of bilirubin in the blood plasma.

Other: infrequently – malaise4, hyperthermia3, asthenia, chest pain4, chills4, increased fatigue4.

Infectious and parasitic diseases: infrequently – cellulitis1, candidiasis, gastroenteritis2, secondary infections3 (including vaginal); frequency unknown – pseudomembranous colitis, erysipelas.

Immunosuppressed patients

In patients with AIDS and other immunodeficiencies receiving clarithromycin in higher doses over a long period of time for the treatment of mycobacterial infections, it is often difficult to distinguish adverse effects of the drug from symptoms of HIV infection or concomitant disease.

The most common adverse events in patients taking a daily dose of clarithromycin of 1000 mg were: nausea, vomiting, dysgeusia (taste distortion), abdominal pain, diarrhea, skin rash, flatulence, headache, constipation, hearing loss, increased AST and ALT activity in the blood plasma. There were also cases of adverse events with a low incidence of occurrence, such as shortness of breath, insomnia and dry oral mucosa.

In patients with suppressed immunity, laboratory parameters were assessed, analyzing their significant deviations from the norm (sharp increase or decrease). Based on this criterion, significant increases in plasma AST and ALT, as well as decreases in white blood cell and platelet counts, were reported in 2–3% of patients receiving clarithromycin 1000 mg daily. An increase in plasma residual urea nitrogen concentrations has also been reported in a small number of patients.

1 Reports of these adverse reactions were received during clinical trials, as well as post-marketing use of clarithromycin in the lyophilisate dosage form for solution for infusion.

2 Reports of these adverse reactions have been received during clinical trials, as well as post-marketing use of clarithromycin in the dosage form of extended-release film-coated tablets.

3 Reports of these adverse reactions have been received during clinical trials, as well as post-marketing use of clarithromycin in powder dosage form for oral suspension.

4 Reports of these adverse reactions have been received during clinical trials, as well as post-marketing use of clarithromycin in film-coated tablet dosage form.

5 In some reports of rhabdomyolysis, clarithromycin was taken concomitantly with other drugs known to be associated with rhabdomyolysis (statins, fibrates, colchicine or allopurinol).

Interaction

The use of the following medications concomitantly with clarithromycin is contraindicated due to the potential for serious side effects

Cisapride, pimozide, terfenadine and astemizole. When clarithromycin was taken concomitantly with cisapride, pimozide, terfenadine or astemizole, an increase in the concentration of the latter in the blood plasma was reported, which can lead to prolongation of the QT interval on the ECG and the appearance of cardiac arrhythmias, including ventricular tachycardia (including torsade de pointes) and ventricular fibrillation (see. “Contraindications”).

Ergot alkaloids. Post-marketing studies show that with simultaneous use of clarithromycin with ergotamine or dihydroergotamine, the following effects associated with acute poisoning with drugs of the ergotamine group are possible: vascular spasm, ischemia of the limbs and other tissues, including the central nervous system. The simultaneous use of clarithromycin and ergot alkaloids is contraindicated (see “Contraindications”).

HMG-CoA reductase inhibitors (statins). Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated (see “Contraindications”) due to the fact that these statins are largely metabolized by the CYP3A4 isoenzyme, and simultaneous use with clarithromycin increases their serum concentrations, which leads to an increased risk of developing myopathy, including rhabdomyolysis.

Cases of rhabdomyolysis have been reported in patients taking clarithromycin concomitantly with these drugs. If clarithromycin is necessary, lovastatin or simvastatin should be discontinued during therapy. Clarithromycin should be used with caution in combination therapy with other statins. It is recommended to use statins whose metabolism does not depend on the CYP3A isoenzyme (for example, fluvastatin). If concomitant use is necessary, it is recommended to take the lowest dose of statin. The development of signs and symptoms of myopathy should be monitored.

Effect of other drugs on clarithromycin

Drugs that are inducers of the CYP3A isoenzyme (for example, rifampicin, phenytoin, carbamazepine, phenobarbital, St. John’s wort) can induce the metabolism of clarithromycin. This may lead to subtherapeutic concentrations of clarithromycin and, accordingly, a decrease in its effectiveness. In addition, it is necessary to monitor the concentration of the CYP3A inducer in the blood plasma, which may increase due to the inhibition of the CYP3A isoenzyme by clarithromycin. With simultaneous use of rifabutin and clarithromycin, an increase in the concentration of rifabutin and a decrease in the concentration of clarithromycin in blood plasma was observed with an increased risk of developing uveitis.

The following drugs have a proven or suspected effect on clarithromycin plasma concentrations and may require dose adjustment or switch to alternative treatment if used concomitantly with clarithromycin

Efavirenz, nevirapine, rifampicin, rifabutin and rifapentine. Strong inducers of the cytochrome P450 system, such as efavirenz, nevirapine, rifampicin, rifabutin and rifapentine, can accelerate the metabolism of clarithromycin and thus reduce the concentration of clarithromycin in the blood plasma and weaken the therapeutic effect, and at the same time increase the plasma concentration of 14-OH-clarithromycin, a metabolite that is also microbiologically active. Since the microbiological activity of clarithromycin and 14-OH-clarithromycin differs against various bacteria, the therapeutic effect may be reduced with simultaneous use of clarithromycin and inducers of the cytochrome P450 system.

Etravirine. The plasma concentration of clarithromycin decreases when used concomitantly with etravirine, but the plasma concentration of the active metabolite 14-OH-clarithromycin increases. Because 14-OH-clarithromycin has low activity against MAC infections, overall activity against these pathogens may be altered, and alternative treatments should be considered for the treatment of MAC.

Fluconazole. Coadministration of fluconazole 200 mg daily and clarithromycin 500 mg twice daily in 21 healthy volunteers resulted in an increase in the mean clarithromycin trough Css and AUC by 33% and 18%, respectively. However, simultaneous administration did not significantly affect the average Css of the active metabolite 14-OH-clarithromycin. No dose adjustment of clarithromycin is required when taking fluconazole simultaneously.

Ritonavir. A pharmacokinetic study showed that co-administration of ritonavir 200 mg every 8 hours and clarithromycin 500 mg every 12 hours resulted in a marked suppression of the metabolism of clarithromycin. When coadministered with ritonavir, clarithromycin Cmax increased by 31%, Cmin increased by 182%, and AUC increased by 77%. Complete suppression of the formation of 14-OH-clarithromycin was noted. Due to the wide therapeutic range of clarithromycin, dose reduction is not required in patients with normal renal function. In patients with renal failure, it is advisable to consider the following dose adjustment options: when creatinine Cl is 30–60 ml/min, the dose of clarithromycin should be reduced by 50%. Ritonavir should not be taken concomitantly with clarithromycin in doses exceeding 1 g/day.

Effect of clarithromycin on other drugs

Antiarrhythmic drugs (quinidine and disopyramide). Ventricular tachycardia of the “pirouette” type may occur with the simultaneous use of clarithromycin and quinidine or disopyramide. When clarithromycin is coadministered with these drugs, ECG monitoring should be performed regularly to monitor for QT prolongation, and serum concentrations of these drugs should also be monitored.

Disopyramide. During post-marketing use, cases of hypoglycemia have been reported with concomitant use of clarithromycin and disopyramide. It is necessary to monitor the concentration of glucose in the blood while using clarithromycin and disopyramide.

Oral hypoglycemic agents/insulin. With the simultaneous use of clarithromycin and hypoglycemic agents for oral administration (for example, sulfonylurea derivatives) and/or insulin, severe hypoglycemia may occur. Concomitant use of clarithromycin with certain hypoglycemic drugs (for example, nateglinide, pioglitazone, repaglinide and rosiglitazone) may lead to inhibition of the CYP3A isoenzyme by clarithromycin, which may result in hypoglycemia. Careful monitoring of blood glucose concentrations is recommended.

Interactions due to CYP3A isoenzyme

Concomitant use of clarithromycin, which is known to inhibit the CYP3A isoenzyme, and drugs primarily metabolized by the CYP3A isoenzyme, may be associated with a mutual increase in their concentrations, which may increase or prolong both therapeutic and side effects. Clarithromycin should be used with caution in patients receiving drugs that are substrates of the CYP3A isoenzyme, especially if these drugs have a narrow therapeutic index (for example, carbamazepine), and/or drugs that are extensively metabolized by this isoenzyme. If necessary, the dose of the drug taken simultaneously with clarithromycin should be adjusted. Also, whenever possible, serum concentrations of drugs primarily metabolized by the CYP3A isoenzyme should be monitored.

The following drugs/classes are metabolized by the same CYP3A isoenzyme as clarithromycin: alprazolam, carbamazepine, cilostazol, cyclosporine, disopyramide, methylprednisolone, midazolam, omeprazole, indirect anticoagulants (e.g. warfarin), atypical antipsychotics (e.g. quetiapine), quinidine, rifabutin, sildenafil, tacrolimus, triazolam and vinblastine. Also, inhibitors of the CYP3A isoenzyme include the following drugs that are contraindicated for simultaneous use with clarithromycin: astemizole, cisapride, pimozide, terfenadine, lovastatin, simvastatin and ergot alkaloids (see “Contraindications”). Drugs that interact in this manner through other isoenzymes within the cytochrome P450 system include phenytoin, theophylline, and valproic acid.

Indirect anticoagulants. When taking warfarin and clarithromycin simultaneously, bleeding, a marked increase in INR and prolongation of PT are possible. In case of simultaneous use with warfarin or other indirect anticoagulants, it is necessary to monitor the INR and PT.

Omeprazole. Clarithromycin (500 mg every 8 hours) was studied in healthy adult volunteers in combination with omeprazole (40 mg daily). With simultaneous use of clarithromycin and omeprazole, plasma Css of omeprazole were increased (Cmax, AUC0–24 and T1/2 increased by 30, 89 and 34%, respectively). The average gastric pH over 24 hours was 5.2 (when omeprazole was taken alone) and 5.7 (when omeprazole was taken concomitantly with clarithromycin).

Sildenafil, tadalafil and vardenafil. Each of these PDE inhibitors is metabolized, at least in part, by the CYP3A isoenzyme. At the same time, the CYP3A isoenzyme can be inhibited in the presence of clarithromycin. Concomitant use of clarithromycin with sildenafil, tadalafil or vardenafil may lead to an increase in the inhibitory effect on PDE. When using these drugs concomitantly with clarithromycin, consider reducing the dose of sildenafil, tadalafil and vardenafil.

Theophylline, carbamazepine. With the simultaneous use of clarithromycin and theophylline or carbamazepine, it is possible to increase the concentration of these drugs in the systemic circulation.

Tolterodine. The primary metabolism of tolterodine occurs through the CYP2D6 isoenzyme. However, in part of the population lacking the CYP2D6 isoenzyme, metabolism occurs through the CYP3A isoenzyme. In this population, inhibition of CYP3A results in significantly higher serum tolterodine concentrations. In populations that are poor metabolizers of CYP2D6, a dose reduction of tolterodine may be required when coadministering CYP3A inhibitors such as clarithromycin.

Benzodiazepines (eg alprazolam, midazolam, triazolam). With the simultaneous use of midazolam and clarithromycin tablets (500 mg 2 times a day), an increase in the AUC of midazolam was noted: 2.7 times after intravenous administration of midazolam and 7 times after oral administration. Concomitant use of clarithromycin with midazolam for oral administration is contraindicated. If midazolam in the dosage form of an IV solution is used concomitantly with clarithromycin, the patient’s condition should be carefully monitored for possible dose adjustment of midazolam.

The same precautions should be applied to other benzodiazepines that are metabolized by CYP3A, including triazolam and alprazolam. For benzodiazepines whose elimination is not dependent on the CYP3A isoenzyme (temazepam, nitrazepam, lorazepam), a clinically significant interaction with clarithromycin is unlikely.

With simultaneous use of clarithromycin and triazolam, effects on the central nervous system, such as drowsiness and confusion, are possible. Therefore, if concurrent use occurs, it is advisable to monitor for symptoms of CNS impairment.

Interactions with other drugs

Aminoglycosides. When taking clarithromycin concomitantly with other ototoxic drugs, especially aminoglycosides, caution should be exercised and the functions of the vestibular and auditory systems should be monitored both during and after therapy.

Colchicine. Colchicine is a substrate of both CYP3A and the P-glycoprotein (Pgp) transporter protein. It is known that clarithromycin and other macrolides are inhibitors of the CYP3A and Pgp isoenzymes. When clarithromycin and colchicine are used concomitantly, inhibition of Pgp and/or CYP3A may result in increased effects of colchicine.

The development of clinical symptoms of colchicine poisoning should be monitored. There have been post-marketing reports of cases of colchicine poisoning when taken concomitantly with clarithromycin, most often in elderly patients. Some of the reported cases occurred in patients suffering from kidney failure. Some cases were reported to be fatal. The simultaneous use of clarithromycin and colchicine is contraindicated (see “Contraindications”).

Digoxin. Digoxin is suspected to be a Pgp substrate. Clarithromycin is known to inhibit Pgp. When clarithromycin and digoxin are used concomitantly, inhibition of Pgp by clarithromycin may result in increased effects of digoxin. Concomitant use of digoxin and clarithromycin may also lead to increased serum concentrations of digoxin.

Some patients have experienced clinical symptoms of digoxin toxicity, including potentially fatal arrhythmias. When clarithromycin and digoxin are taken concomitantly, serum digoxin concentrations should be carefully monitored.

Zidovudine. Concomitant use of clarithromycin tablets and zidovudine orally by adult HIV-infected patients may result in a decrease in plasma Css of zidovudine. Because clarithromycin interferes with the oral absorption of zidovudine, the interaction can be largely avoided by taking clarithromycin and zidovudine 4 hours apart. This interaction has not been observed in HIV-infected children taking clarithromycin pediatric suspension with zidovudine or dideoxyinosine. Since clarithromycin may interfere with the absorption of zidovudine when administered concomitantly orally in adult patients, such an interaction is unlikely to occur when clarithromycin is administered intravenously.

Phenytoin and valproic acid. There is evidence of interaction between inhibitors of the CYP3A isoenzyme (including clarithromycin) with drugs that are not metabolized by the CYP3A isoenzyme (phenytoin and valproic acid). For these drugs, when used simultaneously with clarithromycin, it is recommended to determine their serum concentrations, because there are reports of their increase.

Bidirectional drug interactions

Atazanavir. Clarithromycin and atazanavir are both substrates and inhibitors of the CYP3A isoenzyme. There is evidence of a bidirectional interaction between these drugs. Concomitant use of clarithromycin (500 mg twice daily) and atazanavir (400 mg once daily) may result in a twofold increase in clarithromycin exposure and a 70% decrease in 14-OH-clarithromycin exposure, with a 28% increase in atazanavir AUC. Due to the wide therapeutic range of clarithromycin, dose reduction is not required in patients with normal renal function.

In patients with moderate renal failure (Cl creatinine 30–60 ml/min), the dose of clarithromycin should be reduced by 50%. In patients with creatinine Cl less than 30 ml/min, the dose of clarithromycin should be reduced by 75% using the appropriate dosage form of clarithromycin. Clarithromycin in doses exceeding 1000 mg/day should not be used concomitantly with protease inhibitors.

BKK. When using clarithromycin simultaneously with CCBs that are metabolized by the CYP3A4 isoenzyme (for example, verapamil, amlodipine, diltiazem), caution should be exercised as there is a risk of arterial hypotension. With simultaneous use, plasma concentrations of clarithromycin and CCB may increase. Arterial hypotension, bradyarrhythmia and lactic acidosis are possible when taking clarithromycin and verapamil simultaneously.

Itraconazole Clarithromycin and itraconazole are substrates and inhibitors of the CYP3A isoenzyme, which determines the bidirectional interaction of the drugs. Clarithromycin may increase plasma concentrations of itraconazole, while itraconazole may increase plasma concentrations of clarithromycin. Patients taking itraconazole and clarithromycin concomitantly should be closely monitored for symptoms of increased or prolonged pharmacological effects of these drugs.

Saquinavir. Clarithromycin and saquinavir are substrates and inhibitors of the CYP3A isoenzyme, which determines the bidirectional interaction of the drugs. Coadministration of clarithromycin (500 mg twice daily) and saquinavir (soft gelatin capsules, 1200 mg three times daily) in 12 healthy volunteers increased the plasma AUC and Cmax of saquinavir by 177% and 187%, respectively, compared with saquinavir alone. The AUC and Cmax values ​​of clarithromycin were approximately 40% higher than with clarithromycin alone.

When these two drugs are used concomitantly for a limited time at the doses/formulations indicated above, no dose adjustment is required. The results of drug interaction studies using saquinavir soft gelatin capsules may not be consistent with the effects observed with saquinavir hard gelatin capsules. The results of drug interaction studies with saquinavir alone may not be consistent with the effects observed with saquinarine/ritonavir combination therapy. When taking saquinavir concomitantly with ritonavir, the potential effect of ritonavir on clarithromycin should be considered.

Overdose

Symptoms: Ingestion of a large dose of clarithromycin may cause gastrointestinal symptoms. In one patient with a history of bipolar disorder, changes in mental status, paranoid behavior, hypokalemia, and hypoxemia were described after taking 8 g of clarithromycin.

Treatment: in case of overdose, the unabsorbed drug should be removed from the gastrointestinal tract (gastric lavage, taking activated charcoal, etc.) and symptomatic therapy should be carried out. Hemodialysis and peritoneal dialysis do not have a significant effect on the concentration of clarithromycin in the blood serum, which is also typical for other drugs of the macrolide group.

Storage conditions

At a temperature not exceeding 25 °C, in the original packaging.

Keep out of the reach of children.

Shelf life

3 years.

Do not use the drug after the expiration date.

Manufacturer

KRKA dd Novo Mesto, Slovenia