Lansoprazole
Lansoprazole promotes prolonged suppression of gastric secretion of hydrochloric acid. The use of lansoprazole contributed to a significant decrease in systemic concentrations of the protease inhibitor HIV-atazanavir, which requires the presence of hydrochloric acid for gastric juice. Lansoprazole contributed to a decrease in the severity of the therapeutic effect of atazanavir and HIV resistance. In this way, lansoprazole and other inhibitors of the proton pump should not be used in conjunction with atazanavir. Theoretically, the effect of lansoprazole on the absorption of other drugs, the bioavailability of which depends on the pH of the gastric juice (for example, ketoconazole, ampicillin esters, iron salts, digoxin).
The metabolism of lansoprazole is mediated through the cytochrome P450 system, especially isoenzymes CYP3A and CYP2C19. In studies it was demonstrated that for lansoprazole a clinically significant interaction with other drugs metabolized by isoenzymes of the cytochrome P450 system (warfarin, phenazone, indometacin, ibuprofen, phenytoin, propranolol, prednisone, diazepam and clarithromycin) is uncharacteristic in healthy patients. These compounds are metabolized by various isoenzymes of the cytochrome P450 system, which include isoenzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A. With the joint administration of lansoprazole and theophylline (isozymes CYP1A2, CYP3A) there was a moderate increase in the clearance of theophylline (10%), it is unlikely that this interaction is of clinical significance.However, in some patients, in order to achieve clinically effective concentrations of lansoprazole in the blood, additional titration of the theophylline dose at the beginning and at the end of therapy with lansoprazole. In the study, single or multiple administration of lansoprazole in a dose 60 mg did not affect the pharmacokinetics of warfarin enantiomers and prothrombin time in healthy subjects. However, there are reports of an increase in the international normalized ratio (INR) and prothrombin time in patients who simultaneously received proton pump inhibitors (for example, lansoprazole) and warfarin. The increase in INR and prothrombin time increases the risk of bleeding and even death. Patients sharing a proton pump inhibitor and warfarin, it may be necessary to monitor INR and prothrombin time.
It has been shown that for lansoprazole a clinically significant interaction with amoxicillin is not characteristic.
In a cross-sectional study, a single dose of 30 mg of lansoprazole and 20 mg of omeprazole was studied, both alone and together with 1 g of sucralfate; at a joint admission, slowed down absorption of inhibitors, proton pump by 17% and 16%, respectively.In connection with the data obtained, proton pump inhibitors should be taken 30 minutes before taking sucralfate. In clinical trials, a joint administration of antacids and delayed-release capsules of lansoprazole was carried out, and the combined administration did not affect the efficacy of lansoprazole.
Amoxicillin
Probenecid reduces renal glomerular secretion of amoxicillin.
The simultaneous administration of amoxicillin and probenecid may increase the concentration and duration of amoxicillin in the blood plasma.
Chloramphenicol, macrolides, sulfonamides and tetracyclines can influence the bactericidal action of penicillins. The drug interaction between these drugs was demonstrated in vitro; but its clinical significance is not exactly established.
Effect of drugs on laboratory data
High concentrations of ampicillin in the urine can lead to false positive results in the determination of glucose in the urine through a test system Clinitest®, Benedict's solution and Fehling's solution. Since the onset of this effect is possible with amoxicillin, the use of methods based on the action of the glucose oxidase enzyme (for example, the test system Clinistix®).
When taking ampicillin in pregnant women, there was a transient decrease in plasma concentrations of total conjugated estriol, estriol glucoronide, conjugated estrone and estradiol. Also, this effect can occur when taking amoxicillin.
Clarithromycin
The use of the following drugs together with clarithromycin is contraindicated in connection with the possibility of developing serious side effects.
Cisapride and pimozide
When combined, it is possible to increase the concentrations of cisapride, increase the QT interval, the occurrence of arrhythmias, including ventricular tachycardia, ventricular fibrillation, and ventricular pirouette tachycardia.
Terfenadine and astemisole
When combined, it is possible to increase the concentration of terfenadine / astemizole in the blood, the occurrence of arrhythmias, increased QT interval, ventricular tachycardia, ventricular fibrillation and ventricular pirouette tachycardia.
Ergotamine / dihydroergotamine
When combined, the following effects are possible, associated with acute poisoning with drugs of the ergotamine group: vascular spasm, ischemia of limbs and other tissues, including the central nervous system.
The effect of other drugs on clarithromycin
The following drugs have a proven or suspected effect on the concentration of clarithromycin; In the case of their combined use with clarithromycin, dosage adjustment or alternate 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, reduce the concentration of clarithromycin in the plasma and weaken the therapeutic effect, and at the same time increase the concentration of 14-hydroxyclarithromycin metabolite, which is also microbiologically active.
Fluconazole
The simultaneous administration of fluconazole at a dose of 200 mg daily and clarithromycin at a dose of 500 mg twice daily in 21 healthy volunteers resulted in an increase in the minimum mean equilibrium concentration of clarithromycin (FROMmin) and AUC by 33% and 18% respectively.
At the same time, the combined administration did not significantly affect the average equilibrium concentration of the active metabolite of 14-hydroxyclarithromycin.Correction of the dose of clarithromycin in the case of concurrent administration of fluconazole is not required.
Ritonavir
A pharmacokinetic study showed that the joint intake of ritonavir at a dose of 200 mg every 8 hours and clarithromycin at a dose of 500 mg every 12 hours led to a marked suppression of the metabolism of clarithromycin. With the joint administration of ritonavir CmOh clarithromycin increased by 31%, Cmin increased by 182% and AUG increased by 77%. A complete inhibition of the formation of 14-hydroxyclarithromycin was noted. Due to the wide therapeutic range, dose reduction 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: when creatinine clearance is 30-60 ml / min, the dose of clarithromycin should be reduced by 50% (no more than one tablet of clarithromycin 500 mg per day). Patients with severe renal failure (creatinine clearance <30 mL / min) are reduced by 75%. Ritonavir should not be taken together with clarithromycin in doses exceeding 1 g / day.
Action of clarithromycin on other drugs
Antiarrhythmic drugs (quinidine and disopyramide)
Possible occurrence of ventricular tachycardia of the "pirouette" type when combined use of clarithromycin and quinidine or disopyramide.
With the simultaneous use of clarithromycin with these drugs, the electrocardiogram should be monitored regularly to increase the QT interval, and the serum concentrations of these drugs should be monitored.
Interactions caused by the isoenzyme CYP3A
The combined use of clarithromycin, which is known to inhibit the isoenzyme CYP3A, and drugs primarily metabolized by the isoenzyme CYP3A, can be associated with a mutual increase in their concentrations, which can enhance or prolong both the therapeutic and side effects.
Clarithromycin should be used with caution in patients receiving drugs that are substrates of the isoenzyme CYP3A, especially if the substrate isoenzyme CYP3A has a narrow therapeutic range (for example, carbamazepine), and / or is extensively metabolized by this isoenzyme. In case of need, correction of the dose of the drug taken together with clarithromycin should be carried out, and joint administration of some drugs is contraindicated (see section "Contraindications").Also, if possible, monitoring of serum concentrations of drugs primarily metabolized by isoenzyme CYP3A. Metabolism of the following drugs / classes is carried out by the same isoenzyme CYP3A, as the metabolism of clarithromycin: alprazolam, astemizole, carbamazepine, cilostazol, cisapride, ciclosporin, disopyramide, ergot alkaloids, lovastatin, methylprednisolone, midazolam, omeprazole, indirect anticoagulants (for example, warfarin), pimozide, quinidine, rifabutin, sildenafil, simvastatin, tacrolimus, terfenadine, triazolam and vinblastine.
To drugs interacting in a similar manner through other isoenzymes of the cytochrome P450 system, phenytoin, theophylline and valproic acid.
Inhibitors of HMG-CoA reductase
Like other macrolides, clarithromycin increases concentrations of HMG-CoA reductase inhibitors (eg, lovastatin and simvastatin). It was reported that rare cases of rhabdomyolysis in patients taking these drugs together.
Omeprazole
Clarithromycin (500 mg every 8 hours) was tested in healthy adult volunteers in combination with omeprazole (40 mg daily).
With the combined use of clarithromycin and omeprazole, equilibrium plasma concentrations of omeprazole were increased (Cmax, AUC0-24 and T1/2 increased by 30%, 89% and 34% respectively). The average pH value in the stomach for 24 hours was 5.2 when taking omeprazole alone and 5.7 when taking omeprazole together with clarithromycin.
When receiving only 500 mg of clarithromycin every 8 hours, the average value of equilibrium concentrations of CmOh was about 3.8 mg / ml, and the average value of Cmin - about 1.8 mg / ml, the average AUC0-8 for clarithromycin was 22.9 mg / ml. The time of the maximum concentration (TCmax) and the half-life were 2.1 and 5.3 hours, respectively, with 500 mg of clarithromycin administered three times a day.
When taking clarithromycin along with omeprazole, the values Cmax, FROMmin and AUC0-8 for clarithromycin increased by 10%, 27% and 15%, respectively, compared with the values obtained with the use of clarithromycin together with placebo.
In the equilibrium state, the concentrations of clarithromycin on the gastric mucosa 6 hours after taking the drug were approximately 25 times higher with the use of clarithromycin and omeprazole compared with the use of only clarithromycin.Six hours after taking the medication, the mean concentration of clarithromycin in the stomach tissues was 2-fold higher when taking clarithromycin with omeprazole compared with taking clarithromycin together with placebo.
Indirect anticoagulants
It is possible to enhance the effect of oral anticoagulants. If patients simultaneously receive clarithromycin and indirect anticoagulants, prothrombin time should be carefully monitored.
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. The combined use of clarithromycin with sildenafil, tadalafil or vardenafil may lead to an increase in the inhibitory effect on phosphodiesterase. When these drugs are used together, consider the possibility of reducing the dose of sildenafil, tadalafil and vardenafil.
Theophylline, carbamazepine
It is possible to increase the concentration of theophylline or carbamazepine in the systemic circulation.
Tolterodin
Primary metabolism of tolterodine is via isoenzyme CYP2D6. However, in a 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 serum concentrations of tolterodine. In a population with a low isoenzyme activity CYP2D6, a dose reduction of tolterodine in the presence of inhibitors of the isoenzyme CYP3A, such as clarithromycin.
Triazolobenzodiazepines (for example, alprazolam, midazolam, triazolam)
When combined with 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 oral administration. It is necessary to avoid joint intake of the oral form of midazolam and clarithromycin. If intravenous administration of midazolam is simultaneously assigned clarithromycin, the patient's condition should be carefully monitored for possible dose adjustment. 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 combined use of clarithromycin and triazolam, an effect on the central nervous system, for example, drowsiness and confusion, is possible. Interaction with other drugs
Colchicine
Colchicine is a substrate as an isoenzyme CYP3A, and the carrier protein responsible for excretion of the drug, P-glycoprotein (P-gp). It is known that clarithromycin and other macrolides inhibit isoenzyme CYP3A and P-gp. When co-administered with clarithromycin and colchicine, inhibition of P-gp and / or isoenzyme CYP3A may lead to an increase in the effect of colchicine.
Post-marketing reports on cases of colchicine overdose during its simultaneous administration with clarithromycin were registered, especially in elderly patients. Some of these cases occurred in patients with renal insufficiency. As reported, some cases ended in a fatal outcome.
Digoxin
It is assumed that digoxin is a substratum for P-gp. It is known that clarithromycin inhibits P-gp. When co-administered with clarithromycin and digoxin, inhibition P-gp clarithromycin may lead to an increase in the action of digoxin. Joint reception of digoxin and clarithromycin can also lead to increased serum digoxin concentration in patients, to the development of clinical symptoms of a digoxin overdose, including potentially fatal arrhythmias. When co-administered with clarithromycin and digoxin, the concentration of digoxin in the serum should be carefully monitored.
Zidovudine
Simultaneous oral administration of tablets clarithromycin and zidovudine by adult HIV-infected patients may lead to a decrease in the equilibrium concentration of zidovudine. Because the clarithromycin affects the absorption of zidovudine when taken orally, interactions can be largely avoided by the selection of doses of clarithromycin and zidovudine. This type of interaction is not found in HIV-infected children receiving clarithromycin in the form of a suspension together with zidovudine.
Bi-directional drug interactions
Atazanavir
Clarithromycin and atazanavir are substrates and inhibitors of the isoenzyme CYP3A. There is evidence of bi-directional interaction of these drugs. Simultaneous reception of clarithromycin (500 mg 2 times a day) and atazanavir (400 mg once a day) can lead to an increase AUC atazanavir by 28%, a twofold increase AUC clarithromycin, decrease AUC 14-hydroxyclarithromycin by 70%. Due to the wide therapeutic range of clarithromycin in patients with normal renal function, dose reduction is not required. In patients with moderate renal insufficiency (creatinine clearance 30-60 ml / min), the dose of clarithromycin should be reduced by 50%.
Patients with severe renal failure (creatinine clearance <30 mL / min) are reduced by 75%. Clarithromycin in doses exceeding 1000 mg per day, can not be used in conjunction with HIV protease inhibitors.
Itraconazole
Clarithromycin and itraconazole are substrates and inhibitors of the isoenzyme CYP3A. Clarithromycin can increase the concentration of itraconazole in the plasma, while itraconazole can increase the 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. The simultaneous use of clarithromycin (500 mg twice daily) and saquinavir (in soft gelatin capsules, 1200 mg three times daily) can cause an increase AUC and equilibrium CmOh saquinavir by 177% and 187%, respectively, compared with the administration of saquinavir alone. Values AUC and CmOh clarithromycin were approximately 40 % higher than with the reception of clarithromycin alone. When these two drugs are used together 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 the study of drug interactions in the isolated use of saquinavir may not correspond to the effects observed with saquinavir / ritonavir therapy.When taking saquinavir together with ritonavir, the potential effect of ritonavir on clarithromycin.
Verapamil
When combined with clarithromycin are possible: arterial hypotension, bradyarrhythmia and lactate-acidosis.