The use of the following drugs in conjunction with clarithromycin is contraindicated in connection with the possibility of developing serious side effects
Cisapride, pimozide, terfenadine and astemizole
With the concomitant use of clarithromycin with cisapride, pimozide, terfenadine, or astemizole, an increase in plasma concentrations was reported, which may lead to prolongation of the QT interval and the occurrence of cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation, and ventricular pirouette tachycardia (see section "Contraindications"),
Alkaloids of ergot
Postmarketing studies show that with the combined use of clarithromycin with ergotamine or dihydroergotamine, the following effects associated with acute poisoning with drugs of the ergotamine group are possible: vascular spasm, ischemia of limbs and other tissues, including the central nervous system. Simultaneous reception of clarithromycin with ergot alkaloids is contraindicated (see section "Contraindications").
Inhibitors of HMG-CoA reductase (statins)
Simultaneous reception of clarithromycin with lovastatin or simvastatin is contraindicated (see the section "Contraindications") due to the fact that these statins are largely metabolized by the isoenzyme CYP3A4, and the combined use with clarithromycin increases their serum concentrations, which leads to an increased risk of myopathy, including rhabdomyolysis. There have been reports of rhabdomyolysis in patients taking clarithromycin together 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 combination therapy with other statins.It is recommended to use statins that are independent of the metabolism of the CYP3A isoenzyme (for example, fluvastatin). In case of need for joint intake, 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
Preparations that are inducers of the isoenzyme CYP3A (eg, rifampicin, phenytoin, carbamazepine, phenobarbital, St. John's wort pitted), can induce the metabolism of clarithromycin. This can lead to a subtherapeutic concentration of clarithromycin, which leads to a decrease in its effectiveness. In addition, it is necessary to monitor the concentration of the inductor of the CYP3A isoenzyme in the blood plasma, which can be increased due to inhibition of the CYP3A isoenzyme by clarithromycin. With the combined use of rifabutin and clarithromycin, there was an increase in plasma rifabutin concentration and a decrease in serum concentration of clarithromycin 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 joint application withclarithromycin may require dose adjustments or alternate treatment
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 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 combined use of clarithromycin and enzyme inducers.
Etravirine
The concentration of clarithromycin decreases with the use of etravirine, but the concentration of the active metabolite of 14-OH-clarithromycin increases. Since 14-OH-clarithromycin has low activity against Mycobacterium avium complex (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 equilibrium concentration of clarithromycin (Cmin) 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-OH-clarithromycin. Correction of the dose of clarithromycin in the case of concurrent administration of fluconazole is not required.
Ritonavir
A pharmacokinetic study showed that a joint intake of ritonavir at a dose of 200 mg every eight 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 Cmaxclarithromycin increased by 31%, Cminincreased by 182% and AUC increased by 77%. A 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%; with QC less than 30 ml / min, the dose of clarithromycin should be 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 concurrent administration of clarithromycin with these drugs, the electrocardiogram should be monitored regularly for prolonged QT intervals, and serum concentrations of these drugs should be monitored.
In post-marketing applications, cases of hypoglycemia were reported with the combined use of clarithromycin and disopyramide. It is necessary to monitor the concentration of glucose in the blood with the simultaneous use of clarithromycin and disopyramide.
Oral hypoglycemic agents / insulin
With the combined use of clarithromycin and oral hypoglycemic agents (eg, sulfonylureas) 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. Careful monitoring of glucose concentration is recommended.
Interactions caused by the isoenzyme CYP3A
The combined use 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 concentrations, which may 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 these drugs have a narrow therapeutic range (for example, carbamazepine), and / or are extensively metabolized by this enzyme. If necessary, a dose adjustment of the drug taken 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,and the metabolism of clarithromycin, for example, alprazolam, carbamazepine, cilostazol, ciclosporin, disopyramide, methylprednisolone, midazolam, omeprazole, indirect anticoagulants (for example, warfarin), quinidine, rifabutin, sildenafil, tacrolimus, triazolam and vinblastine. Also, the agonists of the CYP3A isoenzyme are the following drugs that are contraindicated for joint use with clarithromycin: astemizole, cisapride, pimozide, terfenadine, lovastatin, simvastatin and ergot alkaloids (see the section "Contraindications"), drugs interacting in a similar way through other isoenzymes within the cytochrome P450 system include phenytoin, theophylline and valproic acid.
Indirect anticoagulants
With the concomitant administration of warfarin and clarithromycin, bleeding is possible, a marked increase in INR and prothrombin time. In the case of combined use with warfarin or other indirect anticoagulants, it is necessary to monitor INR and prothrombin time.
Omeprazole
Clarithromycin (500 mg every 8 hours) was tested in healthy adult volunteers in combination with omeprazole (40 mg daily).With the combined use of clarithromycin and omeprazole, equilibrium plasma concentrations of omeprazole were increased (Cmax , AUC0-24 uT1/2 increased by 30%, 89% and 34% respectively). The average pH value of the stomach for 24 hours was 5.2 when taking omeprazole alone and 5.7 when taking omeprazole together 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. The combined use of clarithromycin with sildenafil, tadalafil or vardenafil may lead to an increase in the inhibitory effect on phosphodiesterase. When using these drugs together with clarithromycin should consider the possibility of reducing the dose of sildenafil, tadalafil and vardenafil.
Theophylline, carbamazepine
With the combined 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 2D6 cytochrome P450 isoform (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 isozyme, a dose reduction of tolterodine may be required in the presence of CYP3A isoenzyme inhibitors such as clarithromycin.
Benzodiazepines (e.g., alprazolam, midazolam, triazolam)
When combined with midazolam and clarithromycin tablets (500 mg twice daily), augmentation of midazolam AUC was noted: 2.7 times after intravenous administration of midazolam and 7 times after oral administration. Simultaneous reception of clarithromycin with midazolam for oral administration is contraindicated. If, together with clarithromycin, the intravenous form of midazolam is used, the patient's condition should be carefully monitored for possible dose adjustment. 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 combined use of clarithromycin and triazolam, an effect on the central nervous system (CNS) is possible, for example, drowsiness and confusion. In this regard, in the case of joint application, it is recommended to follow the symptoms of the CNS disorder.
Interactions with other drugs
Aminoglycosides
With the simultaneous administration 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 CYP3A isoenzyme and the P-glycoprotein carrier protein (Pgp). It is known that clarithromycin and other macrolides are inhibitors of the isoenzyme CYP3A and Pgp. When co-administered with 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 during 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. When co-administered with clarithromycin and digoxin, inhibition of Pgp with clarithromycin may lead to an increase in the action of digoxin. The combined use 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. When co-administered with clarithromycin and digoxin, the concentration of digoxin in the serum should be carefully monitored.
Zidovudine
Simultaneous reception of tablets of clarithromycin and zidovudine by oral HIV-infected adults can lead to a decrease in the equilibrium concentration of zidovudine.
Because the clarithromycin influences the absorption of zidovudine when taken orally, 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 hardly possible with the use of clarithromycin intravenously.
Phenytoin and valproic acid
There are data on the interactions 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, when combined with clarithromycin, it is recommended to determine their serum concentrations, since there are reports of their increase.
Bi-directional drug interactions
Atazanavir
Clarithromycin and atazanavir are both substrates and inhibitors of the CYP3A isoenzyme. There is evidence of bi-directional interaction of these drugs.
The combined 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, a reduction in its dose in patients with normal renal function is not required. In patients with moderate renal failure (CK 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. Clarithromycin in doses exceeding 1000 mg per day, can not be used in conjunction 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. Plasma concentrations of clarithromycin, as well as blockers of "slow" calcium channels, can increase with simultaneous application.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 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 three times daily) in 12 healthy volunteers caused an increase in AUC and Cmax saquinavir by 177% and 187%, respectively, compared with the administration of saquinavir alone. The values of AUC and Cmax clarithromycin were approximately 40% higher than with monotherapy with clarithromycin.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 with saquinavir monotherapy may not correspond to the effects observed with saquinarine / ritonavir therapy. When taking saquinavir together with ritonavir, the potential effect of ritonavir on clarithromycin.