NAME OF THE MEDICINAL PRODUCT

Clarithromycin 125mg/5ml suspension

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

After reconstitution 1 ml oral suspension contains 25 mg clarithromycin,

5 ml oral suspension contain 125 mg clarithromycin.

The product contains 2.4 g sucrose per 5 ml ready- for- use suspension.

For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Granules for oral suspension.

White to beige granules.

4. CLINICAL PARTICULARS

4.1    Therapeutic indications

Clarithromycin 25 mg/ml granules for oral suspension is indicated in adults, adolescents and children, 6 months to 12 years, for the treatment of the following acute and chronic infections, when caused by clarithromycin susceptible organisms.

•    Infections of the upper respiratory tract such as tonsillitis/pharyngitis, as an alternative when beta lactam antibiotics are not appropriate.

•    Acute otitis media in children.

•    Infections of the lower respiratory tract such as community acquired pneumonia.

•    Sinusitis and acute exacerbation of chronic bronchitis in adults and adolescents over 12 years of age

•    Skin infections and soft tissue infections of mild to moderate severity.

In appropriate combination with antibacterial therapeutic regimens and an appropriate ulcer healing medicinal product for the eradication of Helicobacter pylori in adult 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 25 mg/ml granules for oral suspension depends on the clinical condition of the patient and has to be defined in any case by the physician.

Adults and adolescents:

Standard dosage: The usual dose is 250 mg twice daily.

High dosage treatment (severe infections): The usual dose may be increased to 500 mg twice daily in severe infections.

Elimination of Helicobacter pylori in adults:

In patients with gastro-duodenal ulcers due to H. pylori infection clarithromycin as part of the first line triple therapy is given in a dosage of 500 mg twice daily. The national recommendations for Helicobacter pylori eradication have to be considered.

Dosage in renal functional impairment:

The maximum recommended dosages should be reduced proportionately to renal impairment.

At creatinine clearance rate of less than 30 ml/min, the dosage should be halved to 250 mg daily or in the most severe infections to 250 mg twice daily. The duration of treatment should not exceed 14 days in these patients.

Children 6 months to 12 years of age:

The recommended dose is 7.5 mg/kg twice a day.

Weight	Age	Dosage
8 - 11 kg	1 - 2 years	2.5 ml twice daily
12 - 19 kg	2 - 4 years	5.0 ml twice daily
20 - 29 kg	4 - 8 years	7.5 ml twice daily
30 - 40 kg	8 - 12 years	10.0 ml twice daily

Children weighing less than 8 kg should be treated based on their bodyweight.

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 is limited experience of treatment of children below 6 months of age.

For the indication community acquired pneumonia effect in children under 3 years of age is not documented.

In renal insufficiency, especially if the creatinine clearance is < 30 ml/min, the dose must be halved, i.e. 7.5 mg/kg once a day, and the duration of treatment should not exceed 14 days..

Duration of therapy:

The duration of therapy with Clarithromycin 25 mg/ml granules for oral suspension depends on the clinical condition of the patient. The duration of therapy has in any case to be determined by the physician.

• The usual duration of treatment of children up to 12 years of age is 5 to 10 days.

•    The usual duration of treatment of adults and adolescents is 6 to 14 days.

•    Therapy should be continued at least for 2 days after symptoms have subsided.

•    In streptococcus pyogenes (as a beta-haemolytic streptococcal) infections the duration of therapy should be at least 10 days.

•    Combination therapy for the eradication of H. pylori infection, e.g. clarithromycin 500 mg twice daily in combination with amoxicillin 1000 mg twice daily and omeprazole 20 mg twice daily should be continued for 7 days.

Method of administration:

Before administration the granules must be reconstituted with water, see section 6.6. For administration after reconstitution an oral PE/PP-measuring syringe or a PP-measuring spoon are used.

Granules of the oral suspension can cause a bitter aftertaste when remaining in the mouth. This can be avoided by eating or drinking something immediately after the intake of the suspension

Clarithromycin may be given irrespective of food intake. Food does not affect the extent of bioavailability. Food does only slightly delay the onset of absorption of clarithromycin.

4.3    Contraindications

Clarithromycin 25 mg/ml granules for oral suspension must not be used in patients with a hypersensitivity to the active substance, other macrolide antibiotics or to any of the excipients.

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 active substances is contraindicated: astemizole, cisapride, pimozide and terfenadine. This may result in QT prolongation and cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation and Torsade de Pointes (see section 4.5).

Clarithromycin 25 mg/ml granules for oral suspension must not be administered to hypokalemic patients (risk of prolongation of QT-time, see section 4.4).

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

Clarithromycin must not be used concomitantly with HMG-CoA reductase inhibitors (statins), lovastatin or simvastatin, due to the risk of rhabdomyolysis. Treatment with these agents should be discontinued during clarithromycin treatment (see section 4.4).

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

4.4    Special warning 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).

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 is mainly excreted by the liver. Therefore, caution should be taken in administering clarithromycin to patients with impaired hepatic function.

Cases of fatal hepatic failure (see section 4.8) have been reported. Some patients may have had preexisting 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.

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. Caution is advised with severe renal insufficiency.

Clarithromycin therapy for H. pylori may select for drug-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.

Prolonged or repeated use of clarithromycin may result in superinfections with non-susceptible bacteria or fungi. In case of superinfection, clarithromycin therapy should be stopped and 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 diarrhea (CDAD) has been reported with use of nearly all antibacterial agents including clarithromycin, and may range in severity from mild diarrhea 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 diarrhea 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.

Due to a risk of increased QT-interval, clarithromycin should be used with caution in patients with a coronary artery disease, severe cardiac insufficiency, non-compensated hypokalemia and/or hypomagnesemia, bradycardia (< 50 bpm), or when co-administered with other medicinal products with a QT-prolonging effect (see section 4.5). Clarithromycin must not be used in patients with congenital or documented acquired QT prolongation or history of ventricular arrhythmia (see section 4.3).

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). If concomitant administration of colchicine and clarithromycin is necessary, patients should be monitored for clinical symptoms of colchicine toxicity.

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.

Clarithromycin should be used with caution whenever indicated for use in patients receiving treatment with an inducer of CYP3A4 (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: Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated (see section 4.3). As with other macrolides, clarithromycin has been reported to increase concentrations of HMG-CoA reductase inhibitors (see section 4.5). Rare reports of rhabdomyolysis have been reported in patients taking these drugs concomitantly. Patients should be monitored for signs and symptoms of myopathy. Rare reports of rhabdomyolysis have also been reported in patients taking atorvastatin or rosuvastatin concomitantly with clarithromycin. When used with clarithromycin, atorvastatin or rosuvastatin should be administered in the lowest possible doses. Adjustment of the statin dose or use of a statin that is not dependent on CYP3A metabolism (e.g. fluvastatin or pravastatin) should be considered.

Oral hypoglycemic agents/Insulin: The concomitant use of clarithromycin and oral hypoglycemic agents and/or insulin can result in significant hypoglycemia. With certain hypoglycemic drugs such as nateglinide, pioglitazone, repaglinide and rosiglitazone, inhibition of CYP3A enzyme by clarithromycin may be involved and could cause hypolgycemia when used concomitantly. Careful monitoring of glucose is recommended.

Oral anticoagulants: There is a risk of serious hemorrhage and significant elevations in International Normalized 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.

Exacerbation or aggravation of Myasthenia gravis may occur.

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 (erythrasma), acne vulgaris, and erysipelas and in situations where penicillin treatment cannot be used.

This medicinal product contains 2.4 g powdered sucrose per 5 ml ready-for-use suspension. This should be taken into account in patients with diabetes mellitus. Patients with rare hereditary problems of fructose intolerance, glucosegalactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

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

Postmarketing reports indicate that co-administration of clarithromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm, and ischemia of the extremities and other tissues including the central nervous system. Concomitant administration of clarithromycin and these medicinal products is contraindicated (see section 4.3).

The effect of other medicinal products on clarithromycin

Clarithromycin is an inhibitor of the metabolising enzyme CYP3A4 and the transport protein P-glycoprotein. The degree of inhibition with different CYP3A4 substrates is difficult to predict. Hence, clarithromycin should not be used during treatment with other medicinal products that are substrates for CYP3A4, unless plasma levels, therapeutic effect or adverse events of the CYP3A4 substrate can be closely monitored. A dose reduction may be necessary for medicinal products that are substrates for CYP3A4 if co-administered with clarithromycin. Alternatively, treatment with these products may be interrupted during clarithromycin treatment.

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.

Products that are inducers of CYP3A4 (e.g. rifampicin, phenytoin, carabamazepin, phenobarbital,

St. Johns wort) may induce the metabolism of clarithromycin. This may result in sub-therapeutic levels of clarithromycin leading to a reduced efficacy. When clarithromycin is clearly indicated it might be necessary to increase the dose of clarithromycin and monitor the efficacy and safety of clarithromycin carefully. Furthermore monitoring the plasma levels of the CYP3A4 inducer might be necessary because the latter could be increased owing to the inhibition of CYP3A4 by clarithromycin (see also the relevant product information for the CYP3A4 inducer administered). Concomitant administration of rifabutin and clarithromycin resulted in an increase and decrease, respectively, in serum levels, followed by 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.

Fluconazole

Concomitant administration of fluconazole 200 mg daily and clarithromycin 500 mg twice daily to 21 healthy volunteers led to increases in the mean steady-state minimum clarithromycin concentration (C_min) and area under the curve (AUC) of 33% and 18% respectively. Steady state concentrations of the active metabolite 14-OH-clarithromycin were not significantly affected by concomitant administration of fluconazole. No clarithromycin dose adjustment is necessary.

Ritonavir

Ritonavir (200 mg three times daily) have been shown to inhibit the metabolism of clarithromycin (500 mg twice daily), with an increase in C_max, C_min and AUC of 31, 182 and 77%, respectively, when co-administered with ritonavir. Formation of the active 14-OH-hydroxy metabolite was almost completely inhibited. A general dose reduction is probably not required in patients with normal renal function, but the daily dose of clarithromycin should not exceed 1 g. Dose reduction should be considered in patients with renal impairment. For patients with a creatinine clearance of 30 to 60 ml/min, the clarithromycin dose should be reduced with 50%, and at a creatinine clearance of < 30 ml/min the dose should be reduced with 75%.

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).

Interaction in eradication of H.pylori regimens

Although the plasma concentrations of clarithromycin and omeprazole may be increased when they are administered concurrently, no adjustment to the dosage is necessary. At the dosages recommended, there is no clinically significant interaction between clarithromycin and lansoprazole. Increased plasma concentrations of clarithromycin may also occur when it is coadministered with antacids or ranitidine. No adjustment to the dosage is necessary. There are no pharmacokinetic interactions with relevant antibiotics which are used in H. pylori eradication therapy.

Effect of clarithromycin on other medicinal products

CYP3A-based interactions

Co-administration of clarithromycin, known to inhibit CYP3A, and a drug primarily metabolized by CYP3A may be associated with elevations in drug concentrations that could increase or prolong both therapeutic and adverse effects of the concomitant drug. Clarithromycin should be used with caution in patients receiving treatment with other drugs known to be CYP3A enzyme substrates, especially if the CYP3A substrate has a narrow safety margin (e.g. carbamazepine) and/or the substrate is extensively metabolized by this enzyme.

Dosage adjustments may be considered, and when possible, serum concentrations of drugs primarily metabolized by CYP3A should be monitored closely in patients concurrently receiving clarithromycin.

The following drugs or drug classes are known or suspected to be metabolized by the same CYP3A isozyme: alprazolam, astemizole, carbamazepine, cilostazol, cisapride, cyclosporine, disopyramide, ergot alkaloids, lovastatin, methylprednisolone, midazolam, omeprazole, oral anticoagulants (e.g. warfarin), pimozide, quinidine, rifabutin, sildenafil, simvastatin, sirolimus, tacrolimus, terfenadine, triazolam and vinblastine. Drugs interacting by similar mechanisms through other isozymes within the cytochrome P450 system include phenytoin, theophylline and valproate.

Antiarrhythmics

Cases with torsades de pointes has been reported in patients where clarithromycin has been coadministered with quinidine or disopyramid. These combinations should therefore be avoided, or plasma levels of quinidine or disopyramid closely monitored to allow dose adjustment. Electrocardiograms should be monitored for QT prolongation during co-administration of clarithromycin with these drugs.

Caution is warranted when clarithromyin is administered to patients treated taking other medicinal products with the potential to prolong QT (see section 4.4).

Cyclosporin, tacrolimus and sirolimus

Concomitant use of oral clarithromycin and cyclosporin or tacrolimus have resulted in more than a 2-fold increase of the C_min-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 (see section 4.4 and 4.8).

Omeprazole

Clarithromycin (500 mg every 8 hours) was given in combination with omeprazole (40 mg daily) to healthy adult subjects. The steady-state plasma concentrations of omeprazole were increased (C_max, AUC_0-24, and t_1/2 increased by 30%, 89%, and 34%, respectively), by the concomitant administration of clarithromycin. The mean 24-hour gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when omeprazole was co-administered with clarithromycin.

Sildenafil, tadalafil, and vardenafil

Each of these phosphodiesterase inhibitors is metabolized, at least in part, by CYP3A, and CYP3A may be inhibited by concomitantly administered clarithromycin. Co-administration of clarithromycin with sildenafil, tadalafil or vardenafil would likely result in increased phosphodiesterase inhibitor exposure. Reduction of sildenafil, tadalafil and vardenafil dosages should be considered when these drugs are co-administered with clarithromycin.

Theophylline, carbamazepine

Results of clinical studies indicate there was a modest but statistically significant (p<0.05) increase of circulating theophylline or carbamazepine levels when either of these drugs were administered concomitantly with clarithromycin. Dose reduction may need to be considered.

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 (250 mg twice daily), midazolam AUC was increased 2.7-fold after intravenous administration of midazolam and 7-fold after oral administration. Concomitant administration of oral midazolam and clarithromycin should be avoided. If intravenous midazolam is co-administered with clarithromycin, the patient must be closely monitored to allow dose adjustment. The same precautions should also apply to other benzodiazepines that are metabolised by CYP3A4, especially triazolam but also alprazolam. For benzodiazepines which are not metabolised by CYP3A4 (temazepam, nitrazepam, lorazepam) an interaction with clarithromycin is unlikely.

There have been post-marketing reports of drug interactions and central nervous system (CNS) effects (e.g. somnolence and confusion) with the concomitant use of clarithromycin and triazolam. Monitoring the patient for increased CNS pharmacological effects is suggested.

HMG-CoA reductase inhibitors

Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated (see section 4.3). As with other macrolides, clarithromycin has been reported to increase concentrations of HMG-CoA reductase inhibitors. Rare reports of rhabdomyolysis have been reported in patients taking these drugs concomitantly. Patients should be monitored for signs and symptoms of myopathy. Rare reports of rhabdomyolysis have also been reported in patients taking atorvastatin or rosuvastatin concomitantly with clarithromycin. When used with clarithromycin, atorvastatin or rosuvastatin should be administered in the lowest possible doses. Adjustment of the statin dose or use of a statin that is not dependent on CYP3A metabolism (e.g. fluvastatin or pravastatin) should be considered (see section 4.4).

Oral hypoglycemic agents/Insulin

The concomitant use of clarithromycin and oral hypoglycemic agents and/or insulin can result in significant hypoglycemia. With certain hypoglycemic drugs such as nateglinide, pioglitazone, repaglinide and rosiglitazone, inhibition of CYP3A enzyme by clarithromycin may be involved and could cause hypolgycemia when used concomitantly. Careful monitoring of glucose is recommended.

Other drug interactions

Colchicin

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

Digoxin and other active substances transported by P-glycoprotein

Claritromycin is a potent inhibitor of the transport protein P-glycoprotein (Pgp). This could give rise to increased plasma concentrations of active substances which are transported by this transporter and may also increase distribution of such active substances to organs having Pgp as an distribution barrier eg CNS. The concentration of the Pgp substrate digoxin may be increased when co-administered with clarithromycin.. Elevated digoxin serum concentrations in patients receiving clarithromycin and digoxin concomitantly have 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 levels. 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 metabolized 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.

Other ototoxic drugs, especially aminoglycosides

In case of 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 (see section 4.4).

Bi-directional drug interactions

Atazanavir

Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction. Co-administration of clarithromycin (500 mg twice daily) with atazanavir (400 mg once daily) resulted in a 2-fold increase in exposure to clarithromycin and a 70% decrease in exposure to 14-OH-clarithromycin, with a 28% increase in the AUC of atazanavir. Because of the large therapeutic window for clarithromycin, no dosage reduction should be necessary in patients with normal renal function. For patients with moderate renal function (creatinine clearance 30 to 60 mL/min), the dose of clarithromycin should be decreased by 50%.

For patients with creatinine clearance <30 mL/min, the dose of clarithromycin should be decreased by 75% using an appropriate clarithromycin formulation. Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors.

Itraconazole

Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A, leading to a bidirectional drug interaction. Clarithromycin may increase the plasma levels of itraconazole, while itraconazole may increase the plasma levels of clarithromycin. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged pharmacologic effect.

Saquinavir

Both clarithromycin and saquinavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction. Concomitant administration of clarithromycin (500 mg twice daily) and saquinavir (soft gelatin capsules, 1200 mg three times daily) to 12 healthy volunteers resulted in steady-state AUC and C_max values of saquinavir which were 177% and 187% higher than those seen with saquinavir alone. Clarithromycin AUC and C_max values were approximately 40% higher than those seen with clarithromycin alone. No dose adjustment is required when the two drugs are co-administered for a limited time at the doses/formulations studied. Observations from drug interaction studies using the soft gelatin capsule formulation may not be representative of the effects seen using the saquinavir hard gelatin capsule. Observations from drug interaction studies performed with saquinavir alone may not be representative of the effects seen with saquinavir/ritonavir therapy. When saquinavir is co-administered with ritonavir, consideration should be given to the potential effects of ritonavir on clarithromycin.

Verapamil

Hypotension, bradyarrhythmias and lactic acidosis have been observed in patients taking clarithromycin and verapamil concomitantly

4.6    Pregnancy and lactation

Pregnancy

Data on the use of clarithromycin during the first trimester of more than 200 pregnancies show no clear evidence of teratogenic effects, or of adverse effects on the health of the neonate. Data from a limited number of pregnant women exposed in the first trimester indicate a possible increased risk of abortions. To date no other relevant epidemiological data are available.

Data from animal studies have shown reproductive toxicity (see section 5.3). The risk for humans is unknown. Clarithromycin should only be used during pregnancy after a careful benefit/risk assessment.

Lactation

Clarithromycin and its active metabolite are excreted in 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 born 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. When performing these activities the possible occurrence of the adverse reactions such as dizziness, vertigo, confusion and disorientation should be taken into account.

4.8 Undesirable effects

a. Summary of the safety profile

The most frequent and common adverse reactions related to clarithromycin therapy for both adult and pediatric populations are abdominal pain, diarrhea, nausea, vomiting and taste perversion. These adverse reactions are usually mild in intensity and are consistent with the known safety profile of macrolide antibiotics (see section b of section 4.8).

There was no significant difference in the incidence of these gastrointestinal adverse reactions during clinical trials between the patient population with or without preexisting mycobacterial infections.

b. Tabulated summary of adverse reactions

In this section undesirable effects are defined as follows:

Very common (> 1/10)

Common (> 1/100 to < 1/10)

Uncommon (> 1/1,000 to < 1/100)

Rare (> 1/10,000 to < 1/1,000)

Very rare (< 1/10,000), not known (cannot be estimated from the available data)

Infections and infestations Common: Oral monilia

Uncommon: Candidiasis, infection, vaginal infection Not known: Erysipelas, erythrasma

As with other antibiotics, prolonged use may result in the overgrowth of non-susceptible organisms.

Blood and lymphatic system disorders Uncommon: Leucopenia, thrombocythemia Very rare: Thrombocytopenia Not known: Agranulocytosis

Immune system disorders

Uncommon: Allergic reactions ranging from urticaria and mild skin eruptions to anaphylaxis.

Metabolism and nutrition disorders Uncommon: Anorexia, decreased appetite

Psychiatric disorders Common: Insomnia

Uncommon: Anxiety nervousness, screaming

Very rare: Hallucinations, psychotic disorder, disorientation, depersonalisation, depression, abnormal dreams and confusional state

Nervous system disorders

Common: Headache, smell alteration, taste perversion, dysgeusia Uncommon: Dizziness, tremor Very rare: Paraesthesia, convulsions Not known: Ageusia, parosmia, anosmia

Ear and labyrinth disorders Uncommon: Vertigo, hearing impaired, tinnitus Very rare: Reversible hearing loss Not known: Deafness

Cardiac disorders Uncommon: Palpitations

Very rare: QT prolongation, ventricular tachycardia and Torsades de Pointes Gastrointestinal disorders

Common: Nausea, diarrhoea, vomiting, abdominal pain, dyspepsia, stomatitis, glossitis, reversible tooth and tongue discoloration

Uncommon: Gastritis, constipation, dry mouth, eructation, flatulence

Very rare: Pancreatitis. Pseudomembranous colitis has been reported very rarely with

clarithromycin, and may range in severity from mild to life threatening.

Hepatobiliary disorders

Uncommon: Hepatic dysfunction, which is usually transient and reversible, hepatitis and cholestasis with or without jaundice,

Very rare: Fatal hepatic failure has been reported particularly in patients with pre-existing liver disease or taking other hepatotoxic medicinal products.

Skin and subcutaneous tissue disorders

Common: Rash, hyperhidrosis

Uncommon: Pruritus, urticaria, rash maculo-papular

Very rare: Stevens-Johnson syndrome and toxic epidermal necrolysis

Not known: Drug rash with eosinophilia and systemic symptoms (DRESS), acne

Musculoskeletal, connective tissue and bone disorders Uncommon: Arthralgia, myalgia, muscle spasms Not known: Myopathy

Renal and urinary disorders

Very rare: Interstitial nephritis, renal failure.

General disorders and administration site conditions Uncommon: Pyrexia, asthenia

Investigations

Common: Elevated blood urea nitrogen, liver function test abnormal

Uncommon: Prolongation of prothrombin time, elevated serum creatinine, alanine aminotransferase increased, aspartate aminotransferase increased

Very rare: Hypoglycaemia has been observed especially after concomitant administration with antidiabetic medicinal products and insulin Not known: Urine color abnormal

c. Description of selected adverse reactions

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 diarrhea should be paid as Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents including clarithromycin, and may range in severity from mild diarrhea to fatal colitis (see section 4.4).

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 diarrhea subsequent to the administration of antibacterial agents (see section 4.4).

In the event of severe acute hypersensitivity reactions, such as anaphylaxis, Stevens-Johnson Syndrome and toxic epidermal necrolysis, clarithromycin therapy should be discontinued immediately and appropriate treatment should be urgently initiated (see section 4.4).

As with other macrolides, QT prolongation, ventricular tachycardia, and torsade de pointes have rarely been reported with clarithromycin (see section 4.4 and 4.5).

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 hypoglycemia, some of which have occurred in patients on concomitant oral hypoglycemic agents or insulin (see section 4.4 and 4.5).

There have been post-marketing reports of drug interactions and central nervous system (CNS) effects (e.g. somnolence and confusion) with the concomitant use of clarithromycin and triazolam. Monitoring the patient for increased CNS pharmacological effects is suggested (see section 4.5).

There is a risk of serious hemorrhage and significant elevations in INR and prothrombin time when clarithromycin is co-administered with warfarin. INR and prothrombin times should be frequently monitored while patients are receiving clarithromycin and oral anticoagulants concurrently (see section 4.4 and 4.5).

Special population: Adverse Reactions in Immunocompromised Patients (see section e)

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.

Frequency, type and severity of adverse reactions in children are expected to be the same as in adults.

e. 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, diarrhea, 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.

4.9 Overdose

Symptoms of intoxication:

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.

Therapy of intoxication:

There is no specific antidote on overdose. Serum levels of clarithromycin can not be reduced by haemodialysis or peritoneal dialysis.

Adverse reactions accompanying overdose should be treated by gastric lavage and supportive measures. Severe acute allergic reactions may be seen very rarely, e.g. anaphylactic shock. At first signs of hypersensitivity reactions therapy with clarithromycin must be discontinued and the required measures should be initiated immediately.

5.1 Pharmacodynamic properties

General properties

Pharmacological-therapeutical group:

Macrolides. ATC Code J01FA09.

Mechanism of action:

Clarithromycin exerts its anti-bacterial 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 Haemophilus influenzae where the 14-hydroxy metabolite is two-fold more active than the parent compound.

PK/PD relationship

For clarithromycin the AUC/ MIC is the major PK/ PD parameter correlating best with the efficacy of clarithromycin.

Mechanism of resistance:

The mechanisms of acquired resistance in macrolides are: efflux of active substance by an active pump mechanism, inducible or constitutive production of a methylase enzyme that modifies the ribosomal target, hydrolysis of macrolides by esterases, chromosomal mutations that alter a 50s ribosomal protein.

pathogens	suscepti ble (mg/l)	resistant (mg/l)
Staphylococcus spp.	< 1	> 2
Streptococcus spp. (Gruppen A, B, C, G)	< 0,25	> 0,5l
Streptococcus pneumoniae	< 0,25	> 0,5
Haemophilus influenzae	< 1	> 32
Moraxella catarrhalis	< 0,25	> 0,5

Cross-resistance between clarithromycin and other macrolides and clindamycin and lincomycin may therefore occur. Methicillin-resistant and oxacillin-resistant staphylococci (MRSA) and penicillin-resistant Streptococcus pneumoniae are resistant to all currently available Beta-lactam antibiotics and macrolides such as clarithromycin.

Breakpoints

EUCAST (European Committee on Antimicrobial Susceptibility Testing)

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.

Pathogens for which resistance may be a problem: prevalence of resistance is equal to or greater than 10% in at least one country in the European Union

Aerobic Gram-positive microorganisms Streptococcus pyogenes ¹ Aerobic Gram-negative microorganisms Haemophilus influenzae $

Moraxella catarrhalis Helicobacter pylori Other microorganisms

Chlamydophila pneumoniae ° Legionella pneumophila °

_Mycobacterium avium °_

_Mycobacterium chelonae_

_Mycobacterium intrazellulare °_

_Mycoplasma pneumoniae_

Species for which acquired resistance may

be a problem_

Aerobic Gram-positive microorganisms Staphylococcus aureus (methicillin-susceptible)

Staphylococcus aureus (methicillin-resistant^{) +}

_Streptococcus pneumoniae_

Inherently resistant organisms_

Aerobic Gram-negative microorganisms Escherica coli Klebsiella spp Pseudomonas aeruginosa

No updated data were available at release of tables. Primary literature, scientific standard literature and therapeutic recommendations assume susceptibility. Inherent susceptibility of most of the isolates shows intermediate resistance.

At least one region shows resistance rates higher than 50%.

The resistance rates are in some studies >10%.

The resistance rate is >10% by pre-treated patients.

Other information

Most available clinical experience from controlled randomised clinical trials indicate that clarithromycin 500 mg twice daily in combination with another antibiotic e.g. amoxicillin or metronidazole and e.g. omeprazole (given at approved levels) for 7 days achieve > 80% H. pylori eradication rate in patients with gastro-doudenal ulcers. As expected, significantly lower eradication rates were observed in patients with baseline metronidazole-resistant H. pylori isolates. Hence, local information on the prevalence of resistance and local therapeutic guidelines should be taken into account in the choice of an appropriate combination regimen for H. pylori eradication therapy. Furthermore, in patients with persistent infection, potential development of secondary resistance (in patients with primary susceptible strains) to an antimicrobial medicinal product should be taken into the considerations for a new retreatment regimen.

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%. The bioavailability of the suspension is identical to or slightly higher than the bioavailability of the tablets. The pharmacokinetic profile of the suspension in children corresponds to the pharmacokinetic profile of the suspension in adults. Food slightly delays the absorption but does not affect the extent of bioavailability. Therefore, clarithromycin 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. In children the following steady-state parameters were observed after the ninth dose in a dose regimen of 7,5 mg/kg twice daily on average for clarithromycin: C_max 4,60 pg/ml, AUC 15,7 pg.hour/ml and T_max 2,8 hours. The corresponding average values for the 14-OH metabolite were respectively: 1,64 pg/ml, 6,69 pg.hour/ml and 2,7 hours.

After administration of 250 mg clarithromycin twice daily the microbiologically active 14-hydroxy metabolite attains peak plasma concentrations of 0,6 pg/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 level of the active substance. 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. 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. With a 250 mg every 12 hours dosing, the half-life of the active 14-hydroxy metabolite ranges between 5 to 6 hours.

After oral administration of radioactive clarithromycin 70 - 80% of the radioactivity was found in the faeces. Approximately 20 -30% of clarithromycin appears 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 insufficiency 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, toxicity of clarithromycin was found to be related to the dose and to the 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 (300 mg/kg/day) were clearly higher than the therapeutic doses recommended for humans. Other tissues affected included the stomach, thymus and other lymphoid tissues as well as the kidneys. At near therapeutic doses conjunctival injection and lacrimation occurred only in dogs. At a massive dose of 400mg/kg/day some dogs and monkeys developed corneal opacities and/or oedema. Juvenile animals presented similar toxicity profiles to mature animals although enhanced nephrotoxicity in neonatal rats has been reported In vitro and in vivo studies showed that clarithromycin did not have genotoxic potential. 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 generally noted in rat studies. However, cardiovascular malformations were observed in two studies in rats treated with doses of 150 mg/kg/d. In mouse at doses x70 the clinical dose cleft palate occurred at varying incidence (3-30%). Clarithromycin has been found in the milk of lactating animals.

6.1 List of excipients

Poloxamer 188 Povidone K 30 Hypromellose Macrogol 6000 Titanium dioxide (E171)

Methacrylic acid - ethyl acrylate copolymer (1:1)

Triethyl citrate Glycerol monostearate Polysorbate 80 Sucrose Maltodextrin Potassium sorbate Colloidal anhydrous silica Xanthan gum

Fruit punch flavouring (natural and artificial flavouring substances including maltodextrin, modified starch and maltol).

6.2. Incompatibilities

Not applicable.

Shelf life

3 years.

After reconstitution 14 days.

6.4. Special precautions for storage

The granules for oral suspension: Do not store above 25°C. After reconstitution: Do not store above 25°C.

6.5. Nature and contents of container

60ml, 120ml and 240ml HDPE bottles, with child resistant PP-screw closures, an oral PE/PP-measuring syringe (5ml) with filling marks at 2.5ml, 3.75ml and 5.0ml and a PR/PP-measuring spoon with filling marks at 1.25ml, 2.5ml and 5.0ml.

Clarithromycin 25mg/ml:

1 bottle contains 27.3g granules for oral suspension for 40ml ready-for-use suspension (required water amount: 23.6g) or

34.1g granules for oral suspension for 50ml ready-for-use suspension (required water amount: 29.5g) or

41.0g granules for oral suspension for 60ml ready-for-use suspension (required water amount: 35.4g) or

47.8g granules for oral suspension for 70ml ready-for-use suspension (required water amount: 41.3g) or

54.6g granules for oral suspension for 80ml ready-for-use suspension (required water amount: 47.2g) or

68.3g granules for oral suspension for 100ml ready-for-use suspension (required water amount: 59.0g) or

81.9g granules for oral suspension for 120ml ready-for-use suspension (required water amount: 70.8g).

Double Pack of 2 x 60 ml ready-for-use suspension: 2 x 41.0 g granules for oral suspension each for 2 x 60 ml ready-for-use suspension each (required water amount: 2 x 35.4g each)

Pack sizes:

1, 2, 5, 10, 20, 30, 40, 50, 100 bottles.

Not all pack sizes may be marketed.

6.6. Instruction for use and handling (, and disposal)

The bottle should be filled with two-thirds of the overall required quantity of water, then thoroughly shaken and filled with water up to the mark and shaken again. The bottle should be shaken vigorously before each application.

After reconstitution with water the product results in a white to beige suspension.

If the dose is to be given using the oral dosing syringe, the syringe adaptor should be inserted into the bottle neck.

No Data Held

7 MARKETING AUTHORISATION HOLDER

Sandoz Limited Frimley Business Park,

Frimley,

Camberley,

Surrey,

GU16 7SR.

United Kingdom

8. MARKETING AUTHORISATION NUMBER

PL 04416/0609

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

21/01/2009

10 DATE OF REVISION OF THE TEXT 17/02/2012