The use of the following drugs simultaneously with clarithromycin is contraindicated in connection with the possibility of developing serious side effects:
Cisapride, pimozide, terfenadine and astemizole
With concurrent administration of clarithromycin with cisapride, pimozide, terfenadine, or astemizole, an increase in plasma concentrations was reported, which may lead to an extended QT interval on the ECG and the appearance of cardiac arrhythmias, including ventricular tachycardia (including ventricular pirouette tachycardia) and ventricular fibrillation (see section "Contraindications").
Alkaloids of ergot
Postmarketing studies show that with the simultaneous use of clarithromycin with ergotamine or dihydroergotamine, the following effects are possible,related to acute poisoning with drugs of the group of ergotamines: vascular spasm, ischemia of limbs and other tissues, including the central nervous system. Simultaneous use of clarithromycin and ergot alkaloids is contraindicated (see the section "Contraindications"),
Inhibitors of GMC-CoA reductase (statins)
Simultaneous reception of clarithromycin with lovastatin or simvastatin is contraindicated (see "Contraindications" section) due to the fact that these statins are largely metabolized by the CYP3A4 isoenzyme and concomitant use with clarithromycin increases their serum concentrations, leading to an increased risk of myopathy, including rhabdomyolysis. There have been reports of rhabdomyolysis in patients taking clarithromycin simultaneously with these drugs. If it is necessary to use clarithromycin, stop taking lovastatin or simvastatin for the duration of therapy.
Clarithromycin should be used with caution in the case of combination therapy with other statins. It is recommended to use statins, the metabolism of which does not depend on the isoenzyme CYP3A (for example, fluvastatin).In case of the need for simultaneous administration, it is recommended to take the lowest dose of statin. It should monitor the development of signs and symptoms of myopathy.
The effect of other drugs on clarithromycin
Drugs that are inducers of the isoenzyme CYP3A (for example, rifampicin, phenytoin, carbamazepine, phenobarbital, St. John's wort pitted), can induce the metabolism of clarithromycin. This can lead to a subtherapeutic concentration of clarithromycin and, accordingly, to a decrease in its effectiveness. In addition, it is necessary to observe the concentration of the inductor of the CYP3A isoenzyme in the blood plasma, which can be increased due to inhibition of the isoenzyme CUR3A by clarithromycin. With the simultaneous use of rifabutin and clarithromycin, there was an increase in rifabutin concentration and a decrease in the concentration of clarithromycin in blood plasma with an increased risk of uveitis.
The following drugs have a proven or suspected effect on the concentration of clarithromycin in the blood plasma, in the case of their simultaneous use with clarithromycin, a dose adjustment or alternative treatment may be required:
Efavirenz, nevirapine, rifampicin, rifabutin and rifapentin
Strong inductors of the cytochrome P450 system, such as efavirenz, nevirapine, rifampicin, rifabutin and rifapentin can accelerate the metabolism of clarithromycin and. thus, to reduce the concentration of clarithromycin in the blood plasma and to weaken the therapeutic effect, and at the same time to increase the concentration in the blood plasma of the 14-OH-clarithromycin metabolite, which is also microbiologically active. Since the microbiological activity of clarithromycin and 14-OH-clarithromycin differs with respect to different bacteria, the therapeutic effect may decrease with the simultaneous use of clarithromycin and inducers of the cytochrome P450 system.
Etravirine
The concentration of clarithromycin in the blood plasma decreases with simultaneous use with etravirine, but the concentration in the blood plasma of the active metabolite of 14-OH-clarithromycin increases. Since 14-OH-clarithromycin has low activity against MAC infections, the overall activity against these pathogens may change, therefore alternative treatment should be considered for MAC treatment.
Fluconazole
The simultaneous administration of fluconazole at a dose of 200 mg daily and clarithromycin 500 mg twice daily in 21 healthy volunteers resulted in an increase in the mean minimum concentration of clarithromycin (Cmin) and AUC by 33% and 18% respectively. At the same time, simultaneous administration did not significantly affect the average equilibrium concentration of the active metabolite of 14-OH-clarithromycin. Correction of the dose of clarithromycin in the case of simultaneous administration of fluconazole is not required.
Ritonavir
A pharmacokinetic study showed that simultaneous reception of ritonavir at a dose of 200 mg every 8 hours and clarithromycin and a dose of 500 mg every 12 hours led to a marked suppression of the metabolism of clarithromycin. With simultaneous reception of ritonavir Cmax clarithromycin increased by 31%, Cmin increased by 182% and AUC increased by 77%. The complete suppression of the formation of 14-OH-clarithromycin was noted. Due to the wide therapeutic range of clarithromycin, a reduction in its dose in patients with normal renal function is not required. In patients with renal insufficiency, it is advisable to consider the following options for dose adjustment: with a QC of 30-60 ml / min, the dose of clarithromycin should be reduced by 50%.
Ritonavir should not be taken concomitantly with clarithromycin at doses exceeding 1 g / day.
Action of clarithromycin on other drugs
Antiarrhythmic drugs (quinidine and disopyramide)
Possible occurrence of ventricular tachycardia such as "pirouette" with simultaneous use of clarithromycin and quinidine or disopyramide. With the simultaneous use of clarithromycin with these drugs, ECG monitoring should be performed regularly to prolong the QT interval, and serum concentrations of these drugs should be monitored.
In post-marketing use, cases of development of hypoglycemia were reported with concurrent administration of clarithromycin and disopyramide. It is necessary to monitor the concentration of glucose to the blood with the simultaneous use of clarithromycin and disopyramide.
Hypoglycemic agents for ingestion / insulin
With the simultaneous use of clarithromycin and hypoglycemic agents for oral administration (eg, sulfonylurea derivatives) and / or insulin, pronounced hypoglycemia can be observed. Simultaneous use of clarithromycin with some hypoglycemic drugs (for example, nateglinide, pioglitazone, repaglinide and rosiglitazone) can lead to inhibition of the CYP3A isoenzyme by clarithromycin, which can lead to hypoglycemia. A careful control of the concentration of glucose in the blood is recommended.
Interactions caused by the isoenzyme CYP3A
Simultaneous reception of clarithromycin, which is known to inhibit the CYP3A isoenzyme, and drugs primarily metabolized by the CYP3A isoenzyme, can be associated with a mutual increase in their copy of grace, which can enhance or prolong both therapeutic, hacking and side effects. Clarithromycin should be used with caution in patients receiving drugs that are substrates of the isoenzyme CYP3A, especially if these drugs have a narrow therapeutic range (for example, carbamazepine), and / or drugs that are intensely metabolized by this isoenzyme. If necessary, a dose adjustment of the drug taken concomitantly with clarithromycin should be performed. Also, if possible, monitoring of serum concentrations of drugs that are primarily metabolized by the CYP3A isoenzyme should be conducted.
Metabolism of the following drugs / classes is carried out by the same isoenzyme CYP3A as the metabolism of clarithromycin: alprazolam, carbamazepine, cilostazol, ciclosporin, disopyramide, methylprednisolone, midazolam, omeprazole, indirect anticoagulants (for example, warfarin), quinidine, rifabutin, sildenafil, tacrolimus, triazolam and vinblastine. Also, inhibitors of the isoenzyme CYP3A include the following drugs, contraindicated for simultaneous use with clarithromycin: astemizole, cisapride, pimozide, terfenadine, lovastatin, simvastatin and ergot alkaloids (see the section "Contraindications"). To drugs interacting in a similar manner through other isoenzymes within the cytochrome P450 system include: phenytoin, theophylline and valproic acid.
Indirect anticoagulants
With the simultaneous administration of warfarin and clarithromycin, bleeding, a marked increase in INR and prolongation of prothrombin time is possible. In the case of simultaneous use with warfarin or other indirect anticoagulants, it is necessary to monitor MNO and prothrombin time.
Omeprazole
Clarithromycin (500 mg every 8 hours) was tested in healthy adult volunteers in combination with omeprazole (40 mg daily). With simultaneous 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 of the stomach for 24 hours was 5.2 (with omeprazole alone) and 5.7 (with omeprazole simultaneously with clarithromycin).
Sildenafil, tadalafil and vardenafil
Each of these phosphodiesterase inhibitors is metabolized, at least in part, by the participation of the CYP3A isoenzyme. At the same time, the CYP3A isoenzyme can be inhibited in the presence of clarithromycin. Simultaneous use of clarithromycin with sildenafil, tadalafil or vardenafil may lead to an increase in the inhibitory effect on phosphodiesterase. When using these drugs simultaneously with clarithromycin, the possibility of reducing the dose of sildenafil, tadalafil and vardenafil should be considered.
Theophylline, carbamazepine
With the simultaneous use of clarithromycin and theophylline or carbamazepine, an increase in the concentration of these drugs in the systemic circulation is possible.
Tolterodin
The primary metabolism of tolterodine is via the isoenzyme CYP2D6. However, in the part of the population devoid of the isoenzyme CYP2D6, the metabolism occurs through the isoenzyme CYP3A. In this population, suppression of the CYP3A isoenzyme results in significantly higher serum concentrations of tolterodine. In a population with a low level of metabolism via the CYP2D6 isoenzyme, a dose reduction of tolterodine may be required while using CYP3A isoenzyme inhibitors, such as clarithromycin.
Benzodiazepines (e.g., alprazolam, midazolam, triazolam)
With the simultaneous use of midazolam and clarithromycin tablets (500 mg twice daily), an increase in midazolam AUC was observed: 2.7 times after intravenous administration of midazolam and 7 times after oral administration. The simultaneous use of clarithromycin with midazolam for oral administration is contraindicated. If concurrent with clarithromycin is used midazolam in the form of a drug - a solution for intravenous administration, the patient's condition should be carefully monitored for the possible correction of the dose of midazolam. The same precautions should also be applied to other benzodiazepines that are metabolized by the CYP3A isoenzyme, including triazolam and alprazolam. For benzodiazepines, the excretion of which does not depend on the isoenzyme CYP3A (temazepam, nitrazepam, lorazepam), clinically significant interaction with clarithromycin is unlikely.
With the simultaneous use of clarithromycin and triazolam, there may be an effect on the central nervous system, for example, drowsiness and confusion. In this regard, in the case of simultaneous use, it is recommended to monitor the symptoms of violation of the DSP.
Interactions with other drugs
Aminoglycosides
With simultaneous reception of clarithromycin with other ototoxic drugs.
especially aminoglycosides, care must be taken to monitor the functions of the vestibular and hearing aids, both during therapy and after its termination.
Colchicine
Colchicine is a substrate for both the proenzyme CYP3A and the carrier protein P-glycoprotein (Pgp). It is known that clarithromycin and other macrolides are inhibitors of the isoenzyme CYP3A and Pgp. With the simultaneous use of clarithromycin and colchicine, inhibition of Pgp and / or isoenzyme CYP3A can lead to increased colchicine action. It should monitor the development of clinical symptoms of colchicine poisoning.Post-marketing reports on cases of colchicine poisoning with its simultaneous administration with clarithromycin are registered, more often in elderly patients. Some of these cases occurred with patients suffering from kidney failure. As reported, some cases ended in a fatal outcome. Simultaneous use of clarithromycin and colchicine is contraindicated (see section "Contraindications").
Digoxin
It is assumed that digoxin is the substrate of Pgp. It is known that clarithromycin inhibits Pgp. With the simultaneous use of clarithromycin and digoxin, inhibition of Pgplarithromycin may lead to an increase in the action of digoxin. The simultaneous administration of digoxin and clarithromycin can also lead to an increase in serum digoxin concentration. Some patients experienced clinical symptoms of digoxin poisoning. including potentially fatal arrhythmias. With the simultaneous administration of clarithromycin and digoxin, the concentration of digoxin in serum should be carefully monitored.
Zidovudine
Simultaneous reception of clarithromycin and zidovudine tablets inside adult HIV-infected patients can lead todecrease in the equilibrium concentration of zidovudine in blood plasma. Because the clarithromycin influences the absorption of zidovudine when ingested, interactions can be largely avoided by taking clarithromycin and zidovudine with an interval of 4 hours. Similar interaction was not observed in HIV-infected children who took a children's suspension of clarithromycin with zidovudine or dideoxyinosine. Because the clarithromycin may interfere with the absorption of zidovudine when administered simultaneously in adults in adults, this interaction is unlikely with the use of clarithromycin intravenously.
Phenytoin and valproic acidThere are data on the interaction of inhibitors of the isoenzyme CYP3A (including
clarithromycin) with drugs that are not metabolized by the CYP3A isoenzyme (phenytoin and valproic acid). For these drugs with simultaneous application with clarithromycin, it is recommended to determine their serum concentrations, since there are reports of their increase.
Bi-directional interaction of drugs
Atazanavir
Clarithromycin and atazanavir are both substrates and inhibitors of the CYP3A isoenzyme. There is evidence of bi-directional interaction of these drugs. The simultaneous use of clarithromycin (500 mg twice daily) and atazanavir (400 mg once a day) can lead to a twofold increase in the effect of clarithromycin and a reduction in the effect of 14-OH-clarithromycin by 70% with an increase in Atazanavir AUC by 28%. Due to the wide therapeutic range of clarithromycin, reducing its dose in patients with normal renal function is not required. In patients with moderate renal insufficiency (KK 30-60 ml / min), the dose of clarithromycin should be reduced by 50%. In patients with QC less than 30 ml / min, the dose of clarithromycin should be reduced by 75%, using the appropriate dosage form of clarithromycin for this. Clarithromycin in doses exceeding 1000 mg / day, can not be used simultaneously with protease inhibitors.
Blocks of "slow" calcium channels
With the simultaneous use of clarithromycin and blockers of "slow" calcium channels, which are metabolized by the isoenzyme CYP3A4 (for example, verapamil, amlodipine, diltiazem), you should be careful, since there is a risk of arterial hypotension. With simultaneous use, plasma concentrations of clarithromycin and "slow" calcium channel blockers can increase. Arterial hypotension, bradyarrhythmia and lactic acidosis are possible with concurrent administration of clarithromycin and verapamil.
Itraconazole
Clarithromycin and
itraconazole are substrates and inhibitors of the CYP3A isoenzyme, which determines the bi-directional interaction of the drugs.
Clarithromycin can increase the concentration of itraconazole in the blood plasma, while
itraconazole can increase the plasma concentration of clarithromycin. Patients simultaneously taking
itraconazole and
clarithromycin, should be carefully examined for signs of increased or prolonged pharmacological effects of these drugs.
Saquinavir
Clarithromycin and saquinavir are substrates and inhibitors of the CYP3A isoenzyme, which determines the bi-directional interaction of the drugs. The simultaneous use of clarithromycin (500 mg twice daily) and saquinavir (in soft gelatin capsules, 1200 mg 3 times a day) in 12 healthy volunteers caused an increase in AUC and Cmax saquinavir in blood plasma by 177% and 187%, respectively, compared with the administration of saquinavir alone. The values of AC and Cmax clarithromycin were approximately 40% higher than with single clarithromycin alone. With the simultaneous use of these two drugs for a limited time in the doses / formulations mentioned above, dose adjustment is not required. The results of a study of drug interactions using saquinavir in soft gelatin capsules may not correspond to the effects observed with saquinavir in hard gelatin capsules. The results of drug interaction studies with saquinavir alone may not correspond to the effects observed with saquinavir / ritonavir combination therapy. When taking saquinavir concomitantly with ritonavir, the potential effect of ritonavir on clarithromycin.