Summary of Product Characteristics Updated 14-Jan-2015 | Forum Products Ltd
The use of the following drugs is strictly contraindicated due to the potential for severe drug interaction effects:
Cisapride, pimozide, astemizole and terfenadineClarithromycin has been reported to elevate plasma levels of cisapride when taken concomitantly. Increased levels of these drugs 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 concurrently (see section 4.3).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 section 4.3). 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 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.
Ergotamine/dihydroergotaminePost-marketing reports indicate that co-administration of clarithromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm, and ischemia of the extremities and other tissues including the central nervous system. Concomitant administration of clarithromycin and these medicinal products is contraindicated (see section 4.3).
HMG-CoA reductase inhibitorsConcomitant use of clarithromycin with lovastatin or simvastatin is contraindicated (see section 4.3 and section 4.4).
Effect of other medicinal products on clarithromycinProducts that are inducers of CYP3A4 (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital, St. Johns wort) may induce the metabolism of clarithromycin. This may result in sub-therapeutic levels of clarithromycin leading to a reduced efficacy. Furthermore it might be necessary to monitor the plasma levels of the CYP3A4 inducer, which could be increased owing to the inhibition of CYP3A4 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 rifapentineStrong 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.
EtravirineClarithromycin 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.
FluconazoleConcomitant administration of fluconazole 200mg daily and clarithromycin 500mg twice daily to 21 healthy volunteers led to increases in the mean steady-state minimum clarithromycin concentration (Cmin) and area under the curve (AUC) of 33% and 18% respectively. Steady state concentrations of the active metabolite 14(R)-hydroxyclarithromycin were not significantly affected by concomitant administration of fluconazole. No clarithromycin dose adjustment is necessary.
RitonavirA pharmacokinetic study demonstrated that the concomitant administration of ritonavir 200mg every eight hours and clarithromycin 500mg every 12 hours resulted in a marked inhibition of the metabolism of clarithromycin. The clarithromycin Cmax increased by 31%, Cmin 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. 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, such as clarithromycin immediate release tablets, or clarithromycin sachet, or clarithromycin paediatric suspensions (not all presentations may be marketed).Doses of clarithromycin greater than 1000 mg per day should not be coadministered with protease inhibitors (see section 4.2).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 section below, bidirectional pharmacokinetic interactions).
Effects of clarithromycin on other medicinal products
CYP3A-based interactionsCo-administration of clarithromycin, known to inhibit CYP3A, and a drug primarily metabolized by CYP3A may be associated with elevations in drug concentrations that could increase or prolong both therapeutic and adverse effects of the concomitant drug. Clarithromycin should be used with caution in patients receiving treatment 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 metabolized by this enzyme.Dosage adjustments may be considered, and when possible, serum concentrations of drugs primarily metabolized by CYP3A should be monitored closely in patients concurrently receiving clarithromycin.The following drugs or drug classes are known or suspected to be metabolized by the same CYP3A isozyme: alprazolam, astemizole, carbamazepine, cilostazol, cisapride, cyclosporine, disopyramide, ergot alkaloids, lovastatin, methylprednisolone, midazolam, omeprazole, oral anticoagulants (e.g. warfarin), pimozide, quinidine, rifabutin, sildenafil, simvastatin, sirolimus, tacrolimus, terfenadine, triazolam and vinblastine. Drugs interacting by similar mechanisms through other isozymes within the cytochrome P450 system include phenytoin, theophylline and valproate.
AntiarrhythmicsThere have been post-marketing reports of torsade de pointes occurring with concurrent use of clarithromycin and quinidine or disopyramide. Electrocardiograms should be monitored for QTc prolongation during co-administration of clarithromycin with these drugs. Serum concentrations of these medications should also be monitored during clarithromycin therapy.
Theophylline, carbamazepineResults of clinical studies indicate 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.
Oral anticoagulants (e.g., warfarin, acenocoumarol)In isolated cases, patients receiving combination therapy with clarithromycin and oral anticoagulants may experience increased pharmacologic effects and even toxic effects of these drugs. International normalized ratio (INR) or Prothrombin times should be carefully monitored while patients are simultaneously receiving clarithromycin and oral anticoagulants.
Sildenafil, tadalafil, and vardenafilEach of these phosphodiesterase inhibitors is metabolized, 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 coadministered with clarithromycin.
TolterodineThe 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 and 7-fold after oral administration. Concomitant administration of oral midazolam and clarithromycin should be avoided. If intravenous midazolam is co-administered with clarithromycin, the patient must be closely monitored to allow dose adjustment. The same precautions should also apply to other benzodiazepines that are metabolised by CYP3A, including triazolam and alprazolam. For benzodiazepines which are not metabolised by CYP3A (temazepam, nitrazepam, lorazepam) an 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.
OmeprazoleClarithromycin (500mg every 8 hours) was given in combination with omeprazole (40mg daily) to healthy adult subjects. The steady-state plasma concentrations of omeprazole were increased (Cmax, AUC0-24, and t1/2 increased by 30%, 89% and 34% respectively, when administered concomitantly with clarithromycin for H. pylori eradication; however the change in the mean 24-hour gastric pH value from 5.2 (omeprazole alone) to 5.7 (omeprazole + clarithromycin) is not considered clinically significant.
ColchicineColchicine 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. Patients should be monitored for clinical symptoms of colchicine toxicity (see section 4.4).
DigoxinDigoxin 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 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.
ZidovudineDue to reduced gastrointestinal absorption of zidovudine in the presence of clarithromycin, reduced serum levels of zidovudine were observed in adults during concomitant therapy with clarithromycin and zidovudine. Because clarithromycin appears to interfere with the absorption of simultaneously administered oral zidovudine, patients should observe a 4-hour interval between taking these two drugs. This interaction does not appear to occur in paediatric HIV-infected patients taking clarithromycin suspension with zidovudine. This interaction is unlikely when clarithromycin is administered via intravenous infusion.
Phenytoin and valproateThere have been spontaneous or published reports of interactions with CYP3A inhibitors, including clarithromycin, and drugs not thought to be metabolized by CYP3A, including phenytoin and valproate. Serum level determinations are recommended for these drugs when administered concomitantly with clarithromycin. Increased concentrations have been reported.
Bidirectional pharmacokinetic interactions
AtazanavirBoth clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction. Co-administration of clarithromycin (500mg twice daily) with atazanavir (400mg 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. 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, such as clarithromycin immediate release tablets, or clarithromycin sachet, or clarithromycin paediatric suspensions (not all presentations may be marketed).Doses of clarithromycin greater than 1000mg per day should not be co-administered with protease inhibitors (see also section 4.2).
ItraconazoleBoth 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.
SaquinavirBoth clarithromycin and saquinavir are substrates and inhibitors of CYP3A, and there is evidence of a bidirectional drug interaction. Concomitant administration of clarithromycin (500 mg bid) and saquinavir (soft gelatin capsules, 1200 mg tid) to 12 healthy volunteers resulted in steady-state area under the curve (AUC) and maximum concentration (Cmax) values of saquinavir which were 177% and 187% higher than those seen with saquinavir alone. Clarithromycin AUC and Cmax 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 (see section 4.5: Ritonavir).Observations from drug interaction studies done with unboosted saquinavir 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 section above, effect of other medicinal products on clarithromycin).
VerapamilHypotension, bradyarrhythmias and lactic acidosis have been observed in patients taking clarithromycin and verapamil concomitantly.
a. Summary of the safety profileThe most frequent and common adverse reactions related to clarithromycin for both adult and paediatric populations are abdominal pain, nausea, vomiting and taste perversion.These adverse reactions are usually mild in intensity and are consistent with the known safety profile of macrolide antibiotics (see section b of section 4.8).There was no significant difference in the incidence of these gastrointestinal adverse reactions during clinical trials between the patient population with or without pre-existing mycobacterial infections.
b. Tabulated summary of adverse reactionsThe following table displays adverse reactions reported in clinical trials and from post-marketing experience with clarithromycin immediate-release tablets, granules for oral suspension, powder for solution for injection, extended- release tablets and modified-release tablets.The reactions considered at least possibly related to clarithromycin are displayed by system organ class and frequency using the following convention: very common (≥1/10), common (≥ 1/100 to < 1/10), uncommon (≥1/1,000 to < 1/100) and not known (adverse reactions from post-marketing experience; cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness when the seriousness could be assessed.
|System Organ Class||Very common (≥1/10)||Common (≥ 1/100, <1/10)||Uncommon (≥1/1000, <1/100)||Not known (cannot be estimated from the available data)|
|Infections and infestations||cellulitis1, gastroenteritis2, candidiasis, infection3, vaginal infection||pseudomembranous colitis, erysipelas, erythrasma|
|Blood and the lymphatic system disorders||leukopenia, neutropenia4, eosinophilia4, thrombocythaemia||agranulocytosis, thrombocytopenia|
|Immune system disorders||anaphylactoid reaction1, hypersensitivity||anaphylactic reaction|
|Psychiatric disorders||insomnia||Anxiety, nervousness3, screaming||psychiatric disorder, confusional state, depression, hallucination, disorientation, depersonalisation, abnormal dreams and confusion|
|Metabolism and nutrition disorders||anorexia, decreased appetite||hypoglycaemia6|
|Respiratory, thoracic and mediastinal disorders||asthma1, epitaxis2, pulmonary embolism1|
|General disorders and administration site conditions||Injection site phlebitis1||injection site pain1, injection site inflammation1||pyrexia3, asthenia, chest pain4, chills4, malaise4, fatigue, thirst|
|Nervous system disorders||dysguesia, headache, taste perversion||loss of consciousness1, dyskinesia1, tremor, dizziness, somnolence||convulsions, aguesia, parosmia, anosmia|
|Ear and labyrinth disorders||vertigo, hearing impaired, tinnitus||deafness|
|Cardiac disorders||cardiac arrest1, atrial fibrillation1, electrocardiogram QT prolonged8, extrasystoles1, palpitations||ventricular tachycardia8, torsade de pointes8|
|Gastrointestinal disorders||nausea, diarrhoea10, vomiting, abdominal pain, dyspepsia||esophagitis1, gastrooseophageal reflux disease2, gastritis, proctalgia, stomatitis, glossitis, abdominal distention4, constipation, dry mouth, eructation, flatulence, gastrointestinal haemorrhage||pancreatitis acute; tongue discolouration, tooth discolouration|
|Hepato-biliary disorders||liver function test abnormal||hepatitis4, cholestasis4, alanine aminotransferase increased, aspartate aminotransferase increased, gamma-glutamyltransferase increased4||fatal hepatic failure has been reported particularly in patients with pre-existing liver disease or taking other hepatotoxic drugs|
|Skin and subcutaneous tissue disorders||rash, hyperhidrosis||dermatitis bullous1, dry skin, pruritus, urticaria, rash maculopapular3||Stevens-Johnson syndrome5, toxic epidermal necrolysis5, drug rash with eosinophilia and systemic symptoms (DRESS), acne|
|Musculoskeletal, connective tissue and bone disorders||muscle spams3, musculoskeletal stiffness1, myalgia2||Rhabdomyolysis2, 12, myopathy, exacerbation of symptoms of myasthenia gravis (see section 4.4)|
|Renal and urinary disorders||blood creatinine increased1, blood urea increased1|
|Investigations||albumin globulin ratio abnormal1, alkaline phosphatase increased4, blood lactate dehydrogenase increased4||international normalised ration increased9, increased prothrombin time9, urine colour abnormal|
c. Description of selected adverse reactionsInjection site phlebitis, injection site pain, vessel puncture site pain, and injection site inflammation are specific to the clarithromycin intravenous formulation.In very rare instances, hepatic failure with fatal outcome has been reported and generally has been associated with serious underlying diseases and/or concomitant medications (see section 4.4).A special attention to diarrhoea should be paid as Clostridium difficile-associated diarrhoea (CDAD) has been reported with use of nearly all antibacterial agents including clarithromycin, and may range in severity from mild diarrhoea to fatal colitis (see section 4.4).In the event of severe acute hypersensitivity reactions, such as anaphylaxis, Stevens-Johnson Syndrome and toxic epidermal necrolysis, clarithromycin therapy should be discontinued immediately and appropriate treatment should be urgently initiated (see section 4.4).As with other macrolides, QT prolongation, ventricular tachycardia, and torsade de pointes have rarely been reported with clarithromycin (see section 4.4 and 4.5).Pseudomembranous colitis has been reported with nearly all antibacterial agents, including clarithromycin, and may range in severity from mild to life threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhoea subsequent to the administration of antibacterial agents (see section 4.4).In some of the reports of rhabdomyolysis, clarithromycin was administered concomitantly with statins, fibrates, colchicine or allopurinol (see section 4.3 and 4.4).There have been post-marketing reports of colchicine toxicity with concomitant use of clarithromycin and colchicine, especially in elderly and/or patients with renal insufficiency, some with a fatal outcome (see sections 4.4 and 4.5).There have been rare reports of hypoglycaemia, some of which have occurred in patients on concomitant oral hypoglycaemic agents or insulin (see section 4.4 and 4.5).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 (see section 4.5).There is a risk of serious haemorrhage and significant elevations in INR and prothrombin time when clarithromycin is co- administered with warfarin. INR and prothrombin times should be frequently monitored while patients are receiving clarithromycin and oral anticoagulants concurrently (see section 4.4 and 4.5).There have been rare reports of clarithromycin ER tablets in the stool, many of which have occurred in patients with anatomic (including ileostomy or colostomy) or functional gastrointestinal disorders with shortened GI transit times. In several reports, tablet residues have occurred in the context of diarrhoea. It is recommended that patients who experience tablet residue in the stool and no improvement in their condition should be switched to a different clarithromycin formulation (e.g. suspension) or another antibiotic.Special population: Adverse Reactions in Immunocompromised Patients (see section e).
d. Paediatric populationsClinical trials have been conducted using clarithromycin paediatric suspension in children 6 months to 12 years of age. Therefore, children under 12 years of age should use clarithromycin paediatric suspension. There are insufficient data to recommend a dosage regimen for use of the clarithromycin IV formulation in patients less than 18 years of age.Frequency, type and severity of adverse reactions in children are expected to be the same as in adults.
e. Other special populations
Immunocompromised patientsIn AIDS and other immunocompromised patients treated with the higher doses of clarithromycin over long periods of time for mycobacterial infections, it was often difficult to distinguish adverse events possibly associated with clarithromycin administration from underlying signs of Human Immunodeficiency Virus (HIV) disease or intercurrent illness.In adult patients, the most frequently reported adverse reactions by patients treated with total daily doses of 1,000mg and 2,000mg of clarithromycin were: nausea, vomiting, taste perversion, abdominal pain, diarrhoea, rash, flatulence, headache, constipation, hearing disturbance, Serum Glutamic Oxaloacetic Transaminase (SGOT) and Serum Glutamic Pyruvate Transaminase (SGPT) elevations. Additional low-frequency events included dyspnoea, insomnia and dry mouth. The incidences were comparable for patients treated with 1,000mg and 2,000mg, but were generally about 3 to 4 times as frequent for those patients who received total daily doses of 4,000mg of clarithromycin.In these immunocompromised patients, evaluations of laboratory values were made by analysing those values outside the seriously abnormal level (i.e. the extreme high or low limit) for the specified test. On the basis of these criteria, about 2% to 3% of those patients who received 1,000mg or 2,000mg of clarithromycin daily had seriously abnormal elevated levels of SGOT and SGPT, and abnormally low white blood cell and platelet counts. A lower percentage of patients in these two dosage groups also had elevated Blood Urea Nitrogen levels. Slightly higher incidences of abnormal values were noted for patients who received 4,000mg daily for all parameters except White Blood Cell.
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