Fromilid uno, retard pills 500mg, 14pcs

Composition

1 film-coated extended-release tablet contains:

Core:

Active ingredient:

Clarithromycin 500.00 mg

Auxiliary substances:

Sodium alginate, sodium calcium alginate, lactose monohydrate, povidone K 25, polysorbate-80, colloidal silicon dioxide, magnesium stearate, talc

Film shell:

Hypromellose, talc, iron oxide yellow dye (E 172), titanium dioxide (E 171), propylene

glycol Pharmacological action

antibiotic macrolide

Clinical Pharmacology

Pharmacodynamics

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

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

Clarithromycin in vitro is highly active against Legionella pneumophila, 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 acts on clinically significant mycobacterium species. Enterobacteriaceae and Pseudomonas spp. as well as other non-lactose-fermenting gram-negative bacteria, they are not sensitive to clarithromycin.

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

• 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.

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

Helicobacter pylori

Sensitivity of Helicobacter pylori to clarithromycin was studied on isolates of Helicobacter pylori isolated from 104 patients before starting therapy with the drug. Helicobacter pylori strains resistant to clarithromycin were isolated in 4 patients, strains with moderate resistance were isolated in 2 patients, and Helicobacter pylori isolates were sensitive to clarithromycin in the remaining 98 patients. Clarithromycin has an effect 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 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

• Campylobacteria:

– CamPylobacter 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 main metabolite have either an additive or synergistic effect against hemophilus influenzae in vitro and in vivo, depending on the bacterial strain.

Sensitivity test

Quantitative methods that require measuring the diameter of the growth suppression zone provide the most accurate estimates of the sensitivity of bacteria to antimicrobial drugs. One of the recommended methods for determining sensitivity uses disks impregnated with 15 micrograms of clarithromycin (Kirby-Bauer disco-diffusion method); when interpreting the test, the diameters of growth suppression zones correlate with the values of clarithromycin BMD. MPC values are determined by dilution in broth or agar. When using these techniques, a report from the laboratory that the strain is “sensitive” indicates that the infectious agent is likely to respond to treatment. A “resistant” response indicates that the pathogen may not respond to treatment. The answer “intermediate sensitivity” suggests that the therapeutic effect of the drug may be ambiguous or the microorganism may be sensitive when using higher doses of the drug (intermediate sensitivity is also called “moderate sensitivity”).

Pharmacokinetics

Suction

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

Distribution, metabolism and elimination

In vitro

Clarithromycin binds to plasma proteins by 70% at concentrations ranging from 0.45 to 4.5 mcg / ml. At a concentration of 45 micrograms/ml, binding decreases to 41%, probably as a result of saturation of the binding sites. This is only observed at concentrations that are many times higher than the therapeutic concentration.

Healthy volunteers

In patients taking 500 mg of clarithromycin once a day after meals, the maximum concentration (With_max) of clarithromycin and 14-OH-clarithromycin in blood plasma was 1.3 and 0.48 mcg / ml, respectively. The elimination half-lives (T_1/2) of clarithromycin and the metabolite were 5.3 hours and 7.7 hours, respectively. When taking a single dose of clarithromycin in dosage form – tablets with a prolonged release, film-coated,1000 mg (2 x 500 mg), With_max clarithromycin and its hydroxylated metabolite in blood plasma was 2.4 mcg/ml and 0.67 mcg/ml, respectively. T_1/2 of clarithromycin at a dose of 1000 mg was 5.8 hours, while the same indicator for 14-OH-clarithromycin was 8.9 hours. The time to reach the maximum concentration (TCmax) when taking both 500 mg and 1000 mg clarithromycin orally was approximately 6 hours. C-14-Oh-clarithromycin m ax did not increase in proportion to the oral dose of clarithromycin, while T_1/2 of both clarithromycin and its hydroxylated metabolite tended to lengthen with increasing dose. This non-linear pharmacokinetics of clarithromycin, combined with a decrease in the formation of 14-hydroxylated and N-demethylated products at high dosages, indicates a non-linear metabolism of clarithromycin, which becomes more pronounced at high dosages.

Approximately 40% of the oral dose of clarithromycin is excreted by the kidneys. Approximately 30% is excreted through the intestines.

Patients

Clarithromycin and its metabolite (14-OH-clarithromycin) are rapidly absorbed into body tissues and fluids.There are limited data indicating that the concentration of clarithromycin in the cerebrospinal fluid when taken orally is insignificant (that is, only 1-2% of the concentration in the blood serum with normal permeability of the blood-brain barrier). The concentration in the tissues is usually several times higher than in the blood serum.

Impaired liver function

In patients with moderate to severe hepatic impairment, but with preserved renal function, no dose adjustment of clarithromycin is required. Steady-state plasma concentrations and systemic clearance of clarithromycin do not differ between patients in this group and healthy patients. The steady-state concentration of 14-OH-clarithromycin in patients with impaired liver function is lower than in healthy patients.

Impaired renal function

With impaired renal function, the minimum concentration (With_min) of clarithromycin in blood plasma, T_1/2, and the area under the concentration-time curve (AUC) of clarithromycin and its metabolite (14-OH-clarithromycin) increase with m ax. The elimination constant and excretion by the kidneys decrease. The degree of changes in these parameters depends on the degree of impaired renal function.

Elderly patients

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

Indications

Infectious and inflammatory diseases caused by clarithromycin-sensitive microorganisms:

• lower respiratory tract infections (such as bronchitis, pneumonia),
• upper respiratory tract and ENT infections (tonsillitis, pharyngitis, sinusitis, acute otitis media),
• skin and soft tissue infections (such as folliculitis, inflammation of the subcutaneous tissue, erysipelas).

Use during pregnancy and lactation

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

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

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

Contraindications

• Hypersensitivity to clarithromycin, macrolides and other components of the drug.
• Concomitant use of clarithromycin with the following medications: astemizole, cisapride, pimozide, terfenadine (see section “Interaction with other medications”).
• Concomitant use of clarithromycin with ergot alkaloids, for example, ergotamine, dihydroergotamine (see the section “Interaction with other drugs”).
• Concomitant use of clarithromycin with midazolam for oral use (see section “Interaction with other drugs”).
• Concomitant 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 the section “Interaction with other drugs”).
• Concomitant use of clarithromycin with colchicine.
• Concomitant use with ticagrelor or ranolazine.
• Prolongation of the QT interval on an electrocardiogram (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 hepatic insufficiency occurring simultaneously with renal insufficiency.
• Cholestatic jaundice/hepatitis in the anamnesis that developed with the use of clarithromycin (see the section “Special instructions”).
• Porphyria.
• Breast-feeding period.
• Age up to 18 years (according to indications: tonsillitis, acute otitis media), up to 12 years (according to other indications).
• Lactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome.

Side effects

Classification of the incidence of side effects (number of reported cases/number of patients) recommended by the World Health Organization (WHO):

very common ≥ 1/10

common ≥ 1/100 to < 1/10

uncommon ≥ 1/1000 to < 1/100

rare ≥ 1/10000 to < 1/1000

very rare < 1/10000

frequency unknown (side effects from post-marketing experience; frequency cannot be estimated based on available data).

Allergic reactions:

frequent: rash;

infrequent: 1 anaphylactoid reaction, hypersensitivity,1 bullous dermatitis, pruritus, urticaria, maculopapular rash 3;

frequency not known: anaphylactic reaction, angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS syndrome), acute generalized absentmindly pustules (OGAP).

From the nervous system:

frequent: headache, insomnia;

rare: loss of consciousness 1,1 dyskinesia, dizziness, drowsiness, tremor, anxiety, irritability 3;

frequency unknown: convulsions, psychotic disorders, confusion, depersonalization, depression, disorientation, hallucinations, disorders of the dream (“nightmare” dreaming), paresthesia, mania.

From the side of the skin:

common: intense sweating;

frequency unknown: acne.

From the urinary system:

frequency unknown: renal failure, interstitial nephritis.

From the side of metabolism and nutrition:

infrequently: anorexia, decreased appetite.

From the musculoskeletal system:

infrequently: muscle spasm, musculoskeletal stiffness, myalgia;

frequency unknown: rhabdomyolysis 2*, myopathy.

From the digestive system:

frequent: diarrhea, vomiting, dyspepsia, nausea, pain in the abdomen;

infrequent: 1 esophagitis, gastroesophageal reflux disease 2, gastritis, proctalgia 2, stomatitis, glossitis, abdominal distension 4, constipation, dryness of the mucous membrane of the mouth, belching, flatulence,4 cholestasis, hepatitis including cholestatic or hepatocellular 4;

frequency unknown: acute pancreatitis, change the color of the tongue and teeth, hepatic failure, cholestatic jaundice.

Respiratory system disorders:

infrequently: bronchial asthma 1, nosebleed 2, pulmonary embolism 1.

From the sensory organs:

often: dysgeusia (perversion of taste);

infrequently: vertigo, hearing impairment, tinnitus;

frequency unknown: deafness, ageusia (loss of taste sensations), parosmia, anosmia.

From the cardiovascular system:

often: vasodilation 1;

infrequently: cardiac arrest 1, atrial fibrillation 1, prolongation of the QT interval on the electrocardiogram, extrasystole 1, palpitation sensation;

frequency unknown: ventricular tachycardia, including pirouette type, ventricular fibrillation, bleeding.

Laboratory parameters:

often: abnormal liver function laboratory parameters;

infrequently: increased creatinine concentration 1, increased urea concentration 1 in blood plasma, changes in the albumin / globulin ratio 1, leukopenia, neutropenia 4, eosinophilia 4, thrombocythemia 3, increased activity of alanine aminotransferase (AJIT), aspartate aminotransferase (ACT), gamma-glutamyltransferase (GGT)4, alkaline phosphatase 4 (ALP), lactate dehydrogenase (LDH)4 in blood plasma;

frequency unknown: agranulocytosis, thrombocytopenia, increase in the value of the international normalized ratio (INR), prolongation of prothrombin time, change in urine color, increased bilirubin concentration in blood plasma.

Other services:

very common: phlebitis at the injection site 1;

common: pain at the injection site 1, inflammation at the injection site 1;

uncommon: malaise 4, hyperthermia 3, asthenia, chest pain 4, chills 4, fatigue 4.

Infectious and parasitic diseases:

infrequently: cellulitis 1, candidiasis, gastroenteritis 2, secondary infections 3 (including vaginal infections);

frequency unknown: pseudomembranous colitis, erysipelas.

Patients with reduced immunity

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

The most common adverse events in patients receiving a daily dose of clarithromycin equal to 1000 mg were nausea, vomiting, dysgeusia, abdominal pain, diarrhea, skin rash, flatulence, headache, constipation, hearing impairment, increased activity of ACT and ALT in blood plasma. There were also cases of adverse events with a low frequency of occurrence, such as shortness of breath, insomnia and dryness of the oral mucosa.

In patients with reduced immunity, laboratory parameters were evaluated, analyzing their significant deviations from the norm (a sharp increase or decrease). Based on this criterion,2-3% of patients who received clarithromycin at a dose of 1000 mg daily showed a significant increase in the activity of ACT and ALT in blood plasma, as well as a decrease in the number of white blood cells and platelets. In a small number of patients, an increase in the concentration of residual urea nitrogen in the blood plasma was also recorded.

* In some reports of rhabdomyolysis, clarithromycin has been taken concomitantly with other medications known to be associated with rhabdomyolysis (statins, fibrates, colchicine, or allopurinol).

1 Reports of these adverse reactions have been received during clinical trials, as well as post-marketing use of clarithromycin in the dosage form of lyophilizate for the preparation of an infusion solution.

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 the dosage form of powder for the preparation of a suspension for oral use.

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

Interaction

The use of the following medications simultaneously with clarithromycin is contraindicated due to the possibility of serious side effects

of Cisapride, pimozide, terfenadine and astemizole

When clarithromycin is co-administered with cisapride, pimozide, terfenadine or astemizole, an increase in the concentration of the latter in blood plasma has been reported, which can lead to prolongation of the QT interval on the ECG and the appearance of cardiac arrhythmias, including ventricular tachycardia (including ventricular tachycardia of the “pirouette” type) and ventricular fibrillation (see section “Contraindications”).

Ergot alkaloids

Post-marketing studies show that when clarithromycin is co-administered with ergotamine or dihydroergotamine, the following effects associated with acute ergotamine poisoning are possible: vascular spasm, ischemia of the extremities and other tissues, including the central nervous system (CNS). Concomitant use of clarithromycin and ergot alkaloids is contraindicated (see section “Contraindications”).

HMG-CoA reductase inhibitors (statins)

Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated (see section “Contraindications”) due to the fact that these statins are largely metabolized by the CYP3A4 isoenzyme, and concomitant 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 for the duration of 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 simultaneous use is necessary, it is recommended to take the lowest dose of statin. The development of signs and symptoms of myopathy should be monitored.

Midazolam for oral use

With the simultaneous use of midazolam and clarithromycin in tablet form (500 mg 2 times a day), there was a 7-fold increase in the AUC of midazolam after oral use. Concomitant use of clarithromycin with midazolam for oral use is contraindicated.

Effect of other medications on clarithromycin

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

The following drugs have a proven or suspected effect on the concentration of clarithromycin in the blood plasma, if they are used simultaneously with clarithromycin, a dose adjustment or transition to alternative treatment may be required

Efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine

Strong inducers of cytochrome P-450, such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine may accelerate the metabolism of clarithromycin and thus lower the concentration of clarithromycin in the blood plasma and may weaken the therapeutic effect, and to increase the concentration in blood plasma of 14-Oh-clarithromycin – metabolite that is also microbiologically active. Since the microbiological activity of clarithromycin and 14-OH-clarithromycin differs with respect to different bacteria, the therapeutic effect may be reduced with the simultaneous use of clarithromycin and cytochrome P450 inducers.

Etravirine

The concentration of clarithromycin in the blood plasma decreases with simultaneous use with etravirine, but the concentration in the blood plasma of the active metabolite 14-OH-clarithromycin increases. Since 14-OH-clarithromycin has low activity against MAC infections, the overall activity against these pathogens may vary, so alternative treatment should be considered for MAC treatment.

Fluconazole

Concomitant use of fluconazole 200 mg daily and clarithromycin 500 mg twice daily in 21 healthy volunteers resulted in an increase in the mean minimum steady-state concentration (cmin) of clarithromycin and AUC by 33% and 18%, respectively. At the same time, concomitant use did not significantly affect the average steady-state concentration of the active metabolite 14-OH-clarithromycin. Dose adjustment of clarithromycin in the case of concomitant use of fluconazole is not required.

Ritonavir

A pharmacokinetic study showed that concomitant use of ritonavir 200 mg every 8 hours and clarithromycin 500 mg every 12 hours resulted in a marked suppression of clarithromycin metabolism. When ritonavir was co-administered with clarithromycin, the cmin increased by 31%, the_cmin increased by 182%, and the AUC increased by 77%. Complete suppression of 14-OH-clarithromycin production was observed. Due to the wide therapeutic range of clarithromycin, no dose reduction is required in patients with normal renal function. In patients with renal insufficiency, it is advisable to consider the following dose adjustment options: with a creatinine clearance of 30-60 ml / min, the dose of clarithromycin should be reduced by 50%. Similar dose adjustments should be considered in patients with reduced renal function if ritonavir is used as a pharmacokinetic “booster” when using other HIV protease inhibitors, including atazanavir and saquinavir (see section “Bidirectional drug interactions”).

Ritonavir should not be concomitantly administered with clarithromycin in doses exceeding 1 g / day.

Effect of clarithromycin on other medicinal products

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 co-administered with these drugs, the ECG should be monitored regularly for prolongation of the QT interval, and serum concentrations of these drugs should also be monitored.

Hypoglycaemia has been reported in post-marketing use with concomitant use of clarithromycin and disopyramide. It is necessary to monitor the concentration of glucose in the blood with the simultaneous use of clarithromycin and disopyramide.

Hypoglycemic agents for oral use/insulin

Concomitant use of clarithromycin and hypoglycemic agents for oral use (for example, sulfonylureas) and / or insulin may cause severe hypoglycemia. Concomitant use of clarithromycin with certain hypoglycemic drugs (e. g. nateglinide, pioglitazone, repaglinide, and rosiglitazone) may result in inhibition of the CYP3A isoenzyme by clarithromycin, resulting in hypoglycemia. Careful monitoring of blood glucose levels is recommended.

Interactions caused by the 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 range (for example, carbamazepine), and/or drugs that are intensively metabolized by this isoenzyme. If necessary, the dose of the drug taken simultaneously with clarithromycin should be adjusted. Serum concentrations of drugs primarily metabolized by the CYP3A isoenzyme should also be monitored whenever possible.

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. The following drugs that are contraindicated for concomitant use with clarithromycin are also considered inhibitors of the CYP3A isoenzyme: astemizole, cisapride, pimozide, terfenadine, lovastatin, simvastatin and ergot alkaloids (see the section “Contraindications”). Drugs that interact in a similar way through other isoenzymes within the cytochrome P450 system include: phenytoin, theophylline, and valproic acid.

Indirect anticoagulants

With simultaneous use of warfarin and clarithromycin, bleeding, a pronounced increase in INR and prolongation of prothrombin time may occur. In the case of concomitant use with warfarin or other indirect anticoagulants, INR and prothrombin time should be monitored.

Omeprazole

Clarithromycin (500 mg every 8 hours) was studied in healthy adult volunteers in combination with omeprazole (40 mg daily). When clarithromycin and omeprazole were co-administered, steady-state plasma concentrations of omeprazole were increased (_cmax, AUC_0-24, and T_1/2 increased by 30%,89%, and 34%, respectively). The average pH of the stomach during 24 hours was 5.2 (when taking omeprazole alone) and 5.7 (when taking omeprazole simultaneously with clarithromycin).

Sildenafil, tadalafil and vardenafil

Each of these phosphodiesterase 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 increase the inhibitory effect on phosphodiesterase. When using these drugs simultaneously with clarithromycin, you should consider reducing the dose of sildenafil, tadalafil and vardenafil.

Theophylline, carbamazepine

Concomitant use of clarithromycin and theophylline or carbamazepine may increase the concentration of these drugs in the systemic circulation.

Tolterodine

The primary metabolism of tolterodine is via the CYP2D6 isoenzyme. However, in the part of the population lacking the CYP2D6 isoenzyme, metabolism occurs via the CYP3A isoenzyme. In this population, suppression of the CYP3A isoenzyme leads to significantly higher serum tolterodine concentrations. In a population with a low level of metabolism through the CYP2D6 isoenzyme, it may be necessary to reduce the dose of tolterodine with simultaneous use of inhibitors of the CYP3A isoenzyme, such as clarithromycin.

Benzodiazepines (e. g. alprazolam, midazolam [intravenous solution], triazolam)

With the simultaneous use of midazolam and clarithromycin tablets (500 mg 2 times a day), there was an increase in the AUC of midazolam by 2.7 times after intravenous use of midazolam. If a midazolam dosage form solution for intravenous use is used simultaneously with clarithromycin, the patient’s condition should be carefully monitored for possible dose adjustment of midazolam. use of the drug through the oral mucosa, which makes it possible to bypass presystemic elimination of the drug, is likely to lead to an interaction similar to that observed with intravenous use of midazolam, and not with oral use.

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

With the simultaneous use of clarithromycin and triazolam, effects on the central nervous system may occur, for example, drowsiness and confusion. In this regard, in the case of simultaneous use, it is recommended to monitor the symptoms of CNS disorders.

Interactions with other drugs

Colchicine

Colchicine is a substrate of both the CYP3A isoenzyme and the P-glycoprotein transporter protein (Pgp). Clarithromycin and other macrolides are known to inhibit the CYP3A and Pgp isoenzymes. When clarithromycin and colchicine are co-administered, inhibition of Pgp and / or the CYP3A isoenzyme may increase the effect of colchicine. The development of clinical symptoms of colchicine poisoning should be monitored. There have been post-marketing reports of colchicine poisoning when co-administered with clarithromycin, more often in elderly patients. Some of the reported cases occurred in patients with renal insufficiency. Some cases were reported to be fatal. Concomitant use of clarithromycin and colchicine is contraindicated (see section “Contraindications”).

Digoxin

Digoxin is assumed to be a Pgp substrate. Clarithromycin is known to inhibit Pgp. When clarithromycin and digoxin are co-administered, inhibition of Pgp by clarithromycin may lead to increased digoxin action. Concomitant use of digoxin and clarithromycin may also lead to an increase in serum digoxin concentrations. Some patients experienced clinical symptoms of digoxin poisoning, including potentially fatal arrhythmias. When clarithromycin and digoxin are administered concomitantly, the concentration of digoxin in the blood serum should be carefully monitored.

Zidovudine

Concomitant oral use of clarithromycin and zidovudine tablets in adult HIV-infected patients may lead to a decrease in the steady-state concentration of zidovudine in blood plasma. Since clarithromycin affects the absorption of zidovudine when taken orally, interactions can be largely avoided by taking clarithromycin and zidovudine at 4-hour intervals. This interaction was not observed in HIV-infected children who received a pediatric suspension of clarithromycin with zidovudine or dideoxyinosine. Since clarithromycin may interfere with the absorption of zidovudine when administered concomitantly by mouth in adult patients, such an interaction is unlikely to occur when clarithromycin is administered intravenously.

Phenytoin and valproic acid

There are data on the interaction of 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 concomitantly with clarithromycin, it is recommended to determine their serum concentrations, since there are reports of their increase.

Bidirectional drug interaction

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% reduction in 14-OH-clarithromycin exposure with a 28% increase in atazanavir AUC. Due to the wide therapeutic range of clarithromycin, no dose reduction is required in patients with normal renal function. In patients with moderate renal insufficiency (creatinine clearance 30-60 ml/min), the dose of clarithromycin should be reduced by 50%. In patients with creatinine clearance 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 simultaneously with protease inhibitors.

Slow Calcium Channel Blockers

Caution should be exercised when concomitantly using clarithromycin and slow calcium channel blockers that are metabolized by the CYP3A4 isoenzyme (for example, verapamil, amlodipine, diltiazem), since there is a risk of hypotension. When used concomitantly, plasma concentrations of clarithromycin and slow calcium channel blockers may increase. Hypotension, bradyarrhythmia, and lactic acidosis may occur with concomitant use of clarithromycin and verapamil.

Itraconazole

Clarithromycin and itraconazole are substrates and inhibitors of the CYP3A isoenzyme, which determines the bidirectional interaction of drugs.Clarithromycin may increase the plasma concentration of itraconazole, while itraconazole may increase the plasma concentration of clarithromycin. Patients taking itraconazole and clarithromycin concomitantly should be carefully evaluated 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 drugs. Concomitant use of clarithromycin (500 mg twice daily) and saquinavir (in soft gelatin capsules,1200 mg 3 times daily) in 12 healthy volunteers caused an increase in the AUC andcmax of saquinavir in blood plasma by 177% and 187%, respectively, compared with saquinavir alone. Clarithromycin AUC and CMAX values were approximately 40% higher than with clarithromycin alone. When these two drugs are used simultaneously for a limited time in the doses/formulations indicated above, no dose adjustment is required. The results of drug interaction studies with the use of saquinavir in soft gelatin capsules may not correspond to the effects observed with the use of saquinavir in hard gelatin capsules. The results of the study of drug interactions with saquinavir alone may not correspond to the effects observed with the combination of saquinavir/ritonavir. When taking saquinavir concomitantly with ritonavir, the potential effect of ritonavir on clarithromycin should be considered.

How to take, course of use and dosage

The drug Fromilid ® uno is prescribed orally.

The tablet should be swallowed whole, not broken or chewed.

Adults and children over 12 years of age – 1 tablet (500 mg) 1 time a day with meals.

For tonsillitis and acute otitis media: adults and children over 18 years of age – 1 tablet (500 mg) 1 time a day with meals.

For severe infections, the dose is increased to 2 tablets (1000 mg) 1 time a day with meals.

The usual duration of treatment is from 5 to 14 days. The exceptions are community-acquired pneumonia and sinusitis, which require treatment for 6 to 14 days.

Impaired renal function

For patients with severe renal insufficiency (creatinine clearance less than 30 ml / min), the usual recommended dose is 250 mg once a day, in which case Fromilid®, film-coated tablets,250 mg, may be used. For more severe infections, the recommended dose is 1 500 mg tablet with a prolonged release of clarithromycin.

In patients with moderate renal insufficiency (creatinine clearance from 30 to 60 ml/min), no dose adjustment is required.

Overdose

Symptoms: Ingestion of a large dose of clarithromycin may cause symptoms of gastrointestinal disorders.

One patient with a history of bipolar disorder after taking 8 g of clarithromycin described changes in mental state, paranoid behavior, hypokalemia and hypoxemia.

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 performed. Hemodialysis and peritoneal dialysis do not significantly affect the concentration of clarithromycin in the blood serum, which is typical for other drugs of the macrolide group.

Description

Oval, biconvex tablets, covered with a film-coated brown-yellow color, with the marking U on one side.

View at the break: a rough mass of white or almost white color with a film shell of brown-yellow color.

Special instructions

·  Moderate to severe renal failure.

·  Moderate to severe hepatic insufficiency.

* Concomitant use of clarithromycin with benzodiazepines such as alprazolam, triazolam, midazolam for intravenous use (see section “Interaction with other drugs”).

* Concomitant 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 the section “Interaction with other drugs”).

* Concomitant use with drugs that induce the CYP3A4 isoenzyme, for example, rifampicin, phenytoin, carbamazepine, phenobarbital, St. John’s wort (see the section “Interaction with other drugs”).

* Concomitant use with slow calcium channel blockers that are metabolized by the CYP3A4 isoenzyme (for example, verapamil, amlodipine, diltiazem).

* Concomitant use with statins that do not depend on the metabolism of the CYP3A4 isoenzyme (for example, fluvastatin).

· Patients with ischaemic heart disease( CHD), severe heart failure, hypomagnesemia, impaired conduction or clinically significant bradycardia, as well as patients taking Class IA antiarrhythmic drugs (quinidine, procainamide) and Class III antiarrhythmic drugs (dofetilide, amiodarone, sotalol) at the same time.

* Pregnancy.

Contraindicated in children under 12 years of age.

Children over 12 years of age – 1 tablet (500 mg) 1 time a day with meals.

Use with caution in patients with hepatic insufficiency.

For patients with severe renal insufficiency (creatinine clearance less than 30 ml / min), the usual recommended dose is 250 mg once a day, in which case Fromilid®, film-coated tablets,250 mg, may be used. For more severe infections, the recommended dose is 1 500 mg tablet with a prolonged release of clarithromycin.

In patients with moderate renal insufficiency (creatinine clearance from 30 to 60 ml/min), no dose adjustment is required.

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 should be prescribed.

When using clarithromycin, hepatic dysfunction (increased activity of “liver” enzymes in blood plasma, hepatocellular and/or cholestatic hepatitis with or without jaundice) has been reported. Hepatic dysfunction can be severe, but is usually reversible. There are cases of liver failure with a fatal outcome, mainly associated with the presence of serious concomitant diseases and/or the simultaneous use of other medications. If signs and symptoms of hepatitis appear, such as anorexia, jaundice, dark urine, pruritus, abdominal pain on palpation, clarithromycin therapy should be discontinued immediately.

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

Cases of pseudomembranous colitis, the severity of which can range from mild to life-threatening, have been reported with virtually all antibacterial agents, including clarithromycin. Antibacterial drugs can alter the normal intestinal microflora, which can lead to the growth ofcystridium difficile. Pseudomembranous colitis caused by Clostridium difficile should be suspected in all patients with diarrhea after the use of antibacterial agents. After the course of antibiotic therapy, careful medical supervision of the patient is necessary. Cases of pseudomembranous colitis were described 2 months after the use of antibiotics.

From the cardiovascular system

Macrolide treatment, including clarithromycin, has been associated with prolonged cardiac repolarization and QT interval, leading to a risk of cardiac arrhythmia and ventricular tachycardia of the pirouette type (see section “Side effects”). Since the following situations may lead to an increased risk of ventricular arrhythmias (including ventricular tachycardia of the “pirouette” type), then:

– clarithromycin should not be used in the following categories of patients:

• in patients with hypokalemia (see section “Contraindications”);
• concomitant use of clarithromycin with astemizole, cisapride, pimozide and terfenadine is contraindicated (see section”Contraindications”);
• in patients with congenital or acquired registered QT interval prolongation or a history of ventricular arrhythmia (see section”Contraindications”).

– clarithromycin should be used with caution in the following categories of patients:

• in patients with CHD, severe heart failure, conduction disturbances, or clinically significant bradycardia;
• in patients with electrolyte disturbances, such as hypomagnesemia;
• in patients taking concomitant medications associated with prolongation of the QT interval (see the section “Interaction with other medications”).

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

Given the growing resistance of Streptococcus pneumoniae to macrolides, it is important to conduct sensitivity testing when prescribing clarithromycin to patients with community-acquired pneumonia.In 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. Both pathogens can be resistant to macrolides. Therefore, it is important to conduct an antibiotic sensitivity 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.

In the event of acute hypersensitivity reactions, such as anaphylactic reaction, severe skin adverse reactions (SSCT) (for example, OGEP), Stevens-Johnson syndrome, toxic epidermal necrolysis and drug rash with eosinophilia and systemic symptoms (DRESS-syndrome), it is necessary to immediately stop taking clarithromycin and start appropriate therapy.

In the case of concomitant use with warfarin or other indirect anticoagulants, it is necessary to monitor INR and prothrombin time (see the section “Interaction with other drugs”).

There are no data on the effect of clarithromycin on the ability to drive a car and mechanisms. The potential for dizziness, vertigo, confusion, and disorientation that may occur with this medication should be taken into account.

Caution should be exercised when driving vehicles and engaging in other potentially dangerous activities that require increased concentration of attention and speed of psychomotor reactions.

Form of production

Extended-release film-coated tablets,500 mg.

5 or 7 tablets are placed in a PVC blister/PVDC – aluminum foil (PVC/PVDC-Al).

1 blister (blister of 5 tablets) or 1 or 2 blisters (blister of 7 tablets) are placed in a cardboard pack together with the instructions for use.

When packing at KRKA-RUS LLC, Russia:

1 blister (blister of 5 tablets) or 1 or 2 blisters (blister of 7 tablets) are placed in a cardboard pack together with the instructions for use.

Storage conditions

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

Keep out of reach of children.

Shelf

life is 3 years.

Do not use the drug after the expiration date.

Active ingredient

Clarithromycin

Conditions of release from pharmacies

By prescription

Dosage form

long-acting tablets

Purpose

Children over 12 years of age, Children as prescribed by a doctor, Adults as prescribed by a doctor, Pregnant women in the second and third trimester as prescribed by a doctor

Indications

Boils, Skin infections, Gastrointestinal infections caused by Helicobacter Pylori, Respiratory tract infections, Sore throat, Pharyngitis, Tonsillitis, Stomach and duodenal ulcers, Colds, Bronchitis, Sinusitis, Otitis media