Fromilid - instructions for use, doses, side effects, contraindications, price, where to buy

Fromilid® (Fromilid®)

The use of the following drugs 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 absorption of zidovudine when taken orally, 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 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 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.

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

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.

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.

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.

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.

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

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.

Instructions for use FROMILID®

Clarithromycin is metabolized in the liver, where it can inhibit the action of cytochrome P450 enzymes. When used simultaneously with clarithromycin, the serum concentration of drugs metabolized by these enzymes may increase and lead to side effects. Therefore, clarithromycin should not be co-administered with terfenadine, cisapride, pimozide or astemizole. Clinical experience shows that the use of any of these drugs concomitantly with clarithromycin can lead to prolongation of the QT interval, ventricular tachycardia, ventricular fibrillation and torsades de pointes.

Clarithromycin should not be administered concomitantly with ergot alkaloids, because Serum concentrations of alkaloids may increase and cause toxic effects.

During therapy with some drugs that require long-term administration, it is necessary to measure their serum concentration and, if necessary, adjust the dose. These drugs include theophylline, digoxin, disopyramide, triazolam, midazolam, carbamazepine, phenytoin, cyclosporine, tacrolimus, rifabutin and itraconazole.

The simultaneous use of clarithromycin and HMG-CoA reductase inhibitors (lovastatin, simvastatin) can cause myalgia and myopathy, increasing the risk of rhabdomyolysis. While using clarithromycin, the use of these drugs is not recommended.

The simultaneous use of clarithromycin and colchicine, especially in cases of impaired renal function, can lead to an increase in the concentration of colchicine and the manifestation of its toxic effect.

It is necessary to repeatedly monitor prothrombin time in patients taking clarithromycin concomitantly with warfarin and other anticoagulants.

The simultaneous administration of clarithromycin and zidovudine reduces the absorption of the latter.

Co-administration of ritonavir and clarithromycin leads to a significant increase in the AUC of clarithromycin (up to 77%) and a significant decrease in the AUC of its metabolite, 14-hydroxyclarithromycin (up to 100%). If renal function is normal, no dose adjustment is required. For mild renal failure with CC <60 ml/min (1.0 ml/sec), patients should be prescribed 1/2 dose of clarithromycin; if CC < 30 ml/min (0.5 ml/sec) - patients should be prescribed 1/4 of the dose of the drug.