Fromilide Uno - instructions for use, dose, side effects, contraindications

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Dosage form: & nbsptablets of prolonged action, film-coated

Composition:

1 tablet contains:

core: active substance: clarithromycin 500.00 mg (based on the active substance 980 μg / mg - 1020 μg / mg); Excipients: sodium alginate 80.00 mg, sodium calcium alginate 90.00 mg, lactose monohydrate 225.00 mg, povidone 30.00 mg, polysorbate 80 30.00 mg, silicon dioxide colloid 5.00 mg, magnesium stearate 10.00 mg , talc 30.00 mg;

film sheath: hypromellose 14.45 mg, talc 1.33 mg, iron dye oxide yellow (E172) 0.50 mg, titanium dioxide (E171) 2.64 mg, propylene glycol 1.08 mg.

Description:

Oval, biconvex tablets, covered with a film coating of brownish-yellow color, marked U on one side.

View of the break: a rough mass of white or almost white with a film coating of brownish-yellow color.

Pharmacotherapeutic group:antibiotic-macrolide

Pharmacodynamics:

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

Clarithromycin demonstrated high activity in conditions in vitro for 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. The minimum inhibitory concentrations (MPC) of clarithromycin for most pathogens are less than the erythromycin MPC, on average one log₂ breeding.

Clarithromycin in conditions in vitro highly active in relation to Legionella pneumophila, Mycoplasma pneumoniae. Has a bactericidal effect against Helicobacter pylori, This activity of clarithromycin is higher for neutral pH, than with acid. In addition, the data in the conditions in vitro and in vivo indicate that clarithromycin acts on clinically significant species of mycobacteria. Enterobacteriaceae and Pseudomonas spp. As well as other non-fermenting lactose, gram-negative bacteria are not sensitive to clarithromycin.

The activity of clarithromycin against most strains listed below microorganisms is proved both in conditions in vitro, and in clinical practice for the 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.

Othermicroorganisms:

- 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 does not affect the activity of clarithromycin. Most strains of staphylococcus aureus resistant to methicillin and oxacillin are resistant to clarithromycin.

Helicobacter pylori

Sensitivity Helicobacter pylori to clarithromycin was studied on isolates Helicobacter pylori, isolated from 104 patients prior to initiation of drug therapy. In 4 patients, strains resistant to clarithromycin were isolated Helicobacter pylori, in 2 patients - strains with moderate resistance, in the remaining 98 patients, isolates Helicobacter pylori were sensitive to clarithromycin.

Clarithromycin exerts its effect in conditions in vitro and for most strains of the following microorganisms (however, the safety and efficacy of clarithromycin in clinical practice has not been confirmed by clinical studies, and 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 starting material, or 2 times weaker in respect of most microorganisms. The exception is Haemophilus influenzae, in relation to which the efficiency of the metabolite is twice as high. The starting compound and its main metabolite exert either an additive or a synergistic effect on Haemophilus influenzae in conditions in vitro and in vivo depending on the strain of bacteria.

Pharmacokinetics:

Suction

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

Distribution, metabolism and excretion

In vitro

Clarithromycin binds to plasma proteins by 70% at a concentration of 0.45 to 4.5 μg / ml. At a concentration of 45 μg / ml, binding is reduced to 41%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 1 time per day after meals, the maximum concentration (C_max) of clarithromycin and 14-OH-clarithromycin in blood plasma was 1.3 and 0.48 μg / ml, respectively. Half-life (T_1/2) of clarithromycin and metabolite were 5.3 hours and 7.7 hours, respectively. When taking a single dose of clarithromycin in a dosage form - prolonged-action tablets coated with a film coat, 1000 mg (2x500 mg) C_max clarithromycin and its hydroxylated metabolite in plasma was 2.4 μg / ml and 0.67 μg / ml, respectively.

T_1/2 clarithromycin at a dose of 1000 mg was 5.8 hours, while a similar figure for 14-OH-clarithromycin was 8.9 hours. Time to reach the maximum concentration (TC_max) with oral administration of both 500 mg and 1000 mg of clarithromycin was approximately 6 hours. C_max 14-OH-clarithromycin did not increase in proportion to the oral dose of clarithromycin, while T_1/2both clarithromycin and its hydroxylated metabolite, tended to lengthen with increasing doses.Such nonlinear pharmacokinetics of clarithromycin in combination with a decrease in the formation of 14-hydroxylated and N-detylated products at high dosages indicates a non-linear metabolism of clarithromycin, which becomes more pronounced at high dosages. About 40% of the internal dose of clarithromycin is excreted by the kidneys. The intestine displays about 30%.

Patients

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

Impaired liver function

In patients with moderate to severe hepatic impairment, but with preserved renal function, correction of the dose of clarithromycin is not required. Equilibrium concentration in blood plasma and systemic clearance of clarithromycin do not differ in patients of this group and in healthy patients.The equilibrium concentration of 14-OH-claritromycin in patients with impaired liver function is lower than in healthy patients.

Impaired renal function

When the renal function is impaired, C_max and the minimum concentration (C_min) clarithromycin in blood plasma, T_1/2, the area under the concentration-time curve (AUC) of clarithromycin and its metabolite (14-OH-clarithromycin). 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 the elderly elderly, the concentration of clarithromycin and one hundred metabolite (14-OH-clarithromycin) in the blood plasma was higher, and excretion is slower than in a group of young people. However, after correction for renal clearance of creatinine (CC), there was no difference in both groups. Thus, the main effect on the pharmacokinetic parameters of clarithromycin is the function of the kidneys, not age.

Indications:

Infectious-inflammatory diseases caused by microorganisms sensitive to clarithromycin:

- infections of the lower respiratory tract (such as bronchitis, pneumonia);

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

- infections of the skin and soft tissues (such as folliculitis, inflammation of the subcutaneous tissue, erysipelas).

Contraindications:

- Hypersensitivity to the components of the drug and other macrolides;

- severe renal failure - QC less than 30 ml / min;

- simultaneous reception of clarithromycin with the following drugs: astemizole, cisapride, pimozide, terfenadine (see section "Interaction with other drugs");

- simultaneous reception of clarithromycin with ergot alkaloids, for example, ergotamine, dihydroergotamine (see section "Interaction with other drugs");

- simultaneous reception of clarithromycin with midazolam for oral administration (see section "Interaction with other drugs");

- simultaneous reception of clarithromycin with inhibitors of HMG-CoA reductase (statins), which are largely metabolized by isoenzyme CYP3A4 (lovastatin, simvastatin), due to an increased risk of myopathy, including rhabdomyolysis (see section "Interaction with other drugs");

- simultaneous use of clarithromycin with colchicine;

- interval lengthening QT on an electrocardiogram (ECG) in an anamnesis, ventricular arrhythmia or ventricular tachycardia of the typhus "pirouette";

- hypokalemia (risk of lengthening the interval QT on the ECG);

- severe hepatic insufficiency, which occurs simultaneously with renal insufficiency;

- Cholestatic jaundice / hepatitis in history, developed with the use of clarithromycin (see section "Special instructions").

- porphyria;

- the period of breastfeeding;

- age 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.

Carefully:

- Renal failure of moderate severity;

- hepatic failure of moderate to severe severity;

- simultaneous reception of clarithromycin with benzodiazepines, such as alprazolam, triazolam, midazolam for internal administration ("Interaction with other drugs";

- simultaneous reception with drugs that are metabolized by isoenzyme CYP3A, eg, carbamazepine, cilostazol, ciclosporin, disopyramide, methylprednisolone, omeprazole, indirect anticoagulants (for example, warfarin), quinidine, rifabutin, sildenafil, tacrolimus, vinblastine (see the section "Interaction with other drugs");

- simultaneous reception with drugs that induce isoenzyme CYP3A4, for example, rifampicin, phenytoin, carbamazepine, phenobarbital, St John's wort (see "Interaction with other medicines");

- simultaneous reception with blockers of "slow" calcium channels, which are metabolized by isoenzyme CYP3A4 (e.g., verapamil, amlodipine, diltiazem);

- simultaneous administration with other ototoxic drugs, especially aminoglycosides;

- simultaneous reception with statins that do not depend on the isoenzyme metabolism CYP3A4 (e.g., fluvastatin);

- patients with coronary heart disease (CHD), severe heart failure, hypomagnesemia, severe bradycardia (less than 50 beats per minute), as well as patients taking antiarrhythmic drugs 1A class (quinidine, procainamide) and III class (dofetilide, amiodarone, sotalol);

- Pregnancy.

Pregnancy and lactation:

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

The use of clarithromycin in 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 you need to take during breastfeeding, breastfeeding should be stopped.

Dosing and Administration:

The drug is prescribed inside.

Frohomide® uno tablets should not be broken or chewed, should be swallowed whole.

Adults and children over 12 years - 1 tablet (500 mg) 1 time per day with meals.

With tonsillitis and medium otitis media: adults and children over 18 years - 1 tablet (500 mg) 1 time per day with meals.

In severe infections, the dose is increased to 2 tablets (1000 mg) once a day with meals.

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

Renal impairment

In patients with severe renal failure (CC less than 30 ml / min), the use of the preparation of Formylid® uno is contraindicated.In patients with impaired renal function of moderate severity (CK from 30 to 60 ml / min), the dose of the drug is halved, which is not more than 500 mg (1 tablet) per day.

Side effects:

Classification of the incidence of adverse events (number of reported cases / number of patients) recommended by the World Health Organization (WHO): very often (≥ 1/10); often (≥ 1/100, <1/10); infrequently (≥ 1/1000, <1/100); rarely (≥ 1/10 000, <1/1000); very rarely (<1/10 000), the frequency is unknown (side effects from the post-marketing application experience, the frequency can not be estimated based on available data).

Allergic reactions: hasto - skin rash; infrequently anaphylactoid reaction¹, hypersensitivity, bullous¹ dermatitis, itching, hives, 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; infrequently - loss of consciousness¹, dyskinesia¹, dizziness, drowsiness, tremor, anxiety, increased excitability³; frequency is unknown - convulsions, psychotic disorders, confusion, depersonalization, depression, disorientation, hallucinations, dream disturbances ("nightmarish" dreams), paresthesia, mania.

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

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

From the side of metabolism and nutrition: infrequently - anorexia, a decrease in appetite.

From the side of the musculoskeletal system: infrequently - muscle spasm, musculoskeletal stiffness, myalgia; frequency unknown - rhabdomyolysis²*, myopathy.

Co the sides of the digestive system: often - diarrhea, vomiting, dyspepsia, nausea, pain in the abdomen; infrequently - esophagitis¹, gastroesophageal reflux disease², gastritis, proctalgia², stomatitis, glossitis, bloating⁴, constipation, dryness of the oral mucosa, eructations, flatulence, holography⁴, hepatitis, including cholestatic or hepatocellular⁴; frequency unknown - acute pancreatitis, discoloration of the tongue and teeth, hepatic insufficiency, cholestatic jaundice.

From the respiratory system: infrequently - bronchial asthma¹, nose bleed², pulmonary embolism¹.

From the sense organs: often - dysgeusia (perversion of taste); infrequently - vertigo, hearing impairment, ringing in the ears; frequency is unknown - deafness, agevzia (loss of taste sensations), parosmia, anosmia.

From the side of the cardiovascular system: often - vasodilation¹; infrequent - sudden cardiac arrest¹, atrial fibrillation¹, lengthening the interval QT on an electrocardiogram, an extrasystole¹, atrial flutter; The frequency is unknown - ventricular tachycardia, including the "pirouette" type.

Laboratory indicators: often - deviation of laboratory parameters of liver function; infrequent increase in creatinine concentration¹, increased urea concentration¹ in blood plasma, a change in the albumin / globulin ratio¹, leukopenia, neutropenia⁴, eosinophilia⁴, thrombocythemia, increased activity of alanine aminotransferase (ALT), aspartate aminotransferase (ACT), gamma-glutamyltransferase (GGT)⁴, alkaline phosphatase⁴ (APF), lactate dehydrogenase (LDH)⁴in the blood plasma; frequency unknown - agranulocytosis, thrombocytopenia,an increase in the value of the international normalized ratio (INR), prolongation of prothrombin time, a change in the color of urine, an increase in the concentration of bilirubin in the blood plasma.

Other: infrequent - malaise¹, hyperthermia³, asthenia, chest pain⁴, chills⁴, increased fatigue⁴.

Infectious and parasitic diseases: infrequently - cellulite¹, candidiasis, gastroenteritis², secondary infections³ (including vaginal); frequency unknown - pseudomembranous colitis, erysipelas.

Patients with depressed immunity

Have patients with AIDS and other immunodeficiency clarithromycin at 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 a concomitant disease.

The most frequent adverse events in patients taking 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 ACT and ALT in blood plasma.There have also been cases of adverse events with a low incidence, such as: shortness of breath, insomnia and dryness of the oral mucosa.

In patients with suppressed immunity, laboratory indicators 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 in a dose of 1000 mg daily, there was a significant increase in activity ACT and ALT in blood plasma, as well as a decrease in the number of leukocytes and platelets. A small number of patients also reported an increase in the concentration of residual urea nitrogen in the blood plasma.

* In some reports of rhabdomyolysis clarithromycin was taken concomitantly with other drugs (LC), with the reception of which, as is known, is associated with the development of rhabdomyolysis (statins, fibrates, colchicine or allopurinol).

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

²Reports of these adverse reactions were obtained during clinical trials, as well as the post-marketing application of clarithromycin in the form of a sustained-release tablet coated with a film coat.

³Reports of these adverse reactions were obtained during clinical trials, as well as post-marketing use of clarithromycin in a powdered dosage form to prepare a suspension for oral administration.

⁴Reports of these adverse reactions were obtained during clinical trials, as well as post-marketing use of clarithromycin in tablet formulations coated with a film coat.

Overdose:

Symptoms: ingestion of a large dose of clarithromycin can cause symptoms of violations from the gastrointestinal tract.

In one patient with bipolar disorder in the history after the administration of 8 g of clarithromycin, changes in the mental state, paranoid behavior, hypokalemia and hypoxemia are described.

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

Interaction:

The use of the following drugs simultaneously with clarithromycin is contraindicated in connection with the possibility of developing serious side effects:

Cisapride, pimozide, terfenadine and astemizole

With the simultaneous use of clarithromycin with cisapride, pimozide, terfenadine, or astemizole, an increase in plasma concentrations of plasma was reported, which may lead to lengthening of the interval QT on ECG and the appearance of cardiac arrhythmias, including ventricular tachycardia (including ventricular tachycardia of the "pirouette" type) and ventricular fibrillation (see "Contraindications").

Alkaloids of ergot

Postmarketing studies show that with the 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 limbs and other tissues, including the central nervous system.Simultaneous use of clarithromycin and ergot alkaloids is contraindicated (see the section "Contraindications"),

MMC Inhibitors-CoA reductase (statins)

Simultaneous reception of clarithromycin with lovastatin or simvastatin is contraindicated (see "Contraindications" section) due to the fact that these statins are largely metabolized by isoenzyme CYP3A4, and simultaneous use with clarithromycin increases their serum concentrations, which leads to an increased risk of myopathy, including rhabdomyolysis. There have been reports of rhabdomyolysis in patients taking clarithromycin simultaneously with these drugs. If it is necessary to use clarithromycin, stop taking lovastatin or simvastatin for the duration of therapy.

Clarithromycin should be used with caution in the case of combination therapy with other statins. It is recommended to use statins, the metabolism of which does not depend on the isoenzyme CYP3A (eg, fluvastatin). In case of the need for simultaneous administration, it is recommended to take the lowest dose of statin. It should monitor the development of signs and symptoms of myopathy.

The effect of other drugs on clarithromycin

Drugs that are inducers of isoenzyme CYP3A (eg, rifampicin, phenytoin, carbamazepine, phenobarbital, St. John's wort pitted), can induce the metabolism of clarithromycin. This can lead to a subtherapeutic concentration of clarithromycin and, accordingly, to a decrease in its effectiveness. In addition, it is necessary to observe the concentration of the inductor of the CYP3A isoenzyme in the blood plasma, which can be increased due to inhibition of the isoenzyme CUR3A by clarithromycin. With the simultaneous use of rifabutin and clarithromycin, there was an increase in rifabutin concentration and a decrease in the concentration of clarithromycin in blood plasma with an increased risk of uveitis.

The following drugs have a proven or suspected effect on the concentration of clarithromycin in the blood plasma, in the case of their simultaneous use with clarithromycin, a dose adjustment or alternative treatment may be required:

Efavirenz, nevirapine, rifampicin, rifabutin and rifapentin

Strong inductors of the cytochrome P450 system, such as efavirenz, nevirapine, rifampicin, rifabutin and rifapentin can accelerate the metabolism of clarithromycin and. thus, to reduce the concentration of clarithromycin in the blood plasma and to weaken the therapeutic effect, and at the same time to increase the concentration in the blood plasma of the 14-OH-clarithromycin metabolite, which is also microbiologically active. Since the microbiological activity of clarithromycin and 14-OH-clarithromycin differs with respect to different bacteria, the therapeutic effect may decrease with the simultaneous use of clarithromycin and inducers of the cytochrome P450 system.

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 of 14-OH-clarithromycin increases. Since 14-OH-clarithromycin has a low activity against infections MAC, the overall activity against these pathogens may change; therefore, for treatment MAC alternative treatment should be considered.

Fluconazole

Simultaneous reception of fluconazole at a dose of 200 mg daily and clarithromycin 500 mg twice daily in 21 healthy volunteers led to an increase in the average value of the minimum equilibrium concentration of clarithromycin (C_min) and AUC by 33% and 18% respectively.At the same time, simultaneous administration did not significantly affect the average equilibrium concentration of the active metabolite of 14-OH-clarithromycin. Correction of the dose of clarithromycin in the case of simultaneous administration of fluconazole is not required.

Ritonavir

A pharmacokinetic study showed that simultaneous reception of ritonavir at a dose of 200 mg every 8 hours and clarithromycin and a dose of 500 mg every 12 hours led to a marked suppression of the metabolism of clarithromycin. With simultaneous reception of ritonavir C_max clarithromycin increased by 31%, C_min increased by 182% and AUC increased by 77%. The complete suppression of the formation of 14-OH-clarithromycin. Due to the wide therapeutic range of clarithromycin, a reduction in its dose in patients with normal renal function is not required. In patients with renal insufficiency, it is advisable to consider the following options for dose adjustment: with a QC of 30-60 ml / min, the dose of clarithromycin should be reduced by 50%.

Ritonavir should not be taken concomitantly with clarithromycin at doses exceeding 1 g / day.

Action of clarithromycin on other drugs

Antiarrhythmic drugs (quinidine and disopyramide)

Possible occurrence of ventricular tachycardia such as "pirouette" with simultaneous use of clarithromycin and quinidine or disopyramide. With concurrent administration of clarithromycin with these drugs, ECG monitoring should be performed on a regular basis to prolong the interval QT, and the serum concentrations of these drugs should be monitored.

In post-marketing use, cases of development of hypoglycemia were reported with concurrent administration of clarithromycin and disopyramide. It is necessary to monitor the concentration of glucose to the blood with the simultaneous use of clarithromycin and disopyramide.

Hypoglycemic agents for ingestion / insulin

With the simultaneous use of clarithromycin and hypoglycemic agents for oral administration (eg, sulfonylurea derivatives) and / or insulin, pronounced hypoglycemia can be observed. Simultaneous use of clarithromycin with some hypoglycemic drugs (for example, nateglinide, pioglitazone, repaglinide and rosiglitazone) can lead to inhibition of the isoenzyme CYP3A clarithromycin, resulting in the development of hypoglycemia.A careful control of the concentration of glucose in the blood is recommended.

Interactions caused by the isoenzyme CYP3A

Simultaneous reception of clarithromycin, which is known to inhibit the isoenzyme CYP3A, and drugs, primarily metabolized by isoenzyme CYP3A, can be associated with a mutual increase in their copy of grace, which can enhance or prolong both therapeutic, hacking and side effects. Clarithromycin should be used with caution in patients receiving drugs that are substrates of the isoenzyme CYP3A, especially if these drugs have a narrow therapeutic range (for example, carbamazepine), and / or drugs that are intensely metabolized by this isoenzyme. If necessary, a dose adjustment of the drug taken concomitantly with clarithromycin should be performed. Also, if possible, monitoring of serum concentrations of drugs that are primarily metabolized by the CYP3A isoenzyme should be conducted.

Metabolism of the following drugs / classes is carried out by the same isoenzyme CYP3A, as the metabolism of clarithromycin: alprazolam, carbamazepine, cilostazol, ciclosporin, disopyramide, methylprednisolone, midazolam, omeprazole, indirect anticoagulants (for example, warfarin), quinidine, rifabutin, sildenafil, tacrolimus, triazolam and vinblastine. Also to inhibitors of isoenzyme CYP3A include the following drugs, contraindicated for simultaneous use with clarithromycin: astemizole, cisapride, pimozide, terfenadine, lovastatin, simvastatin and ergot alkaloids (see the section "Contraindications"). To drugs interacting in a similar manner through other isoenzymes within the cytochrome P450 system include: phenytoin, theophylline and valproic acid.

HDirect anticoagulants

With the simultaneous administration of warfarin and clarithromycin, bleeding, a marked increase in INR and prolongation of prothrombin time is possible. In the case of simultaneous use with warfarin or other indirect anticoagulants, it is necessary to monitor MNO and prothrombin time.

Omeprazole

Clarithromycin (500 mg every 8 hours) was tested in healthy adult volunteers in combination with omeprazole (40 mg daily). With the simultaneous use of clarithromycin and omeprazole, equilibrium plasma concentrations of omeprazole were increased (C_max, AUC0-24 and T1/2 increased by 30%, 89% and 34% respectively). The average pH value of the stomach for 24 hours was 5.2 (with omeprazole alone) and 5.7 (with omeprazole simultaneously with clarithromycin).

Sildenafil, tadalafil and vardenafil

Each of these phosphodiesterase inhibitors is metabolized, at least in part, by the participation of an isoenzyme CYP3A. At the same time, isoenzyme CYP3A can be inhibited in the presence of clarithromycin. Simultaneous use of clarithromycin with sildenafil, tadalafil or vardenafil may lead to an increase in the inhibitory effect on phosphodiesterase. When using these drugs simultaneously with clarithromycin, the possibility of reducing the dose of sildenafil, tadalafil and vardenafil should be considered.

Theophylline, carbamazepine

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

Tolterodin

Primary metabolism of tolterodine is via isoenzyme CYP2D6. However, in the part of the population deprived of isoenzyme CYP2D6, metabolism occurs through isoenzyme CYP3A. In this population, suppression of the isoenzyme CYP3A leads to significantly higher concentrations of tolterodine in the blood serum. In a population with a low level of metabolism via isoenzyme CYP2D6, a dose reduction of tolterodine may be required with simultaneous application of isoenzyme inhibitors CYP3A, such as clarithromycin.

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

With the simultaneous use of midazolam and clarithromycin tablets (500 mg twice daily), there was an increase AUC midazolam: 2.7 times after intravenous administration of midazolam and 7 times after ingestion. The simultaneous use of clarithromycin with midazolam for oral administration is contraindicated. If concurrent with clarithromycin is used midazolam in the form of a drug - a solution for intravenous administration, the patient's condition should be carefully monitored for the possible correction of the dose of midazolam. The same precautions should be applied to other benzodiazepines, which are metabolized by the isoenzyme CYP3A, including triazolam and alprazolam. For benzodiazepines, the excretion of which does not depend on the isoenzyme CYP3A (temazepam, nitrazepam, lorazepam), clinically significant interaction with clarithromycin is unlikely.

With the simultaneous use of clarithromycin and triazolam, there may be an effect on the central nervous system, for example, drowsiness and confusion. In this regard, in the case of simultaneous use, it is recommended to monitor the symptoms of violation of the DSP.

Interactions with other drugs

Aminoglycosides

With simultaneous reception of clarithromycin with other ototoxic drugs.

especially aminoglycosides, care and control must be exercised functions of the vestibular and hearing aids, both during therapy and after its termination.

Colchicine

Colchicine is a substrate of both proenzyme CYP3A, and the carrier protein of P-glycoprotein (Pgp). It is known that clarithromycin and other macrolides are inhibitors of the isoenzyme CYP3A and Pgp. With the simultaneous use of clarithromycin and colchicine, inhibition Pgp and / or isoenzyme CYP3A can lead to an increase in the action of colchicine. It should monitor the development of clinical symptoms of colchicine poisoning. Post-marketing reports on cases of colchicine poisoning with its simultaneous administration with clarithromycin are registered, more often in elderly patients.Some of these cases occurred with patients suffering from kidney failure. As reported, some cases ended in a fatal outcome. Simultaneous use of clarithromycin and colchicine is contraindicated (see section "Contraindications").

Digoxin

It is assumed that digoxin is a substrate Pgp. It is known that clarithromycin inhibits Pgp. With simultaneous use of clarithromycin and digoxin inhibition Pgp clarithromycin may lead to an increase in the action of digoxin. The simultaneous administration of digoxin and clarithromycin can also lead to an increase in serum digoxin concentration. Some patients experienced clinical symptoms of digoxin poisoning. including potentially fatal arrhythmias. With the simultaneous administration of clarithromycin and digoxin, the concentration of digoxin in serum should be carefully monitored.

Zidovudine

Simultaneous reception of tablets of clarithromycin and zidovudine inside adult HIV-infected patients can lead to a decrease in the equilibrium concentration of zidovudine in blood plasma. Because the clarithromycin influences the absorption of zidovudine when ingested, interactions can be largely avoided by taking clarithromycin and zidovudine with an interval of 4 hours. Similar interaction was not observed in HIV-infected children who took a children's suspension of clarithromycin with zidovudine or dideoxyinosine. Because the clarithromycin may interfere with the absorption of zidovudine when administered simultaneously in adults in adults, this interaction is unlikely with the use of clarithromycin intravenously.

Fenitoin and valproic acid

There are data on the interaction of inhibitors of the isoenzyme CYP3A (including clarithromycin) with drugs that are not metabolized by the CYP3A isoenzyme (phenytoin and valproic acid). For these drugs with simultaneous application with clarithromycin, it is recommended to determine their serum concentrations, since there are reports of their increase.

Bi-directional interaction of drugs

Atazanavir

Clarithromycin and atazanavir are both substrates and isoenzyme inhibitors CYP3A. There is evidence of bi-directional interaction of these drugs.The simultaneous use of clarithromycin (500 mg twice daily) and atazanavir (400 mg once a day) can lead to a twofold increase in the effect of clarithromycin and a decrease in the effect of 14-OH-clarithromycin by 70% AUC atazanavir by 28%. Due to the wide therapeutic range of clarithromycin, reducing its dose in patients with normal renal function is not required. In patients with moderate renal insufficiency (KK 30-60 ml / min), the dose of clarithromycin should be reduced by 50%. In patients with QC less than 30 ml / min, the dose of clarithromycin should be reduced by 75%, using the appropriate dosage form of clarithromycin for this. Clarithromycin in doses exceeding 1000 mg / day, can not be used simultaneously with protease inhibitors.

Blocks of "slow" calcium channels

With the simultaneous use of clarithromycin and blockers of "slow" calcium channels, which are metabolized by the isoenzyme CYP3A4 (e.g., verapamil, amlodipine, diltiazem), you should be careful, since there is a risk of arterial hypotension. With simultaneous use, plasma concentrations of clarithromycin and "slow" calcium channel blockers can increase.Arterial hypotension, bradyarrhythmia and lactic acidosis are possible with concurrent administration of clarithromycin and verapamil.

Itraconazole

Clarithromycin and itraconazole are substrates and inhibitors of the isoenzyme CYP3A, which determines the bi-directional interaction of drugs. Clarithromycin can increase the concentration of itraconazole in the blood plasma, while itraconazole can increase the plasma concentration of clarithromycin. Patients simultaneously taking itraconazole and clarithromycin, should be carefully examined for signs of increased or prolonged pharmacological effects of these drugs.

Saquinavir

Clarithromycin and saquinavir are substrates and inhibitors of the isoenzyme CYP3A, which determines the bi-directional interaction of drugs. Simultaneous use of clarithromycin (500 mg twice daily) and saquinavir (in soft gelatin capsules, 1200 mg 3 times a day) in 12 healthy volunteers caused an increase AUC and C_max saquinavir in blood plasma by 177% and 187%, respectively, compared with the administration of saquinavir alone. Values AUC and C_max clarithromycin were approximately 40% higher than with single clarithromycin alone. With the simultaneous use of these two drugs for a limited time in the doses / formulations mentioned above, dose adjustment is not required. The results of a study of drug interactions using saquinavir in soft gelatin capsules may not correspond to the effects observed with saquinavir in hard gelatin capsules. The results of drug interaction studies with saquinavir alone may not correspond to the effects observed with saquinavir / ritonavir combination therapy. When taking saquinavir concomitantly with ritonavir, the potential effect of ritonavir on clarithromycin.

Special instructions:

Long-term use of antibiotics can lead to the formation of colonies with an increased number of insensitive bacteria and fungi. When superinfection is necessary to appoint appropriate therapy.

When applying clarithromycin I am reporting liver dysfunction (increased activity of liver enzymes in blood plasma, hepatocellular and / or cholestatic hepatitis with jaundice or without.Hepatic dysfunction can be severe, but is usually reversible. There are cases of hepatic insufficiency with a fatal outcome, mainly related to the presence of serious concomitant diseases and / or simultaneous use of other medicines. When signs and symptoms of hepatitis such as anorexia, jaundice, darkening of the urine, pruritus, abdominal tenderness in palpation, it is necessary to immediately stop the treatment with clarithromycin.

In the presence of chronic liver diseases it is necessary to conduct regular monitoring of the activity of "hepatic" serum enzymes.

In the treatment of almost all antibacterial agents, including clarithromycin, cases of pseudomembranous colitis are described, the severity of which may be range from mild to life threatening. Antibiotic drugs can change the normal intestinal microflora, which can lead to growth Clostridium difficile. Pseudomembranous colitis caused by Clostridium difficile, It is necessary to suspect in all patients with the appearance of diarrhea after the application of antibacterial agents.After the course of antibiotic therapy, careful medical supervision of the patient is necessary. The cases of development of pseudomembranous colitis after 2 months after the application of antibiotics were described.

Clarithromycin should be used with caution in patients with ischemic heart disease, severe heart failure, hypomagnesemia, severe bradycardia (less than 50 beats / min), and also with simultaneous use with antiarrhythmic drugs IA class (quinidine, procainamide) and III class (dofetilide, amiodarone, sotalol). With these conditions and with the simultaneous use of clarithromycin with these drugs, ECG monitoring should be performed regularly for prolongation of the QT interval.

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

Given the growing resistance Streptococcus pneumoniae to macrolides, it is important to conduct sensitivity testing in the appointment of clarithromycin to patients with community-acquired pneumonia. With hospital pneumonia clarithromycin should be used in combination with appropriate antibiotics.

Infections of the skin and soft tissues of mild and moderate severity are most often caused Staphylococcus aureus and Streptococcus pyogenes. In this case, both pathogens can be resistant to macrolides. Therefore, it is important to conduct a test to determine the sensitivity to antibiotics.

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

In the case of acute hypersensitivity reactions, such as anaphylactic reaction, Stevens-Johnson syndrome, toxic epidermal necrolysis and drug rash with eosinophilia and systemic symptoms (DRESS-syndrome) should immediately stop taking clarithromycin and begin appropriate therapy.

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

Effect on the ability to drive transp. cf. and fur:

Data on the effect of clarithromycin on the ability to drive and machinery are absent. Consideration should be given to the potentialdizziness, vertigo, confusion and disorientation, which may occur with the use of this drug.

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

Form release / dosage:

Tablets of prolonged action, film-coated, 500 mg.

Packaging:

For 5 or 7 tablets are swept in a blister of PVC / PVDC - aluminum foil (PVC/PVDC-AI).

- 1 blister (blister for 5 tablets) placed in a pack of cardboard along with instructions for use;

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

Storage conditions:

At a temperature of no higher than 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.

Terms of leave from pharmacies:On prescription

Registration number:LS-000609

Date of registration:31.05.2010

The owner of the registration certificate:KRKA, dd, Novo mesto, AOKRKA, dd, Novo mesto, AO

Manufacturer: & nbsp

KRKA, d.d. Slovenia

Representation: & nbspKRKA KRKA Slovenia

Information update date: & nbsp21.05.2015

Illustrated instructions

Instructions

Fromilide® Uno (Fromilid® Uno)