Klariger 500 mg Film-coated Tablets

3. PHARMACEUTICAL FORM

Film-coated tablet (tablet)

Yellow, oval, biconvex film coated tablets with ‘“C500’” on one side and ‘“G’” on the other.

4.1 Therapeutic indications

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

Clarithromycin is indicated in adults and children aged 12 years and older.

Clarithromycin Tablets are indicated for treatment of infections caused by susceptible organisms. Indications include:

Lower respiratory tract infections for example, acute and chronic bronchitis, and pneumonia (see section 4.4 and 5.1 regarding Sensitivity Testing).

Upper respiratory tract infections for example, sinusitis and pharyngitis.

Clarithromycin is indicated appropriate for initial therapy in community acquired respiratory infections and has been shown to be active in vitro against common and atypical respiratory pathogens as listed in the microbiology section.

Clarithromycin is also indicated in skin and soft tissue infections of mild to moderate severity (such as e.g. folliculitis, cellulitis, erysipelas pyoderma, impetigo) (see section 4.4 and 5.1 regarding Sensitivity Testing).

Clarithromycin in the presence of acid suppression effected by omeprazole or lansoprazole is also indicated for the eradication of Helicobacter pylori in patients with duodenal ulcers. See section 4.2.

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

Clarithromycin is indicated in adults and children 12 years and older.

4.2 Posology and method of administration

Posology
For doses of 250 mg twice daily, the 250 mg tablet must be used, as the 500 mg tablet cannot be halved.

Patients with respiratory tract/skin and soft tissue infections.

Adults:
Clarithromycin Tablets are available in two strengths, 250 mg and 500 mg. The usual dose is 250 mg twice daily although this may be increased to 500 mg twice daily in severe infections. The usual duration of treatment is 6 to 14 days.

Children older than aged 12 years and older:
As for adults.

Children younger than 12 years
Use of Clarithromycin Tablets is not recommended for children younger than 12 years. 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 (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.

Eradication of HelicobacterH. pylori in patients with duodenal ulcers (Adults)

The usual duration of treatment is 6 to 14 days.

Triple Therapy:
Clarithromycin 500 mg twice daily and lansoprazole 30 mg twice daily should be given with amoxicillin 1000 mg twice daily.

Triple Therapy:
Clarithromycin 500 mg twice daily and lansoprazole 30 mg twice daily should be given with metronidazole 400 mg twice daily (susceptibility testing is recommended if the potential effectiveness of metronidazole therapy is uncertain).

Triple Therapy:
Clarithromycin 500 mg twice daily and omeprazole 40 mg daily should be given with amoxicillin 1000 mg twice daily or metronidazole 400 mg twice daily (susceptibility testing is recommended if the potential effectiveness of metronidazole therapy is uncertain).

Triple Therapy:
Clarithromycin 500 mg twice daily and omeprazole 20 mg daily should be given with amoxicillin 1000 mg twice daily and omeprazole 20 mg daily.

Dual Therapy: The usual dose of Clarithromycin is 500 mg three times daily for 14 days. Clarithromycin should be administered with omeprazole 40 mg once daily.

The tablets should be swallowed whole with some liquid.

Elderly:
As for adults.

Renal impairment:
In patients with renal impairment with creatinine clearance < 30 ml/min, the dosage of clarithromycin should be reduced by 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.

Patients with hepatic dysfunction:  Dosage adjustments are not usually required, but caution should be exercised when administering clarithromycin to patients with impaired hepatic function.

Paediatric population
Children younger than 12 years: Use of Clarithromycin tablets is not recommended for children younger than 12 years. 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 (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.

Method of administration
The tablets should be swallowed whole with some liquid.

Clarithromycin may be given without regard to meals as food does not affect the extent of bioavailability.

4.3 Contraindications

Hypersensitivity to clarithromycin, to any other macrolide antibiotic drug, or to any of the excipients listed in section 6.1.

Concomitant administration of clarithromycin and ergot alkaloids (e.g. ergotamine or dihydroergotamine) is contraindicated, as this may result in ergot toxicity (see section 4.5).

Concomitant administration of clarithromycin and oral midazolam is contraindicated (see section 4.5).

Concomitant administration of clarithromycin and any of the following drugs is contraindicated:

• astemizole, an antihistamine
• cisapride, a motility stimulant
• pimozide, an antipsychotic 
• terfenadine, an antihistamine.

Elevated astemizole (an antihistamine), cisapride (a motility stimulant), pimozide (an antipsychotic) and terfenadine (an antihistamine) levels have been reported in patients receiving either of these drugs and clarithromycin concomitantly. Thisas this may result in QT prolongation and cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation and Torsades de pointes Torsade de Pointes (see section 4.5).

Concomitant administration with ticagrelor or ranolazine is contraindicated.

Similar effects have been observed with concomitant administration of other macrolides.

Clarithromycin should not be given to patients with history of QT prolongation (congenital or documented acquired QT prolongation) or ventricular cardiac arrhythmia, including torsades Torsades de pointespointe (see sections 4.4 and 4.5).

Concomitant administration with ticagrelor or ranolazine is contraindicated.
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). Treatment with these agents should be discontinued during clarithromycin treatment (see section 4.4).

As with other strong CYP3A4 inhibitors, clarithromycin should not be used in patients taking colchicine (see sections 4.4 and 4.5).

Clarithromycin should not be given to patients with hypokalaemia (risk of prolongation of QT-time)

Clarithromycin should not be used in patients who suffer from severe hepatic failure in combination with renal impairment.

As with other strong CYP3A4 inhibitors, clarithromycin should not be used in patients taking colchicine.

4.4 Special warnings and precautions for use

Use of any antimicrobial therapy, such as clarithromycin, to treat Helicobacter pylori infection may select for drug-resistant organisms.

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).

Caution is advised in patients with severe renal insufficiency (see section 4.2).

Clarithromycin is principally excreted by the liver. Therefore, caution should be exercised in administering the this antibiotic 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.

Clarithromycin can be used in patients with known hypersensitivity to penicillin or when penicillin would be inappropriate for other reasons.

Attention should be paid to the possible cross-resistance and cross-allergy between clarithromycin and other macrolides, clindamycin and lincomycin.

Clarithromycin should not be combined with other ototoxic drugs, especially with aminoglycosides. Monitoring of vestibular and auditory function should be carried out during and after treatment. 

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.

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 clarithromycin and colchicine is contraindicated (see section 4.3).

Caution is advised regarding concomitant administration of clarithromycin and triazolobenzodiazepines, such as triazolam, and intravenous or oromucosal midazolam (see section 4.5).

Prolongation of the QT Interval
Prolonged cardiac repolarisation and QT interval, imparting a risk of developing cardiac arrhythmia and Torsadestorsade 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 of ventricular arrhythmias (including Torsadestorsade de pointes), clarithromycin should be used with caution in the following patients:
• Patients with a 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 a 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 (associated with erythrasma), acne vulgaris, and erysipelas and in situations where penicillin treatment cannot be used.

In the event of severe acute hypersensitivity reactions, such as anaphylaxis, severe cutaneous adverse reactions (SCAR) (e.g. Acute generalised exanthematous pustulosis (AGEP),  Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and Drug reaction with eosinophilia and systemic symptoms (DRESS), 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 whenever indicated for use in patients receiving treatment with an inducer of CYP3A4 enzyme due to the possibility of sub therapeutic levels of clarithromycin (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 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). Caution should be exercised when prescribing clarithromycin with other statins.  Rhabdomyolysis has been reported in patients taking clarithromycin with 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 possible doses of the statin.  Use of a statin that is not dependent on CYP3A metabolism (e.g. fluvastatin) should be considered (see section 4.5).

Oral hypoglycaemic agents/insulin:
The concomitant use of clarithromycin and oral hypoglycaemic agents (such as sulfonylureas) 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 Normalised Ratio (INR) and prothrombin time when clarithromycin is co-administered with warfarin (see section 4.5). INR and prothrombin times should be frequently monitored while patients are receiving clarithromycin and oral anticoagulants concurrently.

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 (erythrasma), 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, toxic epidermal necrolysis, DRESS and Henoch-Schönlein purpura, clarithromycin therapy should be discontinued immediately and appropriate treatment should be urgently initiated.

Streptococcus pyogenes:
Clarithromycin is generally effective in the eradication of Streptococci from the oropharynx. However, data establishing the efficacy of this antibiotic in the subsequent prevention of rheumatic fever are not available.

In pharyngitis related to beta-haemolytic streptococcal infection the treatment duration should be at least 10 days.

H. pylori:
Use of any antimicrobial therapy, such as clarithromycin, to treat H. pylori infection may select for drug-resistant organisms.

Long-term use may, as with other antibiotics, result in colonisation with increased numbers of non-susceptible bacteria and fungi. If superinfections occur, appropriate therapy should be instituted.

Attention should also be paid to the possibility of cross-resistance and cross-allergy between clarithromycin and other macrolides, clindamycin and lincomycin.

Oral anticoagulants: There is a risk of serious haemorrhage and significant elevations in International Normalised Ratio (INR) and prothrombin time when clarithromycin is co-administered with warfarin (see section 4.5). INR and prothrombin times should be frequently monitored while patients are receiving clarithromycin and oral anticoagulants concurrently.

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 clarithromycin and colchicine is contraindicated (see section 4.3).

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 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 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 Ergot alkaloids
Postmarketing reports indicate that co-administration of clarithromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterised 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).

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.

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.

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 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.

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. A 39% reduction in AUC for clarithromycin and a 34% increase in AUC for the active 14-hydroxy metabolite have been seen when clarithromycin was used concomitantly with the CYP3A4 inducer efavirenz. In such circumstances, it may be necessary to increase the dose of clarithromycin and monitor the safety and efficacy. Monitoring the plasma levels of the CYP3A4 inducer may be necessary because the levels could be increased owing to the inhibition of CYP3A4 by clarithromycin (see also the relevant medicinal product information for the CYP3A4 inducer administered).

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.

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 gm/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)

The effect tEffects of clarithromycin tablets on other medicinal products

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. Alternatively, treatment with these medicinal products may be interrupted during clarithromycin treatment.

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 exhaustive. 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 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 hypoglycaemia 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 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 (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.  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 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. 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.

The effect of other medicinal products on clarithromycin tablets

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.
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. A 39% reduction in AUC for clarithromycin and a 34% increase in AUC for the active 14-hydroxy metabolite have been seen when clarithromycin was used concomitantly with the CYP3A4 inducer efavirenz. In such circumstances, it may be necessary to increase the dose of clarithromycin and monitor the safety and efficacy.  Monitoring the plasma levels of the CYP3A4 inducer may be necessary because the levels could be increased owing to the inhibition of CYP3A4 by clarithromycin (see also the relevant medicinal product information for the CYP3A4 inducer administered).

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.

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 gm/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)

Other drug interactions

Aminoglycosides
Caution is advised regarding concomitant administration of clarithromycin with other ototoxic drugs, especially with aminoglycosides. See section 4.4.

4.8 Undesirable effects

*Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Patient exposure is estimated to be greater than 1 billion patient treatment days for clarithromycin

d. Paediatric populations

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.

5.1  Pharmacodynamic properties

Therapeutic Class Pharmacotherapeutic group: General anti-infectives for systemic use: Antibiotics Antibacterial for systemic use, macrolide.
ATC Code: J01 FA09

4.1 Therapeutic indications

Clarithromycin Tablets are indicated for treatment of infections caused by susceptible organisms. Indications include:

Lower respiratory tract infections for example, acute and chronic bronchitis, and pneumonia.

Upper respiratory tract infections for example, sinusitis and pharyngitis.

Clarithromycin is appropriate for initial therapy in community acquired respiratory infections and has been shown to be active in vitro against common and atypical respiratory pathogens as listed in the microbiology section.

Clarithromycin is also indicated in skin and soft tissue infections of mild to moderate severity (such as cellulitis, pyoderma, impetigo).

Clarithromycin in the presence of acid suppression effected by omeprazole or lansoprazole is also indicated for the eradication of HelicobacterH. pylori in patients with duodenal ulcers. See section 4.2.
Consideration should be given to official guidance on the appropriate use of antibacterial agents.

Clarithromycin is indicated in adults and children 12 years and older.

Clarithromycin is usually active against the following organisms in vitro:
Gram-positive Bacteria: Staphylococcus aureus (methicillin susceptible); Streptococcus pyogenes (Group A beta-haemolytic streptococci); alpha-haemolytic streptococci (viridans groups); Streptococcus (Diplococcus) pneumoniae; Streptococcus agalactiae; Listeria monocytogenes.

Gram-negative Bacteria: Haemophilus influenzae; Haemophilus parainfluenzae; Moraxella (Branhamella) catarrhalis; Neisseria gonorrhoeae; Legionella pneumophila; Bordetella pertussis; Helicobacter pylori; Campylobacter jejuni.

Mycoplasma: Mycoplasma pneumoniae; Ureaplasma urealyticum.

Other Organisms: Chlamydia trachomatis; Mycobacterium avium; Mycobacterium leprae.

Anaerobes: Macrolide-susceptible Bacteroides fragilis; Clostridium perfringens; Peptococcus species; Peptostreptococcus species; Propionibacterium acnes.

Clarithromycin has bactericidal activity against several bacterial strains. The organisms include Haemophilus influenzae; Streptococcus pneumoniae; Streptococcus pyogenes; Streptococcus agalactiae; Moraxella (Branhamella) catarrhalis; Neisseria gonorrhoeae; H. pylori and Campylobacter sppspecies.

The activity of clarithromycin against H. pylori is greater at neutral pH than at acid pH.

4.2 Posology and method of administration

Posology
For doses of 250 mg twice daily, the 250 mg tablet must be used, as the 500 mg tablet cannot be halved.

Children younger than 12 years: Use of Clarithromycin tablets/IV is not recommended for children younger than 12 years. Use Clarithromycin paediatric suspension

4.3 Contraindications

Hypersensitivity to clarithromycin, to any other macrolide antibiotic drug, or to any of the excipients listed in section 6.1.

Concomitant administration of clarithromycin and ergotamine or dihydroergotamine is contraindicated, as this may result in ergot toxicity.

Concomitant administration of clarithromycin and any of the following drugs is contraindicated:

• astemizole, an antihistamine
• cisapride, a motility stimulant
• pimozide, an antipsychotic 
• terfenadine, an antihistamine.

Elevated astemizole, cisapride, pimozide and terfenadine levels have been reported in patients receiving either of these drugs and clarithromycin concomitantly. This may result in QT prolongation and cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation and Torsade de Pointes (see section 4.5).

Concomitant administration with ticagrelor or ranolazine is contraindicated.

Similar effects have been observed with concomitant administration of other macrolides.

Clarithromycin should not be given to patients with history of QT prolongation (congenital or documented acquired QT prolongation) or ventricular cardiac arrhythmia, including torsades de pointe (see sections 4.4 and 4.5).

4.4 Special warnings and precautions for use

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 of ventricular arrhythmias (including torsade de pointes)Due to a risk of increased QT-interval, clarithromycin should be used with caution in the following patients:
• patients Patients with a coronary artery disease, severe cardiac insufficiency orhypomagnesaemia, conduction disturbances or clinically relevant bradycardia (less than 50 bpm)
• Patients with electrolyte disturbances such as hypomagnesaemia.  Clarithromycin must not be given to patients with hypokalaemia (see section 4.3)
• or Patients concomitantly taking when co-administered with other medicinal products associated with a QT prolongation QT-prolonging effect  (see section 4.5).
• Concomitant administration of clarithromycin with astemizole, cisapride, pimozide and terfenadine is contraindicated (see section 4.3)
• Clarithromycin should must not be used in patients with congenital or documented aquired acquired QT prolongation or a history of ventricular arrhythmia (see section 4.3).

4.5 Interaction with other medicinal products and other forms of interaction

The effect of clarithromycin tablets on other medicinal products

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. Alternatively, treatment with these medicinal products may be interrupted during clarithromycin treatment.

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. Drugs interacting by similar mechanisms through other isozymes within the cytochrome P450 system include phenytoin, theophylline and valproate.

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 hypoglycaemia hypolgycaemia when used concomitantly. Careful monitoring of glucose 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 Pgp and/or CYP3A by clarithromycin may lead to increased exposure to colchicine. Concomitant administration of clarithromycin and colchicine is contraindicated (see section sections 4.3 and section 4.4).

4.8 Undesirable effects

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		Oral moniliasis	Candidiasis,  vaginal infection		Erysipelas, pseudomembranous colitis,
Blood and lymphatic system			Leukopenia, neutropenia1, eosinophilia1		Agranulocytosis, thrombocytopenia
Immune system disorders			Hypersensitivity		Anaphylactic reaction, angioedema
Metabolism and nutrition disorders			Anorexia, decreased appetite
Psychiatric disorders		Insomnia	Anxiety	Nightmares	Psychotic disorder, confusional state, depersonalisation, depression, disorientation, hallucination, abnormal dreams, mania
Nervous system disorders		Dysgeusia, headache, taste perversion,	Dizziness, somnolence4, tremor	Paraesthesia	Convulsion, ageusia parosmia, anosmia
Ear and labyrinth disorders			Vertigo, hearing impaired, tinnitus		Deafness
Cardiac disorders			Electrocardiogram QT prolonged, palpitations		Torsade de pointes, ventricular tachycardia, ventricular fibrillation
Vascular disorders					Haemorrhage
Gastrointestinal disorders		Diarrhoea3, vomiting, dyspepsia, nausea,  abdominal pain, stomatitis, glossitis	Abdominal distension1, constipation, dry mouth, eructation, flatulence, gastritis		Pancreatitis acute, tongue discolouration, tooth discolouration
Hepatobiliary disorders		Liver function test abnormal	Cholestasis1, hepatitis1, alanine aminotransferase increased, aspartate aminotransferase increased, gamma-glutamyltransferase increased1		Hepatic failure, jaundice hepatocellular
Skin and subcutaneous tissue disorders		Rash, hyperhidrosis	Pruritus, urticaria		Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS), acne, Henoch-Schonlein purpura
Musculoskeletal and connective tissue disorders					Rhabdomyolysis4, myopathy
Renal and urinary disorders					Renal failure, nephritis interstitial
General disorders and administration site conditions			Malaise1, asthenia, chest pain1, chills1, fatigue1
Investigations		Elevated BUN (blood urea nitrogen)	Serum creatinine raised, blood alkaline phosphatase increased1, blood lactate dehydrogenase increased1		International normalised ratio increased, urine color colour abnormal prothrombin time prolonged

5.3 Preclinical safety data

Fertility and reproduction studies in rats have shown no adverse effects. Teratogenicity studies in rats (Wistar (p.o.) and Sprague-Dawley (p.o. and i.v.)), New Zealand White rabbits and cynomolgus cynomolgous monkeys failed to demonstrate any teratogenicity from clarithromycin. However, a further similar study in Sprague-Dawley rats indicated a low (6%) incidence of cardiovascular abnormalities which appeared to be due to spontaneous expression of genetic changes. Two mouse studies revealed a variable incidence (3-30%) of cleft palate and embryonic loss was seen in monkeys but only at dose levels which were clearly toxic to the mothers.

 

Change to a separate SPC for 500 mg as 250 mg permanently ceased marketing.

Extensive updates to the SmPC in line with the reference product and Core Safety Profile.

In section 6.3, the shelf-life of blisters has been changed from 2 years to 3 years.

Extensive updates to sections 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9 in line with Core Safety Profile.

4.4 Special warnings and precautions for use
......addition of following paragraph
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).

4.5 Interaction with other medicinal products and other forms of interaction
......addition of following paragraph under heading Inducers of CYP3A4

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 colchicines. Patients should be monitored for clinical symptoms of colchicine toxicity (see Section 4.4).

4.8 Undesirable effects
......addition of following paragraph
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 Sections 4.4 and 4.5).