Fromilid, 500 mg, film-coated tablets, 14 pcs.

Pharmacological properties of the drug Fromilid

Clarithromycin is a semisynthetic macrolide antibiotic. Inhibits protein synthesis in microbial cells. It acts mainly bacteriostatically, but has a bactericidal effect against certain microorganisms. Active against intracellular microorganisms - Mycoplasma pneumoniae, Legionella pheumophila, Chlamydia trachomatis and C. Pneumoniae, Ureaplasma Urealyticum; gram-positive microorganisms (streptococci and staphylococci, Listeria monocytogenes, Corynebacterium spp .); gram-negative microorganisms ( Haemophilus influenzae and N. ducreyi, Moraxella catarrhalis, Bordetella pertussis, Neisseria gonorrhoeae and N. meningitidis, Borrelia burgdorferi, Pasteurella multocida, Campylobacter spp. and Helicobacter pylori ); some anaerobes ( Eubacterium spp., Peptococcus spp., Propionibacterium spp., Clostridium perfringens and Bacteroides melaninogenicus ); Toxoplasma gondii and all mycobacteria except M. tuberculosis . When taken orally, it is well absorbed from the digestive tract. Clarithromycin penetrates well into biological fluids and inflamed tissues of the body, where it reaches concentrations 10 times higher than the concentration in the blood plasma, in the tonsils - 331 times, in the cells of the nasal mucosa - 27.5 times, in the inflammatory exudate of the middle ear - in 8.82 times. About 20% of clarithromycin is immediately metabolized to the main metabolite, 14-hydroxyclarithromycin. After taking the drug at a dose of 250 mg, the half-life is 3-4 hours, at a dose of 500 mg - 5-7 hours. Approximately 20-30% of clarithromycin is excreted in the urine unchanged, the rest - in the form of metabolites.

Fromilid, 14 pcs., 250 mg, film-coated tablets

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 a 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

Medicines that are inducers of the CYP3A isoenzyme (for example, rifampicin, phenytoin, carbamazepine, phenobarbital, St. John's wort)

may induce the metabolism of clarithromycin. This may result in subtherapeutic concentrations of clarithromycin and, consequently, 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 dosage 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, rifampin, 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 concentration in the blood plasma of 14-OH- clarithromycin is 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.

Co-administration of fluconazole 200 mg daily and clarithromycin 500 mg twice daily in 21 healthy volunteers resulted in an increase in the mean steady-state clarithromycin Cmin and AUC by 33–18%, 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: if the creatinine Cl is 30–60 ml/min, the clarithromycin dose should be reduced by 50%; if the creatinine Cl is less than 30 ml/min, the clarithromycin dose should be reduced by 75%. 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 taken concomitantly with these drugs, ECG monitoring should be performed regularly to monitor for QT interval prolongation, as well as serum concentrations of these drugs should be monitored.

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 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 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 metabolism of the following drugs/classes is carried out by the same CYP3A isoenzyme as the Claritromycin metabolism: alprazzols, carbamazepine, cylostazole, cyclosporine, dysopiramid, methylpredazolon, omeprazole, indirect anticogulants (e.g. varfarin), quinidine, rifabutin, siring. Lam and Vinblastin . 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 result in increased phosphodiesterase inhibitory effects. 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 a solution for intravenous administration, 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.

Interaction 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 for both the CYP3A isoenzyme and the P-gp transporter protein. It is known that clarithromycin and other macrolides are inhibitors of the CYP3A and P-gp isoenzyme. When clarithromycin is used concomitantly with colchicine, inhibition of P-gp 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 predicted to be a P-gp substrate. Clarithromycin is known to inhibit P-gp. When clarithromycin and digoxin are used concomitantly, inhibition of P-gp 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 the steady-state plasma concentration 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. separately. 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 saquinavir/ritonavir combination therapy. When taking saquinavir concomitantly with ritonavir, the potential effect of ritonavir on clarithromycin should be considered.

Indications for use of the drug Fromilid

Infections of the ENT organs and respiratory tract: tonsillopharyngitis, acute sinusitis, otitis, acute bronchitis, chronic bronchitis in the acute phase, bacterial and atypical pneumonia, infections of the skin and soft tissues, infection with mycobacteria ( M. complex , M. kansasi, M. marinum M. leprae); for the prevention of infections in patients with AIDS; for the eradication of H. pylori in patients with peptic ulcers of the stomach or duodenum (in combination with other drugs).

Use of the drug Fromilid

Tablets Swallow without chewing, with a small amount of water. Adults and children over the age of 12 years are usually prescribed 250 mg every 12 hours. For the treatment of sinusitis, severe infections and infections caused by Haemophilus influenzae, 500 mg is prescribed every 12 hours. The duration of treatment is 7-14 days. For eradication of H. pylori, a dose of 250–500 mg 2 times a day is prescribed in combination with other drugs, usually for 7 days. For the treatment and prevention of infections caused by bacteria Micobacterium avium complex , 500 mg Fromilid is prescribed every 12 hours. This dose can be increased. The maximum daily dose is 2 g. Children are prescribed 15 mg/kg in 2 divided doses. The dose should not exceed 500 mg every 12 hours. The maximum daily dose for children is 1 g. Treatment of infections caused by Micobacterium avium complex is long-term. In case of renal failure (creatinine clearance ≤30 ml/min or serum creatinine level 290 µmol/l), the dose should be halved or the interval between doses of the drug should be doubled. Suspension Children under 12 years of age are prescribed a suspension at a daily dose of 15 mg/kg in 2 doses, washed down with water. The suspension contains small granules that should not be chewed (they have a bitter taste). A dispenser is used to receive the suspension. One full dispenser contains 5 ml of suspension (125 mg of clarithromycin). After each use, the dispenser should be rinsed with water. The table shows the doses recommended for children based on body weight.

The frequency of administration is 2 times a day. Duration of treatment is 7–14 days. To prevent infection with bacteria Micobacterium avium complex, children are prescribed 15 mg/kg in 2 doses, but not more than 500 mg every 12 hours. The maximum dose for children is 1 g/day. The treatment is long-term. To restore the suspension, add 42 ml of water to the bottle and shake. The level of the finished suspension should match the mark on the bottle.

Fromilid 500 mg No. 14 tablet.

Instructions for medical use of the drug FROMILID® Trade name Fromilid® International nonproprietary name Clarithromycin Dosage form Film-coated tablets 250 mg and 500 mg Composition One tablet contains the active substance - clarithromycin 250 mg or 500 mg, excipients: corn starch, microcrystalline cellulose 101, microcrystalline cellulose 102, colloidal anhydrous silicon dioxide, pregelatinized starch, potassium polacrilin, talc, magnesium stearate, shell composition: hypromellose 6 cps, talc, yellow iron oxide (E172), propylene glycol, titanium dioxide (E171). Description Film-coated tablets of light brownish-yellow color, oval, with a biconvex surface. Pharmacotherapeutic group Antimicrobial drugs for systemic use. Macrolides. ATC code J01FA09 Pharmacological properties Pharmacokinetics Clarithromycin is stable in the presence of gastric juice. Bioavailability is approximately 55% of the oral dose. Food may slow absorption but does not significantly affect the bioavailability of clarithromycin. About 20% of clarithromycin is rapidly metabolized to 14-hydroxyclarithromycin, which has a biological effect similar to that of clarithromycin. In healthy volunteers, clarithromycin reaches serum concentrations proportional to the oral dose. Clarithromycin reaches maximum serum concentrations 3 hours after oral administration. After taking a single oral dose of 250 mg of clarithromycin, the average concentration ranges from 0.62 mcg/ml to 0.84 mcg/ml; after taking a single oral dose of 500 mg of clarithromycin - from 1.77 mcg/ml to 1.89 mcg/ml. The corresponding concentrations of 14-hydroxyclarithromycin, i.e. metabolites range from 0.4 mcg/ml to 0.7 mcg/ml after taking a dose of 250 mg and from 0.67 mcg/ml to 0.8 mcg/ml after taking a dose of 500 mg. The area under the concentration-time curve is 4 mcg/ml/h after a 250 mg dose and 11 mcg/ml/h after a 500 mg dose. After taking repeated doses of 250 mg of clarithromycin 2 times a day, the maximum concentration of clarithromycin is 1 mcg/ml and 14-hydroxyclarithromycin is 0.6 mcg/ml. Macrolides have a low level of ionization, they dissolve in fats, which allows them to penetrate well into the tissues and fluids of the body. In general, clarithromycin reaches concentrations in tissues that are almost 10 times higher than in serum. High concentrations are found in the lungs (8.8 mg/kg), tonsils (1.6 mg/kg), nasal mucosa, skin, saliva, alveolar cells, sputum and middle ear. The volume of distribution of clarithromycin in healthy volunteers after taking a single dose of 250 mg and/or 500 mg ranges from 226 to 266 l or 2.5 l/kg. The volume of distribution of 14-hydroxyclarithromycin ranges from 304 to 309 L. The binding of clarithromycin to serum proteins is negligible and reversible. Clarithromycin is metabolized in the liver. At least 7 metabolites have been identified. Of these, the most important is 14-hydroxy-clarithromycin, which has a biological effect similar to that of clarithromycin. Clarithromycin is excreted in the urine as a metabolite or unchanged, a smaller percentage is excreted in the feces (4%). About 20% of a 250 mg dose and 30% of a 500 mg dose are excreted unchanged in the urine. From 10 to 15% of the drug dose is excreted in the urine in the form of 14-hydroxyclarithromycin. The half-life of clarithromycin taken 2 times a day at 250 mg is from 3 to 4 hours; 500 mg - from 5 to 7 hours. Children The pharmacokinetics of clarithromycin at a dose of 7.5 mg/kg body weight when taken twice a day is the same as in adults. Elderly patients No dosage adjustment is required for elderly patients, except in cases of severe renal impairment. Effect of the disease on pharmacokinetics After taking 200 mg of clarithromycin, an increase in the maximum concentration and area under the curve (AUC) and a decrease in the elimination of clarithromycin are observed in patients with severe renal failure. Therefore, it is necessary to reduce the dose of the drug or increase the interval between doses for patients with severe renal failure. The steady-state blood concentration of clarithromycin in patients with liver failure does not differ from the concentration in healthy people, but the concentration of 14-hydroxy metabolite is lower in patients with liver failure. Pharmacodynamics Fromilid® is a macrolide antibiotic. Macrolides reversibly bind to the P region of the 50S ribosomal subunits and inhibit RNA-dependent protein synthesis. Fromilid prevents transpeptidation (protein chain elongation) and/or translocation (transfer of amino acids from transfer RNA to messenger RNA). Since important peptides are not produced, protein synthesis does not occur, which disrupts the normal functioning of the cell. The active metabolite of clarithromycin, 14-hydroxyclarithromycin, is also effective. Moreover, it is twice as effective as clarithromycin against H. influenzae. The main effect of Fromilid® is bacteriostatic, but Fromilid® can also have a bactericidal effect against Streptococcus pyogenes, Streptococcus pneumoniae, Moraxella catarrhalis. Fromilid® has a bacteriostatic and bactericidal effect against numerous clinically significant gram-positive and gram-negative bacteria, such as aerobes, anaerobes or facultative anaerobes, other bacteria (mycoplasma, ureaplasma, chlamydia, legionella) and atypical mycobacteria. Table 1 Bacteria sensitive to clarithromycin Aerobes, gram-positive bacteria Aerobes, gram-negative bacteria Anaerobic bacteria Bacillus spp. Bordetella pertussis Gram-positive bacteria Corynebacterium spp. Campylobacter jejuni Eubacterrium spp. Listeria monocytogenes H. influenzae Clostridium perfringens Staphylococcus aureus, methicillin-sensitive Helicobacter pylori Peptococcus spp. Streptococcus agalactiae Legionella pneumophila Peptostreptococcus spp. Streptococcus pneumoniae Moraxella catarrhalis Propionibacterium acnes Streptococcus pyogenes Neisseria gonorrhoeae Gram-negative bacteria Streptococcus viridans Neisseria meningitis Bacteroides spp. Pasteurella multocida Bacteroides fragilis Prevotella melaninogenica Other microorganisms Chlamydia pneumoniae Chlamydia trachomatis Mycoplasma pneumoniae Ureaplasma urealyticum Borrelia burgdorferi Toxoplasma gondii Mycobacterium avium complex Mycobacterium fortuitum Mycobacterium chelonae Mycobacterium kansasii Mycobacterium xenopi Mycobacterium leprae By indications for use - infections of the ENT organs, upper and lower respiratory tract (tonsillopharyngitis, acute sinusitis, otitis media, acute bacterial bronchitis, exacerbation of chronic bronchitis, community-acquired bacterial pneumonia, atypical pneumonia) - infections caused by mycobacteria (M. avium complex, M. kansasii, M. marinum, M. leprea) and their prevention in patients with AIDS - infections of the skin and soft tissues - eradication of Helicobacter pylori in patients with duodenal or gastric ulcers as part of combination therapy - for the treatment of other infectious and inflammatory diseases caused by microorganisms sensitive to the drug. Method of administration and dosage Do not break the tablets. The tablets are swallowed whole with a small amount of liquid. Adults and children over 12 years of age are prescribed 250 mg every 12 hours. For the treatment of sinusitis, severe infections and infections caused by Haemophilus influenzae, 500 mg is prescribed 2 times a day. Eradication of Helicobacter pylori in patients with duodenal or gastric ulcer as part of combination therapy. Prescribe 500 mg 2 times a day, usually for 7 days. For the treatment and prevention of the spread of infection caused by Mycobacterium avium complex, 500 mg of the drug should be prescribed every 12 hours. The maximum daily dose is 2 g. Treatment of infection caused by Mycobaterium avium is long-term. No dose adjustment is necessary for patients with mild to moderate hepatic impairment if renal function is normal. In case of renal failure, if creatinine clearance is less than 0.5 ml/sec (30 ml/min.) or serum creatinine is more than 290 mmol/L (3.3 mg/100 ml), the dose should be reduced by 2 times or the interval between doses should be doubled. Side effects Often (≥1/10) - headache - change in taste - nausea, vomiting, abdominal pain, dyspepsia, diarrhea - rash Uncommon (≥1/1000 to <1/100) - increased levels of serum transaminases, alkaline phosphatase, creatinine, bilirubin, urea, prothrombin time - stomatitis, glossitis - urticaria Rarely (≥1/10,000 to <1/1000) - hypoglycemia (in patients taking drugs to lower blood sugar) - hypersensitivity reactions (dyspnea, laryngeal edema) - reversible changes in the color of the teeth and tongue - pseudomembranous colitis, candidiasis (with long-term use) Very rarely (<1/10,000) - QT interval prolongation, ventricular tachycardia and ventricular flutter or fibrillation - leukopenia, thrombocytopenia - dizziness, paresthesia, insomnia, seizures - tinnitus, reversible hearing loss or decrease - pancreatitis - interstitial nephritis, renal failure - Stevens-Johnson syndrome, toxic epidermal necrosis (Lyell's syndrome) - drug allergy manifested by rash with eosinophilia and systemic symptoms (DRESS) - arthralgia , myalgia, rhabdomyolysis (with simultaneous use with statins, fibrates, colchicine, allopurine), worsening of myasthenia gravis - anaphylaxis (Quincke's edema, shock) - liver dysfunction, which is transient and reversible, hepatitis and cholecystitis with and without jaundice, fatal liver failure due to severe concomitant diseases and/or simultaneous use of other drugs - nightmares, confusion, fear, hallucinations, psychosis. There are known cases of colchicine toxicity with the combined use of clarithromycin and colchicine, especially in elderly patients, including background of renal failure. Patients with a compromised immune system In patients with AIDS and other patients with a compromised immune system who have used high doses of clarithromycin for longer than recommended for the treatment of mycobacterial infections, it is not always possible to distinguish drug-related adverse reactions from symptoms of the underlying or concomitant diseases. Contraindications - hypersensitivity to macrolide antibiotics and any other component of the drug - severe liver failure - concomitant use with cisapride, pimozide, terfenadine, astemizole or ergot alkaloids - porphyria - hereditary fructose intolerance, glucose-galactose malabsorption syndrome or sucrose-isomaltose deficiency - pregnancy and lactation Drug interactions Clarithromycin is metabolized in the liver, where it can inhibit the action of enzymes of the cytochrome P450 complex. Serum concentrations of drugs that are metabolized through this system may increase with simultaneous use of Fromilid® and cause side effects. Caution should be exercised when using clarithromycin in patients receiving therapy with the following drugs (CYP 3A substrates): alprazolam, astemizole, carbamazepine, cyclostazol, cisapride, cyclosporine, disopyramide, ergot alkaloids, methylprednisolone, midazolam, omeprazole, oral anticoagulants (eg, warfarin) , pimozide, quinidine, rifabutin, sildenafil, tacrolimus, terfenadine, triazolam and vinblastine, phenytoin, theophylline and valproate. Avoid use with oral midazolam. Terfenadine, cisapride, pimozide or astemizole should not be prescribed during treatment with Fromilid®, as this may lead to cardiac arrhythmias (QT prolongation, ventricular tachycardia, ventricular fibrillation and torsade de pointes). There are reports of the development of torsade de pointes (TdP) that occurred with the simultaneous use of clarithromycin with quinidine or disopyramide. With simultaneous use of Fromilid® and theophylline, carbamazepine, digoxin, lovastatin, simvastatin, triazolam, midazolam, phenytoin, cyclosporine, tacrolimus and ergot alkaloids, it is recommended to determine their serum concentration levels, as they may be increased. The prothrombin time should be checked several times in patients receiving Fromilid® concomitantly with warfarin or other oral anticoagulants. The simultaneous administration of Fromilid® and zidovudine reduces the absorption of zidovudine. Co-administration of ritonavir and Fromilid® leads to a significant increase (up to 77%) in the area under the serum concentration curve (AUC) of clarithromycin and a significant decrease in the area under the serum concentration curve (up to 100%) of its metabolite 14-hydroxyclarithromycin. If renal function is normal, no dose adjustment is required. Clarithromycin may increase colchicine exposure. The patient should be monitored for clinical signs of colchicine toxicity. Serum digoxin concentrations in patients should be carefully monitored when administered with clarithromycin. There is a possibility of increased plasma concentrations of phosphodiesterase inhibitors (sildenafil, tadalafil and warvenafil) when used together with clarithromycin, which may require a reduction in the dose of phosphodiesterase inhibitors. The development of arterial hypotension, bradyarrhythmia and lactic acidosis has been reported with the combined use of clarithromycin and verapamil. Special instructions The possibility of cross-resistance between 14- and 15-member macrolides should be taken into account. Doses of the drug should be reduced for patients with severe renal impairment. Patients with a history of liver disease or taking other hepatotoxic drugs may develop life-threatening liver damage. Symptoms of myasthenia gravis may increase in patients receiving clarithromycin. The simultaneous use of clarithromycin, lovastatin and simvastatin is contraindicated. Like other macrolides, clarithromycin increases the concentration of HMC-CoA redutase inhibitors. Rarely, rhabdomyolysis has been reported in patients treated with these drugs together, or in patients treated with atorvastatin or rosuvastatin with clarithromycin. Patients should be monitored for symptoms of myopathy. When used concomitantly with clarithromycin, atorvastatin and rosuvastatin should be used in the lowest doses. In such cases, it is necessary to consider adjusting the dose of statins or using statins whose metabolism is not dependent on the CYP3A enzyme (fluvastatin or privastatin). Effect of clarithromycin on intestinal microflora When taking 250 mg of clarithromycin orally 2 times a day for 7 days, no significant changes were observed in the number of staphylococci, micrococci, enterococci, aerobic diphtheroids, anaerobic cocci, eubacteria, clostridia and Veillonella. Growth of colonies of streptococci, gram-negative intestinal bacteria, lactobacilli, bifidobacteria and Bacteroides spp. was not very strongly inhibited. Increases in Candida albicans have been reported rarely. In case of severe, persistent diarrhea, which may indicate pseudomembranous colitis, you should stop taking the drug and consult your doctor. Use in children Children under 12 years of age should use the drug in the form of a suspension in accordance with the instructions for use Fromilid, granules for the preparation of an oral suspension 125 mg/5 ml. Currently, there is insufficient experience with the use of Fromilid® in the treatment of children under 6 months of age and children infected with Mycobaterium avium under 20 months of age. Features of the effect of the drug on the ability to drive a vehicle or potentially dangerous mechanisms. The drug does not affect the speed of the patient's psychomotor reactions when driving a car or when working with other potentially dangerous mechanisms. Overdose Symptoms: vomiting, abdominal pain, headache and confusion. Treatment: gastric lavage, symptomatic therapy. Hemodialysis is ineffective. Release form and packaging Film-coated tablets 250 mg and 500 mg. 7 tablets are placed in a blister pack made of polyvinyl chloride/polyvinyl dichloride film and aluminum foil. 2 blister packs together with instructions for medical use in the state and Russian languages ​​are placed in a cardboard pack. Storage conditions Store in a dry place at a temperature not exceeding 30°C. Keep out of the reach of children! Shelf life: 5 years Do not use after expiration of shelf life. Conditions for dispensing from pharmacies By prescription Manufacturer KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia. Address of the organization that accepts claims from consumers on the quality of products (products) on the territory of the Republic of Kazakhstan Representative office of “KRKA, tovarna zdravil, dd, Novo mesto” in the Republic of Kazakhstan, 050059, Almaty, Al-Farabi Ave., 5/1, section 3 A, 4th floor. tel. fax www.krka.si

Side effects of the drug Fromilid

Nausea, vomiting, diarrhea, abdominal pain. In cases of severe and prolonged diarrhea, the possibility of pseudomembranous colitis must be excluded. Stomatitis, glossitis, headache, hypersensitivity reactions (urticaria, anaphylactic shock, very rarely Stevens-Johnson syndrome), transient changes in taste, changes in the central nervous system (dizziness, fear, insomnia, nightmares) may also occur. In most cases, side effects are moderate. Very rarely, increased liver enzyme activity and cholestatic jaundice may occur.

Special instructions for the use of the drug Fromilid

The development of cross-resistance of pathogens to other macrolide antibiotics is possible. There is no need to adjust the dose in patients with minor dysfunction if their renal function is preserved. The dose of the drug should be reduced in patients with severe renal impairment. Prescribing the drug to patients with porphyria should be avoided. There is insufficient data on the effectiveness and safety of clarithromycin in children under 6 months of age. Treatment with antibiotics changes the intestinal microbiocenosis, which can lead to the development of infection caused by resistant microorganisms. In case of severe and prolonged diarrhea, the development of pseudomembranous colitis should be excluded. During pregnancy, the drug is prescribed only when the expected therapeutic effect for the expectant mother exceeds the potential risk to the fetus. Breastfeeding should be discontinued during treatment with clarithromycin.

Drug interactions Fromilid

Clarithromycin is metabolized in the liver and may inhibit the activity of cytochrome P450 enzymes. The concentration of drugs that are metabolized by this system may increase during concomitant treatment with clarithromycin and cause side effects. Therefore, terfenadine, cisapride, pimozide or astemizole should not be co-administered with clarithromycin. It is recommended to determine serum concentrations of theophylline, carbamazepine, digoxin, lovastatin, simvastatin, triazolam, midazolam, phenytoin, cyclosporine, tacrolimus and ergot alkaloids if they are prescribed in combination with clarithromycin. Prothrombin time should be monitored in patients taking clarithromycin concomitantly with warfarin or other anticoagulants. The combined administration of clarithromycin and cidovudine reduces the absorption of cidovudine. Co-administration of ritonavir with clarithromycin leads to a significant increase in the concentration of clarithromycin in the blood serum and a significant decrease in the serum concentration of its metabolite, 14-hydroxyclarithromycin.

Fromilid® (Fromilid®)

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 section “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 section "Contraindications").

HMC-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 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 result in subtherapeutic concentrations of clarithromycin and, consequently, 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 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 concentration in the blood plasma 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 mean clarithromycin minimum steady-state concentration (Cmin) and AUC by 33% and 18%, respectively. However, simultaneous administration did not significantly affect the average steady-state concentration 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 co-administered 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 observed. 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: with CC 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.

During post-marketing use, cases of hypoglycemia have been reported with concomitant use of clarithromycin and disopyramide. It is necessary to monitor blood glucose concentrations when using clarithromycin and disopyramide simultaneously.

Oral hypoglycemic agents/insulin

With the simultaneous use of clarithromycin and oral hypoglycemic agents (for example, sulfonylureas) 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 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 copy of grace, 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 (eg, warfarin), 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 section “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 prothrombin time are possible. In case of simultaneous use with warfarin or other indirect anticoagulants, it is necessary to monitor the INR and prothrombin time.

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, steady-state plasma concentrations 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 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 result in increased phosphodiesterase inhibitory effects. 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 oral midazolam is contraindicated. If midazolam in intravenous 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 CSP impairment.

Interactions with other drugs

Aminoglycosides

When taking clarithromycin concomitantly with other ototoxic drugs.

especially aminoglycosides, care must be taken to monitor the functions of the vestibular and auditory apparatus, both during and after therapy.

Colchicine

Colchicine is a substrate of both the proenzyme 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 section "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 experienced clinical symptoms of digoxin poisoning. 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 the steady-state plasma concentration 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 was not 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 interactions between CYP3A inhibitors (including clarithromycin) and drugs that are not metabolized by CYP3A (phenytoin and valproic acid). For these drugs, when used concomitantly with clarithromycin, it is recommended to determine their serum concentrations, as 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 (creatinine clearance 30-60 ml/min), the dose of clarithromycin should be reduced by 50%. In patients with CC 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.

Blockers of "slow" calcium channels

When using clarithromycin simultaneously with blockers of “slow” calcium channels 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 slow calcium channel blockers 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 taking 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 correspond to the effects observed with saquinavir/ritonavir combination therapy. When taking saquinavir concomitantly with ritonavir, the potential effect of ritonavir on clarithromycin should be considered.