Clarithromycin-Teva (Clarithromycin-Teva)

Interaction with other medicinal products

The use is strictly contraindicated

Simultaneous use of clarithromycin with cisapride, pimozide, astemizole and terfenadine strictly contraindicated because of the possibility of severe consequences.

With the simultaneous use of clarithromycin with cisapride, pimozide, elevated plasma concentrations of these drugs may cause prolongation of the QT interval and cardiac rhythm disturbances, including ventricular tachycardia, ventricular fibrillation, and pirouette-type arrhythmias.

The effect of macrolides on the metabolism of terfenadine and astemizole has been reported, which may be the reason for an increase in the concentration of these drugs in the blood plasma and,as a consequence, the development of such adverse reactions as prolongation of the QT interval, ventricular tachycardia, ventricular fibrillation, and pirouette-type arrhythmia.

With the simultaneous use of terfenadine with clarithromycin, the concentration of the acid metabolite terfenadine in the blood plasma increases 2-3 times, which may cause an elongation of the QT interval. This interaction is noted with the simultaneous administration of astemizole with clarithromycin.

Ergotamine / dihydroergotamine (derivatives of ergot alkaloids)

In the post-marketing period, with the simultaneous use of clarithromycin with ergotamine and dihydroergotamine, cases of acute ergotism have been reported: vasospasm, ischemia of limbs and other tissues, including the CNS. The simultaneous use of clarithromycin and derivatives of ergot alkaloids is contraindicated.

Inhibitors of HMG-CoA reductase (statins)

Simultaneous use of clarithromycin with lovastatin or simvastatin is contraindicated, since these statins are actively metabolized by the isoenzyme CYP3A4 and concomitant use with clarithromycin increases their concentration in the blood plasma, which increases the risk of myopathy, including rhabdomyolysis.Reports of cases of rhabdomyolysis were obtained with the use of clarithromycin with these statins. In the event that it is impossible to avoid treatment with clarithromycin, therapy with lovastatin or simvastatin for the entire course of treatment with clarithromycin should be stopped.

Care should be taken when using clarithromycin with statins in situations where simultaneous use of clarithromycin with statins can not be avoided. It is recommended to take the lowest possible dose of statin. The use of statins, the metabolism of which does not depend on the isoenzyme CYP3A (fluvastatin). In these cases, patients should be monitored for signs and symptoms of myopathy.

The effect of other drugs on clarithromycin

Preparations 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, which leads to a decrease in its effectiveness. In addition, it is necessary to observe the activity of the isozyme of the SURCA inductor in the blood plasma, which can increase due to inhibition of the CYP3A isoenzyme by clarithromycin.With the simultaneous use of rifabutin and clarithromycin, an increase in plasma rifabutin concentration and a decrease in serum concentration of clarithromycin with an increased risk of uveitis have been observed.

The following drugs have a proven and expected effect on the concentration of clarithromycin in blood plasma; In the case of their simultaneous use with clarithromycin, dosage adjustment or alternate treatment may be required

Efavirenz, nevirapine, rifampicin, rifabutin and rifapentin

Powerful inducers 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 simultaneous 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 a low activity against the Mycobacterium avium complex (MAC), the overall activity against their pathogens may change, therefore alternative treatment should be considered for MAC treatment.

Fluconazole

With the simultaneous administration of fluconazole at a dose of 200 mg daily and clarithromycin 500 mg twice daily, the mean minimum equilibrium concentration of clarithromycin (Cmin) and AUC increased by 33% and 18%, respectively. At the same time, simultaneous administration did not significantly affect the Cmin 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

Simultaneous reception 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. At simultaneous reception of ritonavir C max, clarithromycin increased by 31%, Cmin increased 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 Do not take concomitantly with clarithromycin at a dose of more than 1 g / day.

Effect of clarithromycin on other drugs

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 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 these drugs have a narrow therapeutic range (for example, carbamazepine), and / or is extensively metabolized by this enzyme.If necessary, a dose adjustment of the drug taken with clarithromycin should be performed. Also, if possible, monitoring serum concentrations of drugs that are primarily metabolized by CYP3A should be monitored.

Metabolism of the following drugs / classes is carried out by the same isoenzyme CYP3A as the metabolism of clarithromycin, for example, alprazolam, carbamazepine, cilostazol, ciclosporin, disopyramide, derivatives of ergot alkaloids, 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 simultaneous use with clarithromycin: astemizole, cisapride, pimozide, terfenadine, lovastatin, simvastatin and derivatives of ergot alkaloids. To drugs interacting in a similar way through other isoenzymes within the cytochrome P450 system, phenytoin, theophylline and valproic acid.

Antiarrhythmics

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 detect an increase in the QT interval, and serum concentrations of these drugs should be monitored.

In the post-marketing period, cases of hypoglycemia were reported with simultaneous use with disopyramide, and therefore it is necessary to monitor the concentration of glucose in the blood.

Hypoglycemic drugs for oral administration / insulin

With the simultaneous use of clarithromycin and oral hypoglycemic agents and / or insulin, pronounced hypoglycemia can be observed. Against the background of simultaneous reception of clarithromycin and some drugs that reduce the concentration of glucose, such as nateglinide, pioglitazone, repaglinide and rosiglitazone, there may be an inhibition of the CYP3A isoenzyme with clarithromycin, which may result in hypoglycemia. Careful monitoring of glucose concentration is recommended.

Omeprazole

The use of clarithromycin (500 mg every 8 hours) in combination with omeprazole (40 mg daily) leads to an increase in equilibrium plasma concentrations of omeprazole (Cmax, AUCo-24, and T1 / 2 increased by 30%, 89% and 34%, respectively).The mean pH of the stomach for 24 hours was 5.2 with the intake of omeprazole alone and 5.7 when taking omeprazole concomitantly 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. With simultaneous use with clarithromycin, a reduction in the doses of these drugs is necessary.

Tolterodin

The primary metabolism of tolterodine is via the 2D6 isoform of cytochrome P450 (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 isozyme, a dose reduction of tolterodine may be required in the presence of CYP3A isoenzyme inhibitors such as clarithromycin.

Triazolebenzodiazepines (e.g., alprazolam, midazolam, triazolam)

With the simultaneous use of midazolam and clarithromycin in the form of tablets (500 mg twice a day), there was an increase in the aUC of midazolam: 2.7 times after iv administration of midazolam and 7 times after ingestion. It is necessary to avoid simultaneous oral administration of midazolam and clarithromycin. If, together with clarithromycin, the medication 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 simultaneous use of clarithromycin and triazolam, there may be an effect on the central nervous system, such as drowsiness and confusion. In this regard, in the case of simultaneous use, it is recommended to monitor the symptoms of CNS disorders.

Oral anticoagulants

With the simultaneous administration of warfarin and clarithromycin, bleeding may develop, a pronounced increase in the international normalized ratio (INR) and prothrombin time. In the case of simultaneous use with warfarin or other anticoagulant medications of indirect action, it is necessary to monitor INR and prothrombin time.

Other interactions

Aminoglycosides

It should be used with caution at the same time with clarithromycin other ototoxic drugs, especially aminoglycosides.

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. With concurrent administration of clarithromycin and colchicine, inhibition of Pgp and / or isoenzyme CYP3A can lead to an increase in the action of colchicine.It should monitor the development of clinical symptoms of colchicine toxicity. In patients with normal renal and hepatic function, a dose of colchicine should be lowered with simultaneous use with clarithromycin.

Digoxin

It is assumed that digoxin is a substrate for Pgp. It is known that clarithromycin inhibits Pgp. With concurrent administration of clarithromycin and digoxin, the inhibition of Pgp by clarithromycin 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 signs of digoxin toxicity, including potentially fatal arrhythmias. With the simultaneous administration of clarithromycin and digoxin, the concentration of digoxin in serum should be carefully monitored.

Zidovudine

Simultaneous ingestion of clarithromycin and zidovudine tablets with adult HIV-infected patients may lead to a decrease in the equilibrium concentration of zidovudine. 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 to be possible with the use of clarithromycin IV.

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 used simultaneously 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 CYP3A. There is evidence of bi-directional interaction of these drugs. The simultaneous use of clarithromycin (500 mg twice daily) with atazanavir (400 mg once a day) can lead to a twofold increase in the effect of clarithromycin and a 70% reduction in the effect of 14-OH-clarithromycin, with an increase in atanzanavir 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 / day, can not be used simultaneously with protease inhibitors.

Blocks of "slow" calcium channels

It must be used with caution at the same time clarithromycin and blockers of "slow" calcium channels metabolized under the action of the CYP3A4 isoenzyme (for example, verapamil, amlodipine, diltiazem) due to the risk of lowering blood pressure. Concentration in the blood plasma of both drugs increases with simultaneous application. Hypotension, bradyarrhythmias and lactic acidosis have been observed in patients taking clarithromycin and verapamil Simultaneously.

Itraconazole

Clarithromycin and itraconazole are substrates and inhibitors of CYP3A, which determines bi-directional drug interactions. 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