Klacid Drug Interactions

Film-coated tablet and Granules for oral suspension: The use of the following drugs is strictly contraindicated due to the potential for severe drug interaction effects: Astemizole, cisapride, domperidone, pimozide, and terfenadine: Elevated cisapride levels have been reported in patients receiving clarithromycin and cisapride concomitantly. This may result in QT prolongation and cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation and torsades de pointes. Similar effects have been observed in patients taking clarithromycin and pimozide concomitantly (see Contraindications).
Macrolides have been reported to alter the metabolism of terfenadine resulting in increased levels of terfenadine which has occasionally been associated with cardiac arrhythmias, such as QT prolongation, ventricular tachycardia, ventricular fibrillation and torsades de pointes (see Contraindications). In one study in 14 healthy volunteers, the concomitant administration of clarithromycin and terfenadine resulted in 2- to 3-fold increase in the serum level of the acid metabolite of terfenadine and in prolongation of the QT interval which did not lead to any clinically detectable effect. Similar effects have been observed with concomitant administration of astemizole and other macrolides.
Ergot alkaloids: Post-marketing reports indicate that co-administration of clarithromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm, and ischaemia of the extremities and other tissues including the central nervous system. Concomitant administration of clarithromycin and ergot alkaloids is contraindicated (see Contraindications).
Oral Midazolam: When midazolam was co-administered with clarithromycin tablets (500 mg twice daily), midazolam AUC was increased 7-fold after oral administration of midazolam. Concomitant administration of oral midazolam and clarithromycin is contraindicated (see Contraindications).
HMG-CoA Reductase Inhibitors (statins): Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated (see Contraindications) as these statins are extensively metabolized by CYP3A4 and concomitant treatment with clarithromycin increases their plasma concentration, which increases the risk of myopathy, including rhabdomyolysis. Reports of rhabdomyolysis have been received for patients taking clarithromycin concomitantly with these statins. If treatment with clarithromycin cannot be avoided, therapy with lovastatin or simvastatin must be suspended during the course of treatment.
Caution should be exercised when prescribing clarithromycin with statins. In situations where the concomitant use of clarithromycin with statins cannot be avoided, it is recommended to prescribe the lowest registered dose of the statin. Use of a statin that is not dependent on CYP3A metabolism (e.g. fluvastatin) can be considered. Patients should be monitored for signs and symptoms of myopathy.
Effects of Other Medicinal Products on Clarithromycin: Drugs that are inducers of CYP3A (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital, St John's wort) may induce the metabolism of clarithromycin. This may result in sub-therapeutic levels of clarithromycin leading to reduced efficacy. Furthermore, it might be necessary to monitor the plasma levels of the CYP3A inducer, which could be increased owing to the inhibition of CYP3A by clarithromycin (see also the relevant product information for the CYP3A4 inducer administered). Concomitant administration of rifabutin and clarithromycin resulted in an increase in rifabutin, and decrease in clarithromycin serum levels together with an increased risk of uveitis.
The following drugs are known or suspected to affect circulating concentrations of clarithromycin; clarithromycin dosage adjustment or consideration of alternative treatments may be required.
Efavirenz, nevirapine, rifampicin, rifabutin and rifapentine: Strong inducers of the cytochrome P450 metabolism system such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine may accelerate the metabolism of clarithromycin and thus lower the plasma levels of clarithromycin, while increasing those of 14-OH-clarithromycin, a metabolite that is also microbiologically active. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers.
Etravirine: Clarithromycin exposure was decreased by etravirine; however, concentrations of the active metabolite, 14-OH-clarithromycin, were increased. Because 14-OH-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered; therefore, alternatives to clarithromycin should be considered for the treatment of MAC.
Fluconazole: Concomitant administration of fluconazole 200 mg daily and clarithromycin 500 mg twice daily to 21 healthy volunteers led to increases in the mean steady-state minimum clarithromycin concentration (C_min) and area under the curve (AUC) of 33% and 18% respectively. Steady state concentrations of the active metabolite 14-OH-clarithromycin were not significantly affected by concomitant administration of fluconazole. No clarithromycin dose adjustment is necessary.
Ritonavir: A pharmacokinetic study demonstrated that the concomitant administration of ritonavir 200 mg every eight hours and clarithromycin 500 mg every 12 hours resulted in a marked inhibition of the metabolism of clarithromycin. The clarithromycin C_max increased by 31%, C_min increased 182% and AUC increased by 77% with concomitant administration of ritonavir. An essentially complete inhibition of the formation of 14-OH-clarithromycin was noted. Because of the large therapeutic window for clarithromycin, no dosage reduction should be necessary in patients with normal renal function. However, for patients with renal impairment, the following dosage adjustments should be considered: For patients with CL_CR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. For patients with CL_CR <30 mL/min the dose of clarithromycin should be decreased by 75%. Doses of clarithromycin greater than 1 g/day should not be co-administered with ritonavir.
Similar dose adjustments should be considered in patients with reduced renal function when ritonavir is used as a pharmacokinetic enhancer with other HIV protease inhibitors including atazanavir and saquinavir (see Bi-directional drug interactions as follows).
Effect of Clarithromycin on Other Medicinal Products: CYP3A-based interactions: Co-administration of clarithromycin, which is known to inhibit CYP3A, and a drug primarily metabolised by CYP3A may be associated with elevations in drug concentrations that could increase or prolong both therapeutic and adverse effects of the concomitant drug.
The use of clarithromycin is contraindicated in patients receiving the CYP3A substrates astemizole, cisapride, domperidone, pimozide and terfenadine due to the risk of QT prolongation and cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation, and torsades de pointes (see Contraindications and Precautions).
The use of clarithromycin is also contraindicated with ergot alkaloids, oral midazolam, HMG CoA reductase inhibitors metabolised mainly by CYP3A4 (e.g. lovastatin and simvastatin), colchicine, ticagrelor and ranolazine (see Contraindications).
Concomitant administration of clarithromycin with lomitapide is contraindicated due to the potential for markedly increased transaminases (see Contraindications).
Caution is required if clarithromycin is co-administered with other drugs known to be CYP3A enzyme substrates, especially if the CYP3A substrate has a narrow safety margin (e.g. carbamazepine) and/or the substrate is extensively metabolised by this enzyme. Dosage adjustments may be considered, and when possible, serum concentrations of drugs primarily metabolised by CYP3A should be monitored closely in patients concurrently receiving clarithromycin. Drugs or drug classes that are known or suspected to be metabolised by the same CYP3A isozyme include (but this list is not comprehensive) alprazolam, carbamazepine, cilostazole, ciclosporin, disopyramide, ibrutinib, methadone, methylprednisolone, midazolam (intravenous), omeprazole, oral anticoagulants (e.g. warfarin, rivaroxaban, apixaban), atypical antipsychotics (e.g. quetiapine), quinidine, rifabutin, sildenafil, sirolimus, tacrolimus, triazolam and vinblastine.
Drugs interacting by similar mechanisms through other isozymes within the cytochrome P450 system include phenytoin, theophylline and valproate.
Antiarrhythmics: There have been post-marketing reports of torsades de pointes occurring with the concurrent use of clarithromycin and quinidine or disopyramide. Electrocardiograms should be monitored for QT prolongation during co-administration of clarithromycin with these drugs. Serum levels of quinidine and disopyramide should be monitored during clarithromycin therapy.
There have been post marketing reports of hypoglycemia with the concomitant administration of clarithromycin and disopyramide. Therefore, blood glucose levels should be monitored during concomitant administration of clarithromycin and disopyramide.
Oral hypoglycemic agents/Insulin: With certain hypoglycemic drugs such as nateglinide, and repaglinide, inhibition of CYP3A enzyme by clarithromycin may be involved and could cause hypoglycaemia when used concomitantly. Careful monitoring of glucose is recommended.
Omeprazole: Clarithromycin (500 mg every 8 hours) was given in combination with omeprazole (40 mg daily) to healthy adult subjects. The steady-state plasma concentrations of omeprazole were increased (C_max, AUC_0-24, and t_1/2 increased by 30%, 89%, and 34%, respectively), by the concomitant administration of clarithromycin. The mean 24-hour gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when omeprazole was co-administered with clarithromycin.
Direct acting oral anticoagulants (DOACs): The DOAC dabigatran is a substrate for the efflux transporter P-gp. Rivaroxaban and apixaban are metabolised via CYP3A4 and are also substrates for P-gp. Caution should be exercised when clarithromycin is co-administered with these agents particularly to patients at high risk of bleeding (see Precautions).
Sildenafil, tadalafil and vardenafil: Each of these phosphodiesterase inhibitors is metabolised, at least in part, by CYP3A, and CYP3A may be inhibited by concomitantly administered clarithromycin. Co-administration of clarithromycin with sildenafil, tadalafil or vardenafil would likely result in increased phosphodiesterase inhibitor exposure. Reduction of sildenafil, tadalafil and vardenafil dosages should be considered when these drugs are co-administered with clarithromycin.
Theophylline, carbamazepine: Results of clinical studies indicate that there was a modest but statistically significant (p≤0.05) increase of circulating theophylline or carbamazepine levels when either of these drugs were administered concomitantly with clarithromycin. Dose reduction may need to be considered.
Tolterodine: The primary route of metabolism for tolterodine is via the 2D6 isoform of cytochrome P450 (CYP2D6). However, in a subset of the population devoid of CYP2D6, the identified pathway of metabolism is via CYP3A. In this population subset, inhibition of CYP3A results in significantly higher serum concentrations of tolterodine. A reduction in tolterodine dosage may be necessary in the presence of CYP3A inhibitors, such as clarithromycin in the CYP2D6 poor metaboliser population.
Triazolobenzodiazepines (e.g., alprazolam, midazolam, triazolam): When midazolam was co-administered with clarithromycin tablets (500 mg twice daily), midazolam AUC was increased 2.7-fold after intravenous administration of midazolam. If intravenous midazolam is co-administered with clarithromycin, the patient must be closely monitored to allow dose adjustment. Drug delivery of midazolam via oromucosal route, which could bypass pre-systemic elimination of the drug, will likely result in a similar interaction to that observed after intravenous midazolam rather than oral administration. The same precautions should also apply to other benzodiazepines that are metabolised by CYP3A, including triazolam and alprazolam. For benzodiazepines which are not dependent on CYP3A for their elimination (temazepam, nitrazepam, lorazepam), a clinically important interaction with clarithromycin is unlikely.
There have been post-marketing reports of drug interactions and central nervous system (CNS) effects (e.g., somnolence and confusion) with the concomitant use of clarithromycin and triazolam. Monitoring the patient for increased CNS pharmacological effects is suggested.
Other drug interactions: Colchicine: Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. When clarithromycin and colchicine are administered together, inhibition of Pgp and/or CYP3A by clarithromycin may lead to increased exposure to colchicine (see Contraindications and Precautions).
Digoxin: Digoxin is thought to be a substrate for the efflux transporter, P-glycoprotein (Pgp). Clarithromycin is known to inhibit Pgp. When clarithromycin and digoxin are administered together, inhibition of Pgp by clarithromycin may lead to increased exposure to digoxin. Elevated digoxin serum concentrations in patients receiving clarithromycin and digoxin concomitantly have also been reported in post marketing surveillance. Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Serum digoxin concentrations should be carefully monitored while patients are receiving digoxin and clarithromycin simultaneously.
Zidovudine: Simultaneous oral administration of clarithromycin tablets and zidovudine to HIV-infected adult patients may result in decreased steady-state zidovudine concentrations. Because clarithromycin appears to interfere with the absorption of simultaneously administered oral zidovudine, this interaction can be largely avoided by staggering the doses of clarithromycin and zidovudine to allow for a 4-hour interval between each medication. This interaction does not appear to occur in paediatric HIV-infected patients taking clarithromycin suspension with zidovudine or dideoxyinosine. This interaction is unlikely when clarithromycin is administered via intravenous infusion.
Phenytoin and Valproate: There have been spontaneous or published reports of interactions of CYP3A inhibitors, including clarithromycin with drugs not thought to be metabolised by CYP3A (e.g. phenytoin and valproate). Serum level determinations are recommended for these drugs when administered concomitantly with clarithromycin. Increased serum levels have been reported.
Hydroxychloroquine and Chloroquine: Observational data have shown that co-administration of azithromycin with hydroxychloroquine in patients with rheumatoid arthritis is associated with an increased risk of cardiovascular events and cardiovascular mortality. Because of the potential for a similar risk with other macrolides when used in combination with hydroxychloroquine or chloroquine, careful consideration should be given to the balance of benefits and risks before prescribing clarithromycin for any patients taking hydroxychloroquine or chloroquine.
Bi-directional drug interactions: Atazanavir: Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction. Co-administration of clarithromycin (500 mg twice daily) with atazanavir (400 mg once daily) resulted in a 2-fold increase in exposure to clarithromycin and a 70% decrease in exposure to 14-OH-clarithromycin, with a 28% increase in the AUC of atazanavir. Because of the large therapeutic window for clarithromycin, no dosage reduction should be necessary in patients with normal renal function. For patients with moderate renal function (creatinine clearance 30 to 60 mL/min), the dose of clarithromycin should be decreased by 50%. For patients with creatinine clearance <30 mL/min, the dose of clarithromycin should be decreased by 75% using an appropriate clarithromycin formulation. Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors.
Calcium Channel Blockers: Caution is advised regarding the concomitant administration of clarithromycin and calcium channel blockers metabolized by CYP3A4 (e.g. verapamil, amlodipine, diltiazem) due to the risk of hypotension. Plasma concentrations of clarithromycin as well as calcium channel blockers may increase due to the interaction. Hypotension, bradyarrhythmias and lactic acidosis have been observed in patients taking clarithromycin and verapamil concomitantly.
Itraconazole: Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A, leading to a bidirectional drug interaction. Clarithromycin may increase the plasma levels of itraconazole, while itraconazole may increase the plasma levels of clarithromycin.
Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged pharmacologic effect.
Saquinavir: Both clarithromycin and saquinavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction. Concomitant administration of clarithromycin (500 mg twice daily) and saquinavir (soft gelatin capsules, 1200 mg three times daily) to 12 healthy volunteers resulted in steady-state AUC and C_max values of saquinavir which were 177% and 187% higher than those seen with saquinavir alone. Clarithromycin AUC and C_max values were approximately 40% higher than those seen with clarithromycin alone. No dose adjustment is required when the two drugs are co-administered for a limited time at the doses/formulations studied. Observations from drug interaction studies using the soft gelatin capsule formulation may not be representative of the effects seen using the saquinavir hard gelatin capsule. Observations from drug interaction studies performed with saquinavir alone may not be representative of the effects seen with saquinavir/ritonavir therapy. When saquinavir is co-administered with ritonavir, consideration should be given to the potential effects of ritonavir on clarithromycin (see Ritonavir as previously mentioned).
Patients taking oral contraceptives should be warned that if diarrhoea, vomiting or breakthrough bleeding occur there is a possibility of contraceptive failure.
Modified-release tablet: Using/taking the following drugs is strictly contraindicated due to the potential for severe drug interaction effects: Astemizole, cisapride, domperidone, pimozide and terfenadine: Elevated cisapride levels have been reported in patients taking clarithromycin and cisapride concomitantly. This can lead to prolongation of the QT interval and arrhythmias including ventricular arrhythmia, ventricular fibrillation and torsades de pointes. Similar effects have been observed in patients taking clarithromycin and pimozide concomitantly (see Contraindications).
It has been reported that Macrolides alter the metabolism of terfenadine. This results in increased levels of terfenadine which has occasionally been associated with cardiac arrhythmias, such as QT prolongation, ventricular tachycardia, ventricular fibrillation and torsades de pointes (see Contraindications). In one study in 14 healthy volunteers, the concomitant administration of clarithromycin and terfenadine resulted in a two- to three-fold increase in the serum level of the metabolite of terfenadine and in prolongation of the QT interval without any clinically detectable effect. Similar effects have been observed with concomitant administration of astemizole and other macrolides.
Ergotamine derivatives: Postmarketing reports indicate that concomitant use of clarithromycin and dihydroergotamine or non-hydrogenated ergot alkaloids has been associated with acute toxicity, characterized by vasospasm and ischemia of the extremities and other tissues, including the central nervous system. Concomitant administration of clarithromycin and ergotamine derivatives is contraindicated (see Contraindications).
Oral midazolam: When midazolam was co-administered with clarithromycin tablets (500 mg twice daily), the midazolam AUC was increased 7-fold after oral administration of midazolam. Concomitant administration of oral midazolam and clarithromycin is contraindicated (see Contraindications).
HMG-CoA Reductase Inhibitors (statins): Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated (see Contraindications), as these statins are extensively metabolized by CYP3A4 and concomitant treatment with clarithromycin increases their plasma concentration, which increases the risk of myopathy, including rhabdomyolysis. There have been reports of patients with rhabdomyolysis who received clarithromycin concomitantly with these statins. If treatment with clarithromycin cannot be avoided, therapy with lovastatin or simvastatin must be suspended during the course of treatment.
Caution should be exercised when prescribing clarithromycin and statins at the same time. In cases where the concomitant use of clarithromycin and statins cannot be avoided, it is recommended to prescribe the lowest permitted dose of the statin. Use of another statin that is not dependent on CYP3A metabolism (e.g. fluvastatin) can be considered. Patients should be monitored for signs and symptoms of myopathy.
Effects of other medicinal products on clarithromycin: The following drugs are known or suspected to affect the plasma concentrations of clarithromycin. Clarithromycin dosage adjustment or an alternative treatment should be considered.
Drugs that are inducers of CYP3A (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital, St John's Wort) may induce the metabolism of clarithromycin. This may result in sub-therapeutic levels of clarithromycin leading to reduced efficacy. Furthermore, it might be necessary to monitor the plasma levels of the CYP3A inducer, as this may be increased owing to the inhibition of CYP3A by clarithromycin (see also the current product information for the CYP3A4 inhibitor administered). Concomitant administration of clarithromycin and rifabutin resulted in an increase in rifabutin and a decrease in clarithromycin serum levels, which again leads an increased risk of uveitis.
Fluconazole: Concomitant administration of fluconazole 200 mg daily and clarithromycin 500 mg twice daily to 21 healthy volunteers led to an increase in the mean steady-state minimum clarithromycin concentration (C_min) and area under the curve (AUC) of 33% and 18% respectively. Steady state concentrations of the active metabolite 14(R)-hydroxy-clarithromycin were not significantly affected by concomitant administration of fluconazole. No clarithromycin dose adjustment is necessary.
Ritonavir: When clarithromycin is administered concomitantly with ritonavir, the systemic availability (AUC), the maximum concentration (C_max) and the minimum concentration (C_min) of clarithromycin increase. Because of the large therapeutic window for clarithromycin, no dosage reduction should be necessary in patients with normal renal function. For patients with moderate renal impairment (creatinine clearance 30 to 60 ml/min), the dose of clarithromycin should be reduced by 50%. For patients with creatinine clearance <30 ml/min, the dose of clarithromycin should be decreased by 75%. Other clarithromycin pharmaceutical forms with a lower active substance content are available to these patients.
When protease inhibitors are taken concomitantly, a daily dose of 1 g clarithromycin should not be exceeded (see Dosage & Administration).
Similar dose adjustments should be considered in patients with reduced renal function when ritonavir is used as a pharmacokinetic enhancer with other HIV protease inhibitors, including atazanavir and saquinavir (see Other possible significant pharmacokinetic interactions as follows).
Efavirenz, nevirapine, rifampicin, rifabutin and rifapentine: Strong inducers of the cytochrome P450 metabolism system, such as nevirapine, rifampicin, rifabutin, rifapentine and efavirenz, may accelerate the metabolism of clarithromycin and thus lower the plasma levels and bioavailability of clarithromycin by around 30-40%, increase those of the microbiologically active metabolite 14(R)-hydroxy clarithromycin (14-OH-clarithromycin by approximately the same amount. As the ratio of the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, when enzyme inducers and clarithromycin are administered concomitantly, it should be checked in individual cases whether the intended therapeutic effect should be impaired by this fact.
Etravirine: Clarithromycin levels were decreased by etravirine; however, concentrations of the active metabolite, 14-OH-clarithromycin, were increased. Because 14-OH-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered; therefore alternatives to clarithromycin should be considered for the treatment of MAC.
Effect of clarithromycin on other medicinal products: CYP3A-based Interactions: Concomitant administration of clarithromycin, known to inhibit CYP3A, and an active substance mainly metabolized by CYP3A may be associated with an increase in active substance concentrations, which can increase or potentiate both the therapeutic and adverse effects of the concomitant drug.
Clarithromycin is contraindicated in patients receiving the CYP3A substrates atemizole, cisapride, domperidone, pimozide and terfenadine due to the risk of prolongation of the QT interval and arrhythmias including tachycardia, ventricular fibrillation and torsades de pointes (see Contraindications and Precautions).
The use of clarithromycin is also contraindicated with ergotamine alkaloids, oral midazolam, HMG CoA reductase inhibitors, mainly metabolized by CYP3A4 (e.g. lovastatin and simvastatin), colchicine, ticagrelor and ranolazine (see Contraindications).
Caution should be exercised if clarithromycin is administered concomitantly with other drugs known as CYP3A enzyme substrates especially if the CYP3A substrate has a narrow therapeutic spectrum (e.g., carbamazepine) and/or the substrate is largely metabolized by this enzyme. Dose adjustments may be taken into consideration and, if possible, the serum concentrations of the drugs essentially metabolized by CYP3A, should be closely monitored in patients receiving clarithromycin concomitantly.
Drugs or drug classes known or suspected to be metabolized by the same CYP3A isozyme include (but this list is not exhaustive) alprazolam, carbamazepine, cilostazol, cyclosporine, disopyramide, ibrutinib, methylprednisolone, midazolam (intravenous), omeprazole, oral anticoagulants (e.g. warfarin), atypical antipsychotics (e.g. quetiapine), quinidine, rifabutin, sildenafil, sirolimus, tacrolimus, triazolam and vinblastine.
Drugs that interact by similar mechanisms through other isozymes of the cytochrome P450 system include phenytoin, theophylline and valproate.
Antiarrhythmics: There have been reports of torsades de pointes occurring after concurrent use of clarithromycin and quinidine or disopyramide. During concomitant administration of clarithromycin and these drugs, electrocardiograms should be monitored for QTc prolongation. Monitoring of the serum concentrations of these active substances during therapy is recommended.
There have been post-marketing reports of hypoglycaemia with the concomitant administration of clarithromycin and disopyramide. Therefore blood glucose levels should be monitored during concomitant administration of clarithromycin and disopyramide.
Oral antidiabetic agents/insulin: When using certain antidiabetic agents concomitantly, such as nateglinide and repaglinide, inhibition of the CYP3A enzyme by clarithromycin may occur and cause hypoglycaemia. Careful monitoring of blood glucose levels is recommended.
Omeprazole: Healthy adult subjects were given 500 mg clarithromycin in combination with 40 mg omeprazole every 8 hours. The steady-state plasma concentrations of omeprazole were increased with the concomitant administration of clarithromycin (maximum omeprazole concentration (C_max), systemic availability (AUC_0-24), and elimination half-life values increased by 30%, 89%, and 34%, respectively). The mean 24-hour gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when omeprazole was co-administered with clarithromycin.
Sildenafil, tadalafil, and vardenafil: All of these phosphodiesterase inhibitors are metabolized, at least in part, by CYP3A, and CYP3A may be inhibited by concomitantly administered clarithromycin. It has been reported that erythromycin increases the systemic availability (area under the curve, AUC) of sildenafil. Co-administration of clarithromycin with sildenafil, tadalafil or vardenafil could possibly result in an increase in the phosphodiesterase inhibitors.
In one study in which vardenafil was co-administered with erythromycin (500 mg three times daily), a quadrupling of the vardenafil AUC and a tripling of the maximum vardenafil concentration (C_max) was observed.
Sildenafil, tadalafil and vardenafil dosages need to be reduced when co-administered with clarithromycin.
Theophylline, carbamazepine: During the therapy with clarithromycin, the metabolism of theophylline or carbamazepine may be inhibited. As a result of this, an increase in the serum concentration of theophylline or carbamazepine is possible and a dose reduction may need to be considered.
Tolterodine: The primary route of metabolism for tolterodine is via the 2D6 isoform of cytochrome P450 (CYP2D6). However, in a subset of the Caucasian population devoid of CYP2D6, metabolism is mainly via CYP3A. In this population, inhibition of CYP3A results in significantly higher serum concentrations of tolterodine. A reduction in the tolterodine dosage may be necessary in the case of slow metabolism with CYP2D6 deficiency in the presence of CYP3A inhibitors such as clarithromycin.
Triazolobenzodiazepines (e.g., alprazolam, midazolam, triazolam): When midazolam was co-administered with clarithromycin tablets (500 mg twice daily), the midazolam AUC was increased 2.7-fold after intravenous administration. If, during the clarithromycin therapy, intravenous midazolam is also administered, the patient should be closely monitored so that the dose can be adjusted if necessary.
Administration of midazolam via the oral mucosa could bypass pre-systemic elimination of the drug and will probably result in interactions similar to those observed after intravenous rather than oral administration.
The same precautions also apply during administration of other benzodiazepines that are metabolized by CYP3A, including triazolam and alprazolam. For benzodiazepines which are not metabolized by CYP3A (temazepam, nitrazepam, lorazepam), an interaction with clarithromycin is unlikely.
There have been post-marketing reports of drug interactions and CNS effects (e.g., somnolence and confusion) with the concomitant use of clarithromycin and triazolam. Therefore, monitoring the patient for increased CNS pharmacological effects is recommended.
Other drug interactions: Colchicine: Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. When clarithromycin and colchicine are administered together, inhibition of CYP3A and/or Pgp by clarithromycin may lead to increased systemic availability of colchicine. Concomitant use of clarithromycin and colchicine by patients with renal or hepatic function disorders is contraindicated (see Contraindications and Precautions).
Digoxin: Digoxin is a substrate for the efflux transporter, P-glycoprotein (Pgp). Clarithromycin is known to inhibit Pgp. When clarithromycin and digoxin are administered together, inhibition of Pgp by clarithromycin may lead to an increased digoxin serum concentration. Elevated digoxin serum levels have also been reported post-marketing in patients who received clarithromycin and digoxin concomitantly.
Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. The serum digoxin concentrations should be carefully monitored while patients are receiving digoxin and clarithromycin concomitantly.
Zidovudine: During concomitant oral therapy with clarithromycin and zidovudine, in HIV-infected adults because of reduced intestinal adsorption, reduced serum levels of zidovudine have been detected. Therefore, in these patients a 4-hour staggered intake should be adhered to. This interaction was not observed in HIV-infected children who took clarithromycin suspension with zidovudine or dideoxyinosine. This interaction is unlikely when clarithromycin is administered as a solution or infusion.
No in vivo data from human are available when describe an interaction of clarithromycin with the following drugs: aprepitant, eletriptan, halofantrine and ziprasidone. However, in vitro data indicate that these drugs are CYP3A substrates, therefore caution is advised when these are used concomitantly with clarithromycin.
Other drugs for which there are spontaneous reports or publications concerning an interaction with clarithromycin: CYP3A-based interactions: There have been reports on interactions of erythromycin and/or clarithromycin with bromocriptine, cyclosporine, tacrolimus, rifabutin, methylprednisolone, vinblastine and cilostazol, which are metabolized via CYP3A.
Concomitant administration of erythromycin or clarithromycin with a drug that is metabolized mainly via CYP3A may be associated with the increase in drug concentrations that potentiate or prolong both the therapeutic and the undesired effects of the co-medication. A dose adjustment should be considered and, if possible, the serum concentrations of the drugs metabolised mainly via CYP3A should be closely monitored in patients who received erythromycin or clarithromycin concomitantly.
Non-CYP3A-based interactions: Phenytoin and valproate: There have also been spontaneous or published reports of interactions of CYP3A inhibitors, including clarithromycin, with drugs which are not known to be metabolized by CYP3A (e.g. phenytoin, valproate and hexobarbital). Serum level determinations are recommended for these drugs when administered concomitantly with clarithromycin. Increased serum levels have been reported.
Other possible significant pharmacokinetic interactions: Atazanavir: Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of bi-directional drug interactions. Co-administration of clarithromycin (500 mg twice daily) with atazanavir (400 mg once daily) resulted in a 2-fold increase in exposure to clarithromycin and a 70% decrease in exposure to 14(R)-hydroxy clarithromycin, with a 28% increase in the AUC of atazanavir.
Because of the large therapeutic window for clarithromycin, no dosage reduction should be necessary in patients with normal renal function. In the case of moderate renal impairment (creatinine clearance 30 to 60 ml/min), the dose of clarithromycin should be decreased by 50%.
For patients with creatinine clearance <30 ml/min, the dose of clarithromycin should be decreased by 75% using appropriate pharmaceutical forms.
The maximum daily dose of 1000 mg clarithromycin when taken with protease inhibitors should not be exceeded (see Dosage & Administration).
For indications that are not based on infections caused by the Mycobacterium avium complex, an alternative therapy should be considered.
Patients who are taking atazanavir and clarithromycin concomitantly should be monitored for signs or symptoms of increased or prolonged pharmacological effect.
Calcium channel blockers: Because of the risk of hypotension, caution is advised in patients taking clarithromycin and calcium channel blockers that are metabolized by CYP3A4 (e.g. verapamil, amlodipine, diltiazem). Plasma concentrations of clarithromycin and of calcium channel blockers may be increased owing to interactions. Hypotension, bradyarrhythmias and lactic acidosis have been observed in patients taking clarithromycin and verapamil concomitantly.
Itraconazole: Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A and there is evidence of bi-directional drug interactions.
Clarithromycin could increase the plasma levels of itraconazole, while itraconazole could increase the plasma levels of clarithromycin.
Regarding the effect of itraconazole and clarithromycin, a case report has been published concerning 3 patients who had higher concentrations of clarithromycin than expected when taking itraconazole concomitantly. In a small pharmacokinetic study with HIV patients, it could be shown that clarithromycin increases the plasma concentrations of itraconazole.
Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged pharmacologic effect.
Saquinavir: Both clarithromycin and saquinavir are substrates and inhibitors of CYP3A, and there is evidence of bi-directional drug interactions.
Concomitant administration of clarithromycin (500 mg twice daily) and saquinavir (soft gelatin capsules, 1200 mg three times daily) to 12 healthy volunteers resulted in system availability in the steady-state (AUC) and a maximum concentration (C_max) of saquinavir which were 177% and 187% higher than those with saquinavir alone. Clarithromycin AUC and C_max values were approximately 40% higher than those seen with clarithromycin alone. Dose adjustment is required when the two drugs are co-administered for a limited time at the strengths and in the pharmaceutical forms studied.
Observations from drug interaction studies using the soft gelatin capsules are not necessarily transferable to the use of the saquinavir hard gelatin capsule.
Observations from drug interaction studies with unboostered saquinavir are not necessarily transferable to the effects that are seen with saquinavir/ritonavir. When saquinavir is co-administered with ritonavir, consideration should be given to the potential effects of ritonavir on clarithromycin (see Effects of other medicinal products on clarithromycin as previously mentioned).