Clarithromycin 250 Mg Film-Coated Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Clarithromycin 250 mg Film-coated Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 250 mg clarithromycin.
Excipients with known effect
250 mg: Each film-coated tablet contains 0.30 mg tartrazine lake (E102) and 0.008 mg Allura red aluminium lake (E129)
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Film-coated tablet.
Yellow, film-coated oval shaped tablet, debossed with “93” on one side and “7157” on the other.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Clarithromycin is indicated for the treatment of acute and chronic bacterial infections when caused by clarithromycin-susceptible bacteria.
- Infections of the upper respiratory tract such as pharyngitis and sinusitis.
- Infections of the lower respiratory tract, such as acute exacerbation of chronic bronchitis, and community-acquired pneumonia.
- Skin and soft tissue infections of mild to moderate severity.
In appropriate combination with antibacterial therapeutic regimens and an appropriate ulcer-healing agent for the eradication of H. pylori in patients with H. pylori-associated ulcers. See section 4.2.
Consideration should be given to official guidance on the appropriate use of antibacterial agents.
4.2 Posology and method of administration
The dosage of clarithromycin depends on the clinical condition of the patient and has to be defined in any case by the physician.
250 and 500 mg tablets are available.
Posology
Adults and adolescents
The recommended dose is 250 mg twice daily.
In severe infections, the dose may be increased to 500 mg twice daily.
In respiratory infections, owing to the high level of resistance of some pathogenic microorganisms (e.g. S. pneumoniae), penicillin remains the antibiotic of first choice. Clarithromycin may be used in patients with known hypersensitivity to penicillin or when penicillin would be inappropriate for other reasons.
Special populations
Paediatric population
Clinical trials have been conducted using clarithromycin pediatric suspension in children 6 months to 12 years of age. Therefore, children under 12 years of age should use clarithromycin pediatric suspension (granules for oral 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.
Clarithromycin tablets are not suitable for children under 12 years of age weighing less than 30 kg. Other pharmaceutical forms are more adapted for these patients.
Elderly As for adults.
Eradication of H. _pylori in adults
In patients with peptic ulcers due to H. pylori infection, clarithromycin can be administered in a dose of 500 mg twice daily in combination with other appropriate antimicrobe treatment and proton-pump inhibitors.
Renal impairment
In patients with renal impairment with creatinine clearance less than 30 ml/min, the dosage of clarithromycin should be reduced by one-half, i.e. 250 mg once daily, or 250 mg twice daily in more severe infections. Treatment should not be continued beyond 14 days in these patients.
Duration of therapy
The duration of therapy with clarithromycin depends on the clinical condition of the patient and in any case shall be determined by the physician.
- The usual duration of treatment is 6 to 14 days.
- Therapy should be continued for at least 2 days after symptoms have subsided.
- In infections caused by Streptococcus pyogenes (group A beta-haemolytic streptococci), the duration should be at least 10 days.
Combination therapy for the eradication of H. pylori infection, e.g. clarithromycin 500 mg (two 250 mg tablets or one 500 mg tablet) twice daily in combination with amoxicillin 1,000 mg twice daily and omeprazole 20 mg twice daily, should be continued for 7 days.
Method of administration
Clarithromycin may be given without regard to food intake (see section 5.2).
4.3 Contraindications
- Hypersensitivity to the active substance, to other macrolides, or to any of the excipients listed in section 6.1.
- Concomitant administration of clarithromycin and ergotamine or dihydroergotamine as this may result in ergot toxicity.
- Concomitant administration of clarithromycin and any of the following drugs is contraindicated: astemizole, cisapride, pimozide, terfenadine as this may result in QT prolongation and cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation, and torsades de pointes (see section 4.5).
- Hypokalaemia (risk of prolongation of QT-time).
- Clarithromycin should not be used concomitantly with HMG-CoA reductase inhibitors (statins) that are extensively metabolised by CYP3A4 (lovastatin or simvastatin), due to the increased risk of myopathy, including rhabdomyolysis.(see section 4.5)
- patients with history of QT prolongation (congenital or documented acquired QT prolongation) or ventricular cardiac arrhythmia, including torsades de pointes (see sections 4.4 and 4.5).
- severe hepatic failure in combination with renal impairment
- concomitant administration with ticagrelor or ranolazine.
- As with other strong CYP3A4 inhibitors, Clarithromycin should not be used in patients taking colchicine.
4.4 Special warnings and precautions for use
The physician should not prescribe clarithromycin to pregnant women without carefully weighing the benefits against risk, particularly during the first three months of pregnancy (see section 4.6).
Hepatic impairment
Clarithromycin is principally excreted by the liver. Therefore, caution should be exercised in administering clarithromycin to patients with impaired hepatic function. Caution should also be exercised when administering clarithromycin to patients with moderate to severe renal impairment.
Cases of fatal hepatic failure (see section 4.8) have been reported. Some patients may have had pre-existing hepatic disease or may have been taking other hepatotoxic medicinal products. Patients should be advised to stop treatment and contact their doctor if signs and symptoms of hepatic disease develop, such as anorexia, jaundice, dark urine, pruritus, or tender abdomen.
Renal impairment
Caution is advised in patients with severe renal insufficiency (see section 4.2).
As with other antibiotics when renal function is poor, dosage of clarithromycin should be suitably reduced depending on the degree of the impairment (see section 4.2). In elderly patients, the possibility of renal impairment should be considered.
Cross reactivity and cross hypersensitivity with other antibiotics
Use of any antimicrobial therapy, such as clarithromycin, to treat H. pylori infection may select for substance-resistant organisms.
Patients who are hypersensitive to lincomycin or clindamycin may also be hypersensitive to clarithromycin. Therefore, caution is required when prescribing clarithromycin for such patients.
Attention should also be paid to the possibility of cross resistance between clarithromycin and other macrolide drugs, as well as lincomycin and clindamycin.
Long-term use may, as with other antibiotics, result in colonization with increased numbers of non-susceptible bacteria and fungi. If superinfections occur, appropriate therapy should be instituted.
Pseudomembranous colitis has been reported with nearly all antibacterial agents, including macrolides, and may range in severity from mild to life-threatening. 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. Treatment with antibacterial agents alters the normal flora of the colon, which may lead to overgrowth of C. difficile. CDAD must be considered in all patients who present with diarrhoea following antibiotic use.
Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. Therefore, discontinuation of clarithromycin therapy should be considered regardless of the indication. Microbial testing should be performed and adequate treatment initiated. Drugs inhibiting peristalsis should be avoided.
As known for other macrolides, clarithromycin may cause exacerbation or aggravation of myasthenia gravis and should therefore be used with caution in patients with myasthenia gravis.
Interference with other medicinal products
There have been post-marketing reports of colchicine toxicity with concomitant use of clarithromycin and colchicine, especially in the elderly, some of which occurred in patients with renal insufficiency. Deaths have been reported in some such patients (see section 4.5). Concomitant administration of colchicine and clarithromycin is contraindicated (see section 4.3).
Caution is advised regarding concomitant administration of clarithromycin and triazolobenzodiazepines, such as triazolam, and midazolam (see section 4.5).
Caution is advised regarding concomitant administration of clarithromycin with other ototoxic drugs, especially with aminoglycosides. Monitoring of vestibular and auditory function should be carried out during and after treatment.
Prolongation of the QT interval
Prolonged cardiac repolarisation and QT interval, imparting a risk of developing cardiac arrhythmia and torsade de pointes, have been seen in treatment with macrolides including clarithromycin (see section 4.8). Therefore as the following situations may lead to an increased risk for ventricular arrhythmias (including torsade de pointes), clarithromycin should be used with caution in the following patients;
• Patients with coronary artery disease, severe cardiac insufficiency, conduction disturbances or clinically relevant bradycardia
• Patients with electrolyte disturbances such as hypomagnesaemia. Clarithromycin must not be given to patients with hypokalaemia (see section 4.3).
• Patients concomitantly taking other medicinal products associated with QT prolongation (see section 4.5).
• Concomitant administration of clarithromycin with astemizole, cisapride, pimozide and terfenadine is contraindicated (see section 4.3).
• Clarithromycin must not be used in patients with congenital or documented acquired QT prolongation or history of ventricular arrhythmia (see section 4.3).
Pneumonia
In view of the emerging resistance of Streptococcus pneumoniae to macrolides, it is important that sensitivity testing be performed when prescribing clarithromycin for community-acquired pneumonia. In hospital-acquired pneumonia, clarithromycin should be used in combination with additional appropriate antibiotics.
Skin and soft tissue infections of mild to moderate severity
These infections are most often caused by Staphylococcus aureus and Streptococcus pyogenes, both of which may be resistant to macrolides. Therefore, it is important that sensitivity testing be performed. In cases where beta-lactam antibiotics cannot be used (e.g. allergy), other antibiotics, such as clindamycin, may be the drug of first choice. Currently, macrolides are only considered to play a role in some skin and soft tissue infections, such as those caused by Corynebacterium minutissimum, acne vulgaris, and erysipelas and in situations where penicillin treatment cannot be used.
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.
Clarithromycin should be used with caution when administered concurrently with medications that induce the cytochrome CYP3A4 enzyme (see section 4.5).
Clarithromycin is an inhibitor of CYP3A4, and concomitant use with other medicinal products that are metabolised to a large extent by this enzyme should be restricted to situations where it is clearly indicated (see section 4.5).
HMG-CoA reductase inhibitors (statins)
Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated (see section 4.3). Cautions should be exercised when prescribing clarithromycin with other statins. Rhabdomyolysis has been reported in patients taking clarithromycin and statins. Patients should be monitored for signs and symptoms of myopathy. 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 dependant on CYP3A metabolism (e.g fluvastatin) can be considered (see section 4.5).
Oral hypoglycaemic agents/insulin:
The concomitant use of clarithromycin and oral hypoglycaemic agents (such as sulphonylureas) and/or insulin can result in significant hypoglycaemia. Careful monitoring of glucose is recommended (see section 4.5).
Oral anticoagulants
There is a risk of serious haemorrhage and significant elevations in International Normalized Ratio (INR) and prothrombin time when clarithromycin is coadministered with warfarin (see section 4.5). INR and prothrombin times should be frequently monitored while patients are receiving clarithromycin and oral anticoagulants concurrently.
Tartrazine Aluminium Lake and Allura Red Aluminium Lake
This medicinal product contains tartrazine and Allura Red Aluminium lake (E129) which may cause allergic reactions
4.5
Interaction with other medicinal products and other forms of interaction
The use of the following drugs is strictly contraindicated due to the potential for severe drug interaction effects
Cisapride, pimozide, astemizole 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 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/dihydroergotamine
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 these medicinal products is contraindicated (see section 4.3).
HMG-CoA Reductase Inhibitors (statins)
Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated (see section 4.3) as these statins are extensively metabolised 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.
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 sections 4.3 and 4.4).
Concomitant administration with ticagrelor or ranolazine is contraindicated (see section 4.3).
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 inhibitor 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.
Clarithromycin is metabolised by the enzyme CYP3A4. Hence, strong inhibitors of this enzyme may inhibit the metabolism of clarithromycin, resulting in increased plasma concentrations of clarithromycin.
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 (Cmin) 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.
Increased plasma concentrations of clarithromycin may also occur when it is coadministered with antacids or ranitidine. No adjustment to the dosage 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 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. However, for patients with renal impairment, the following dosage adjustments should be considered: For patients with CLcr 30 to 60 ml/min the dose of clarithromycin should be reduced by 50%. For patients with CLcr <30 ml/min the dose of clarithromycin should be decreased by 75%. Doses of clarithromycin greater than 1 g/day should not be coadministered 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 section below, Bi-directional drug interactions)
CYP3A-based interactions
Co-administration of clarithromycin, 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. 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 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.
The following drugs or drug classes are known or suspected to be metabolised by the same CYP3A isozyme: alprazolam, astemizole, carbamazepine, cilostazol, cisapride, cyclosporine, disopyramide, ergot alkaloids, lovastatin, methylprednisolone, midazolam, omeprazole, oral anticoagulants (e.g. warfarin, see section 4.4), atypical antipsychotics (e.g. quetiapine), pimozide, quinidine, rifabutin, sildenafil, simvastatin, sirolimus, tacrolimus, terfenadine, triazolam and vinblastine, but this list is not comprehensive. 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 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 hypoglycaemic agents/Insulin
With certain hypoglycaemic drugs such as nateglinide, and repaglinide, inhibition of CYP3A enzyme by clarithromycin may be involved and could cause hypolgycaemia 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 (Cmax, AUC0 24, and t1/2 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.
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. Coadministration 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 coadministered 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 metabolizer 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 coadministered 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 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.
Cyclosporin, tacrolimus and sirolimus
Concomitant use of oral clarithromycin and cyclosporin or tacrolimus have results in more than a 2-fold increase of the Cmin levels of both cyclosporin and tacrolimus. Similar effects are also expected for sirolimus. When initiating treatment with clarithromycin in patients already receiving any of these immunosuppressive agents, cyclosporin, tacrolimus or sirolimus plasma levels must be closely monitored and their doses decreased as necessary. When clarithromycin is discontinued in these patients, close monitoring of plasma levels of cyclosporin, tacrolimus or sirolimus is again necessary to guide dose adjustment.
Warfarin
The use of clarithromycin in patients receiving warfarin may result in potentiation of the effects of warfarin. Prothrombin time should be frequently monitored in these patients.
Other drug interactions
Aminoglycosides
Caution is advised regarding concomitant administration of clarithromycin with other ototoxic drugs, especially with aminoglycosides. (See section 4.4).
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.
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 coadministered with protease inhibitors.
Calcium Channel Blockers
Caution is advised regarding the concomitant administration of clarithromycin and calcium channel blockers metabolised 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 bi-directional 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 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. 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.
4.6 Fertility, pregnancy and lactation
Pregnancy
The safety of clarithromycin for use during pregnancy has not been established. Based on variable results obtained from studies in mice, rats, rabbits and monkeys, the possibility of adverse effects on embryofoetal development cannot be excluded. Therefore, use during pregnancy is not advised without carefully weighing the benefits against risk.
Breast-feeding
The safety of clarithromycin for use during breastfeeding of infants has not been established. Clarithromycin is excreted into human breast milk. Therefore, diarrhoea and fungus infection of the mucous membranes could occur in the breast-fed infant, so that nursing might have to be discontinued. The possibility of sensitisation should be borne in mind. The benefit of treatment of the mother should be weighed against the potential risk for the infant.
4.7 Effects on ability to drive and use machines
There are no data available on the effect of clarithromycin on the ability to drive or use machines. The potential for dizziness, vertigo, confusion and disorientation, which may occur with the medication, should be taken into account before patients drive or use machines.
4.8 Undesirable effects
Summary of the safety profile
The most frequent and common adverse reactions related to clarithromycin therapy for both adult and paediatric populations are abdominal pain, diarrhoea, 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 "Tabulated List of adverse reactions" 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 preexisting mycobacterial infections.
Tabulated list of adverse reactions
The 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), rare (>1/1,0000 to < 1/1000), very rare (< 1/10000) 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 to < 1/10 |
Uncommon >1/1,000 to < 1/100 |
Very rare < 1/10000 |
Not Known (cannot be estimated from the available data) |
|
Infections and infestations |
Cellulitis1, candidiasis, gastroenteritis2,infection3, vaginal infection |
Pseudomembranous colitis, erysipelaserythrasma | |||
|
Blood and lymphatic system |
Leukopenia, • 4 neutropenia , thrombocythemia3, eosinophilia4 |
Agranulocytosis, thrombocytopenia | |||
|
Immune system disorders5 |
Anaphylactoid reaction1, hypersensitivity |
Anaphylactic reaction, angioedema | |||
|
Metabolism and nutrition disorders |
Anorexia, decreased appetite |
Hypoglycaemia6 | |||
|
Psychiatric disorders |
Insomnia |
Anxiety, nervousness3 |
Psychotic disorder, confusional state, depersonalisation, depression, disorientation, hallucination, abnormal dreams, mania | ||
|
Nervous system disorders |
Dysgeusia, headache, taste perversion |
Loss of consciousness1, dyskinesia1, dizziness, somnolence7, tremor |
Paraesthesia |
Convulsion, ageusia, parosmia, anosmia, | |
|
Ear and labyrinth disorders |
Vertigo, hearing impaired, tinnitus |
Deafness | |||
|
Cardiac disorders |
Cardiac arrest1, atrial fibrillation1, electrocardiogram QT prolonged8, extrasystoles1, palpitations |
Torsade de pointes8, ventricular tachycardia8, ventricular fibrillation | |||
|
Vascular disorders |
Vasodilation1 |
Hemorrhage9 | |||
|
Respiratory, thoracic and mediastinal |
Asthma1, epistaxis2, pulmonary embolism1 |
|
disorder | |||||
|
Gastrointestinal disorders |
Diarrhoea10, vomiting, dyspepsia, nausea, abdominal pain |
Oesophagitis1, gastrooesophageal reflux disease2, gastritis, proctalgia2, stomatitis, glossitis, abdominal distension3, constipation, dry mouth, eructation, flatulence, |
Pancreatitis acute, tongue discolouration, tooth discolouration | ||
|
Hepatobiliary disorders |
Liver function test abnormal |
Cholestasis3, hepatitis4, alanine aminotransferase increased, aspartate aminotransferase increased, gamma-glutamyltransferase increased4 |
Hepatic failure11, jaundice hepatocellular | ||
|
Skin and subcutaneous tissue disorders |
Rash, hyperhidrosis |
Dermatitis bullous1, pruritus, urticaria, rash maculo-papular5 |
Stevens-Johnson syndrome4, toxic epidermal necrolysis5, drug rash with eosinophilia and systemic symptoms (DRESS), acne | ||
|
Musculoskeletal and connective tissue disorders |
Muscle spasms5, musculoskeletal stiffness1, myalgia2, arthralgia |
Rhabdomyolysis2,12, myopathy | |||
|
Renal and urinary disorders |
Renal failure, nephritis interstitial | ||||
|
General disorders and administration site conditions |
Injection site phlebitis1 |
Injection site pain1, injection site inflammation1 |
Malaise3, pyrexia4, asthenia, chest pain3, chills3, fatigue4 | ||
|
Investigations |
Albumin globulin ratio abnormal1, blood alkaline phosphatase increased3, blood lactate dehydrogenase increased4 |
International normalised ratio increased9, prothrombin time prolonged9, urine color abnormal |
6,1,9 See section "Description of selected adverse reactions"
Description of selected adverse reactions
Injection 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 sections 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 sections 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 sections 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 "Other special populations")
Paediatric population
Clinical 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.
Other special populations
Immunocompromised patients
In 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 1000 mg and 2000 mg 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 1000 mg and 2000 mg, but were generally about 3 to 4 times as frequent for those patients who received total daily doses of 4000 mg 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 1000 mg or 2000 mg 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 4000 mg daily for all parameters except White Blood Cell.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard
4.9 Overdose
Symptoms
Reports indicate that the ingestion of large amounts of clarithromycin can be expected to produce gastrointestinal symptoms. Symptoms of overdose may largely correspond to the profile of adverse reactions. One patient who had a history of bipolar disorder ingested 8 grams of clarithromycin and showed altered mental status, paranoid behaviour, hypokaliaemia and hypoxaemia.
Management
There is no specific antidote on overdose. As with other macrolides, clarithromycin serum levels are not expected to be appreciably affected by haemodialysis or peritoneal dialysis.
Adverse reactions accompanying overdosage should be treated by the prompt elimination of unabsorbed drug and supportive measures. Severe acute allergic reactions may be seen very rarely, e.g. anaphylactic shock. At the first signs of hypersensitivity reactions therapy with clarithromycin must be discontinued and the required measures should be initiated immediately.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Macrolides ATC code: J01F A09
Mechanism of action
Clarithromycin is a semi-synthetic derivative of erythromycin A. It exerts its antibacterial action by binding to the 50s ribosomal sub-unit of susceptible bacteria and suppresses protein synthesis. It is highly potent against a wide variety of aerobic and anaerobic gram-positive and gram-negative organisms. The minimum inhibitory concentrations (MICs) of clarithromycin are generally two-fold lower than the MICs of erythromycin.
The 14-hydroxy metabolite of clarithromycin also has antimicrobial activity. The MICs of this metabolite are equal or two-fold higher than the MICs of the parent compound, except for H. influenzae where the 14-hydroxy metabolite is two-fold more active than the parent compound.
Mechanisms of resistance
Resistance mechanisms against macrolide antibiotics include alteration of the target site of the antibiotic or are based on modification and/or the active efflux of the antibiotic. Resistance development can be mediated via chromosomes or plasmids, be induced or exist constitutively. Macrolide-resistant bacteria generate enzymes which lead to methylation of residual adenine at ribosomal RNA and consequently to inhibition of the antibiotic binding to the ribosome. Macrolide-resistant organisms are generally cross-resistant to lincosamides and streptogramin B based on methylation of the ribosomal binding site. Clarithromycin ranks among the strong inducers of this enzyme as well. Furthermore, macrolides have a bacteriostatic action by inhibiting the peptidyl transferase of ribosomes.
A complete cross-resistance exists among clarithromycin, erythromycin and azithromycin. Methicillin-resistant staphylococci and penicillin-resistant Streptococcus pneumoniae are resistant to macrolides such as clarithromycin.
Breakpoints
According to the NCCLS (US National Committee on Clinical Laboratory Standards) in 2003 the following breakpoints have been defined for clarithromycin:
- Staphylococcus spp.: <2 pg/ml susceptible, >8 pg/ml resistant
- Haemophilus spp.: <8 pg/ml susceptible
- Streptococcus spp. including S. pneumoniae: <0.25 pg/ml susceptible, >1 pg/ml resistant
Susceptibility
The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.
Commonly susceptible species (ie resistance < 10 % in all EU Member States) Aerobic, Gram-positive microorganisms
Streptococcus group A
Streptococcus group B
Streptococcus group C,F,G
Aerobic, Gram-negative microorganisms
Moraxella catarrhalis
Pasteurella multocida
*Comments regarding resistance see “Mechanisms of resistance”
5.2 Pharmacokinetic properties
Absorption:
Clarithromycin is rapidly and well absorbed from the gastrointestinal tract - primarily in the jejunum - but undergoes extensive first-pass metabolism after oral administration. The absolute bioavailability of a 250 mg clarithromycin tablet is approximately 50%. Food slightly delays the absorption but does not affect the extent of bioavailability. Therefore, clarithromycin tablets may be given without regard to food. Due to its chemical structure (6-O-methylerythromycin) clarithromycin is quite resistant to degradation by stomach acid. Peak plasma levels of 1-2 pg/ml clarithromycin were observed in adults after oral administration of 250 mg twice daily. After administration of 500 mg clarithromycin twice daily the peak plasma level was 2.8 pg/ml.
After administration of 250 mg clarithromycin twice daily the microbiologically active 14-hydroxy metabolite attains peak plasma concentrations of 0.6 ^g/ml. Steady state is attained within 2 days of dosing.
Distribution:
Clarithromycin penetrates well into different compartments, with an estimated volume of distribution of 200-400 l. Clarithromycin provides concentrations in some tissues that are several times higher than the circulating substance levels. Increased levels have been found in both tonsils and lung tissue. Clarithromycin also penetrates the gastric mucus.
Clarithromycin is approximately 80% bound to plasma proteins at therapeutic levels.
Biotransformation and elimination:
Clarithromycin is rapidly and extensively metabolised in the liver. Metabolism involves mainly N-dealkylation, oxidation and stereospecific hydroxylation at position C 14.
The pharmacokinetics of clarithromycin is non-linear due to saturation of hepatic metabolism at high doses. The elimination half-life increased from 2-4 hours following administration of 250 mg clarithromycin twice daily to 5 hours following administration of 500 mg clarithromycin twice daily. The half-life of the active 14-hydroxy metabolite ranges between 5 to 6 hours following administration of 250 mg clarithromycin twice daily.
After oral administration of radioactive clarithromycin 70-80% of the radioactivity was found in the faeces. Approximately 20-30% of clarithromycin is collected as the unchanged active substance in the urine. This proportion is increased when the dose is increased. Renal insufficiency increases clarithromycin levels in plasma, if the dose is not decreased.
Total plasma clearance has been estimated to approximately 700 ml/min, with a renal clearance of approximately 170 ml/min.
Special populations:
Renal impairment: Reduced renal function results in increased plasma levels of clarithromycin and the active metabolite levels in plasma.
5.3 Preclinical safety data
In 4-week studies in animals, the toxicity of clarithromycin was found to be related to the dose and duration of the treatment. In all species, the first signs of toxicity were observed in the liver, in which lesions were seen within 14 days in dogs and monkeys.
The systemic levels of exposure related to this toxicity are not known in detail, but toxic doses were clearly higher than the therapeutic doses recommended for humans.
No mutagenic effects were found in in vitro or in vivo studies with clarithromycin.
Studies on reproduction toxicity showed that administration of clarithromycin at doses 2x the clinical dose in rabbit (iv) and x10 the clinical dose in monkey (po) resulted in an increased incidence of spontaneous abortions. These doses were related to maternal toxicity. No embryotoxicity or teratogenicity was noted in rat studies. However, cardiovascular malformations were observed in rats treated with doses of 150 mg/kg/day. In mouse at doses x70 the clinical dose cleft palate occurred at varying incidence (3-30%).
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Tablet core:
Sodium starch glycolate Microcrystalline cellulose Povidone (PVP K-30)
Magnesium hydroxide Croscarmellose sodium Colloidal anhydrous silica Stearic acid Magnesium stearate
Film-coat:
Hypromellose (E464)
Titanium dioxide (E171)
Macrogol 400 Tartrazine lake (E102)
Allura Red AC Lake (E129)
Indigo Carmine Lake (E132)
Vanillin
6.2 Incompatibilities
Not applicable
6.3 Shelf life
2 years.
6.4 Special precautions for storage
Do not store above 25°C. Keep container in the outer carton.
6.5 Nature and contents of container
Available in blister packs of transparent or white opaque PVC or PVC/PVdC lidded with aluminium foil of 7, 8, 10, 12, 14, 14 calendar pack, 16, 20, 30, 100 & 120 (10x12) as hospital pack.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements
7. MARKETING AUTHORISATION HOLDER
Teva UK Limited Brampton Road, Hampden Park Eastbourne, BN22 9AG United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 00289/0457
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION 30/06/2009
10 DATE OF REVISION OF THE TEXT
18/08/2016
ADRs reported only for the Powder for Solution for Injection formulation
ADRs reported only for the Extended-Release Tablets formulation
ADRs reported only for the Immediate-Release Tablets formulation
5,8,10,11,12 See "Summary of the safety profile"
ADRs reported only for the Granules for Oral Suspension formulation