SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Clarithromycin 250mg/5ml Oral Suspension

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 5 ml of the constituted suspension contains clarithromycin 250 mg

Excipients with known effect

Each 5ml constituted suspension contains:

2508.00mg of sucrose 20mg of aspartame

For the full list of excipients, see section    6.1

3.    PHARMACEUTICAL FORM

Granules for oral suspension

White to off-white granular powder forming white to off-white suspension on reconstitution with water.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Clarithromycin 125mg/5ml Oral Suspension is indicated in children, 6 months to 12 years.

Clarithromycin 125mg/5ml Oral Suspension is indicated for treatment of the following infections in children when caused by clarithromycin-susceptible organisms:

-    Lower respiratory tract infections.

-    Upper respiratory tract infections.

-    Skin and skin structure infections.

-    Acute otitis media.

Clarithromycin 125mg/5ml Oral Suspension 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 group); Streptococcus (Diplococcus) pneumoniae; Streptococcus agalactiae; Listeria monocytogenes.

Gram-negative Bacteria: Haemophilus influenzae, Haemophilusparainfluenzae, 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; Chlamydia pneumoniae.

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

Clarithromycin 125mg/5ml Oral Suspension has bactericidal activity against several bacterial strains. These organisms include H. influenzae, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Moraxella (Branhamella) catarrhalis, Neisseria gonorrhoeae, Helicobacter pylori and Campylobacter species.

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

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

4.2 Posology and method of administration

Posology

The dosage of clarithromycin depends on the clinical condition of the patient and has to be defined in any case by the physician.

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 (Clarithromycin granules for oral suspension). The use of clarithromycin (tablet/I.V) is not recommended for children under 12 years of age.

Clarithromycin 250mg/5ml Oral Suspension

The usual duration of treatment is 5 to 10 days depending on the pathogen involved and the severity of the condition.

The recommended daily dose of Clarithromycin 250mg/ 5ml Oral Suspension in children is given in the following table and is based on an approximate 7.5mg/ kg twice daily dosing regimen. Doses up to 500 mg twice daily have been used in the treatment of severe infections.

For some children, depending on body weight, it may be more appropriate to administer the 250mg/ 5ml oral suspension.

Clarithromycin 250mg/ 5ml Oral Suspension dosage in children

Dosage based on body weight (kg)
Weight (kg)*	Approxim ate age in years	Dose in mg of clarithromycin to be given twice daily	Dose in ml of 125 mg/ 5 ml oral suspension to be given twice daily by pipette***	Dosage per 5ml teaspoonful twice daily
8 - 11	1 - 2	62.5	1.25**	1/4
12 - 19	3 - 6	125	2.5	1/2
20 - 29	7 - 9	187.5	3.75**	3/4**
30 - 40	10 - 12	250	5.0	1

basis (approx. 7.5 mg/ kg twice

*children < 8 kg should be dosed based on a per kg daily)

**in order to avoid the need to estimate quarter teaspoonfuls, it is recommended that the 125mg/ 5ml oral suspension is used for children in these weight bands (please consult the prescribing information for the 125mg/ 5ml oral suspension for details). *** A graduated syringe is provided with the bottle for use as a pipette. This enables more accurate dosing than the 5 ml spoon (also provided with the bottle) when fractions of a spoonful are needed to achieve the right dose

Patients with renal and hepatic insufficiency

Clarithromycin should not be administered to paediatric patients with severe hepatic or renal insufficiency. Caution is required when administering clarithromycin to children with lesser degrees of renal or hepatic insufficiency.

Method of Administration

Clarithromycin 250mg/5 ml Oral Suspension may be given without regard to meals, as food does not affect the extent of bioavailability.

Clarithromycin 250mg/5 ml Oral Suspension should be administered twice daily as recommended in the table above. The doses should be given at 12-hour intervals.

Clarithromycin oral suspension can cause a bitter after-taste. This can be avoided by drinking juice or water soon after intake of the suspension.

4.3 Contraindications

Clarithromycin is contraindicated in patients with known hypersensitivity to clarithromycin, to other macrolide antibiotic drugs or to any of its excipients (see section 6.1).

Concomitant administration of Clarithromycin and ergot derivatives (ergotamine or dihydroergotamine) is contraindicated, as this may result in ergot toxicity (see section 4.5).

Concomitant administration of clarithromycin and any of the following drugs is contraindicated: astemizole, cisapride, pimozide, terfenadine as this may result in QT prolongation and cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation and torsades de pointe (see section 4.5).

Clarithromycin should not be given in 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).

Concomitant administration with ticagrelor or ranolazine is contraindicated

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

Clarithromycin should not be used concomitantly with HMG-CoA reductase inhibitors (statins) that are extensively metabolized by CYP3A4 (lovastatin or simvastatin) or atorvastatin, due to the increased risk of myopathy, including rhabdomyolysis.

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

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).

Clarithromycin is mainly excreted by the liver. Therefore, caution should be taken in administering clarithromycin to patients with impaired hepatic function. Caution should also be exercised when administering clarithromycin to patients with moderate to severe renal impairment.

Cases of fatal hepatic failure (see section 4.8) have been reported. Some patients may have had pre-existing hepatic disease or may have been taking other hepatotoxic medicinal products. Patients should be advised to stop treatment and contact their doctor if signs and symptoms of hepatic disease develop, such as anorexia, jaundice, dark urine, pruritus, or tender abdomen.

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

Use of 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 colonization 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 between clarithromycin and other macrolide drugs, as well as lincomycin and clindamycin. Therefore caution is required when prescribing clarithromycin for such patients.

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 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.

Caution is advised regarding concomitant administration of clarithromycin with other ototoxic drugs, especially with aminoglycosides. Monitoring of vestibular and auditory function should be carried out during and after treatment.

Prolongation of the QT Interval

Prolonged cardiac repolarisation and QT interval, imparting a risk of developing cardiac arrhythmia and torsade de pointes, have been seen in treatment with macrolides including clarithromycin (see section 4.8). Therefore as the following situations may lead to an increased risk for ventricular arrhythmias (including torsade de pointes), clarithromycin should be used with caution in the following patients; ¹

• Clarithromycin must not be used in patients with congenital or documented acquired QT prolongation or history of ventricular cardiac arrhythmia (see section 4.3).

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

Clarithromycin should be used with caution when administered concurrently with medications that induce CYP3A4 enzyme due to the possibility of subtherapeutic levels of clarithromycin (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 patient taking Clarithromycin and statins. Patients should be monitored for signs and symptoms of myopathy.

In situations where the concomitant use of clarithromycin with statins cannot be avoided, it is recommended to prescribe the lowest registered dose of the statin. Use of a statin that is not dependent on CYP3A metabolism (e.g. fluvastatin) can be considered (see 4.5).

Oral hypoglycemic agents/Insulin: The concomitant use of clarithromycin and oral hypoglycemic agents (such as sulphonylurias) 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 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.

In areas with a high incidence of erythromycin A resistance, it is especially important to take into consideration the evolution of the pattern of susceptibility to clarithromycin. Clarithromycin is a semi-synthetic derivative of erythromycin A.

Pneumonia: Due to 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 further appropriate antibiotics.

Clarithromycin is not the first choice for the therapy of pharyngitis. It is only required, especially in streptococcus-infection, if hypersensitivity to penicillin is present or if penicillin is contraindicated for other reasons.

Skin and soft tissue infections of mild to moderate severity: These infections are most often caused by Staphylococcus aureus and Streptococcus pyogenes, both of which may be resistant to macrolides. Therefore, it is important that sensitivity testing be performed. In cases where beta-lactam antibiotics cannot be used (e.g. allergy), other antibiotics, such as clindamycin, may be the drug of first choice. Currently, macrolides are only considered to play a role in some skin and soft tissue infections, such as those caused by Corynebacterium minutissimum, acne vulgaris, and erysipelas and in situations where penicillin treatment cannot be used.

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.

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

Clarithromycin 125mg/5ml Oral Suspension contains 20 mg of aspartame (E951) per 5 ml, a source of phenylalanine. This medicine should be used with caution in patients with phenylketonuria.

Patients with rare hereditary problems of fructose intolerance, glucose-galactose 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 associated with acute ergot toxicity characterized by vasospasm, and ischemia of the extremities and other tissues including the central nervous system. Concomitant administration of clarithromycin and these medicinal products is contraindicated (see section 4.3).

HMG-CoA Reductase Inhibitors (statins)

Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated (see 4.3) as these statins are extensively metabolized by CYP3A4 and concomitant treatment with clarithromycin increases their plasma concentration, which increases the risk of myopathy, including rhabdomyolysis. Reports of rhabdomyolysis have been received for patients taking clarithromycin concomitantly with these statins. If treatment with clarithromycin cannot be avoided, therapy with lovastatin or simvastatin must be suspended during the course of treatment.

Caution should be exercised when prescribing clarithromycin with statins. In situations where the concomitant use of clarithromycin with statins cannot be avoided, it is recommended to prescribe the lowest registered dose of the statin. Use of a statin that is not dependent on CYP3A metabolism (e.g. fluvastatin) can be considered. Patients should be monitored for signs and symptoms of myopathy.

Effects of other medicinal products on clarithromycin

Drugs that are inducers of CYP3A (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital, St John’s wort) may induce the metabolism of clarithromycin. This may result in sub-therapeutic levels of clarithromycin leading to reduced efficacy. Furthermore, it might be necessary to monitor the plasma levels of the CYP3A inducer, which could be increased owing to the inhibition of CYP3A by clarithromycin (see also the relevant product information for the CYP3A4 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.

Etravirine

Clarithromycin exposure was decreased by etravirine; however, concentrations of the active metabolite, 14-OH-clarithromycin, were increased. Because 14-OH-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered; therefore alternatives to clarithromycin should be considered for the treatment of MAC.

Fluconazole

Concomitant administration of fluconazole 200 mg daily and Clarithromycin

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

Ritonavir

A pharmacokinetic study demonstrated that the concomitant administration of ritonavir 200 mg every eight hours and Clarithromycin 500 mg every 12 hours resulted in a marked inhibition of the metabolism of clarithromycin. The clarithromycin C_max increased by 31%, C_min increased 182% and AUC increased by 77% with concomitant administration of ritonavir. An essentially complete inhibition of the formation of 14-OH-clarithromycin was noted. Because of the large therapeutic window for clarithromycin, no dosage reduction should be necessary in patients with normal renal function. However, for patients with renal impairment, the following dosage adjustments should be considered: For patients with CL_cr 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. For patients with CL_CR <30mL/min the dose of clarithromycin should be decreased by 75%. Doses of clarithromycin greater than 1g/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)

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 see section 4.4), atypical antipsychotics (e.g. quetiapine), pimozide, quinidine, rifabutin, sildenafil, simvastatin, tacrolimus, terfenadine, triazolam and vinblastine, but this list is not comprehensive. Drugs interacting by similar mechanisms through other isozymes within the cytochrome P450 system include phenytoin, theophylline and valproate.

Antiarrhythmics

There have been postmarketing reports of torsades de pointes occurring with concurrent use of clarithromycin and quinidine or disopyramide. Electrocardiograms should be monitored for QT prolongation during co-administration of clarithromycin with these drugs. Serum levels of quinidine and disopyramide should be monitored during clarithromycin therapy.

There have been post marketing reports of hypoglycaemia with the concomitant administration of clarithromycin and disopyramide. Therefore blood glucose levels should be monitored during concomitant administration of clarithromycin and disopyramide.

Oral hypoglycemic agents/Insulin

With certain hypoglycemic drugs such as nateglinide, and repaglinide, inhibition of CYP3A enzyme by clarithromycin may be involved and could cause hypoglycaemia when used concomitantly. Careful monitoring of glucose is recommended.

Omeprazole

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

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. Coadministration of clarithromycin with sildenafil, tadalafil or vardenafil would likely result in increased phosphodiesterase inhibitor exposure. Reduction of sildenafil, tadalafil and vardenafil dosages should be considered when these drugs are coadministered with clarithromycin.

Theophylline, carbamazepine

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

Tolterodine

The primary route of metabolism for tolterodine is via the 2D6 isoform of cytochrome P450 (CYP2D6). However, in a subset of the population devoid of CYP2D6, the identified pathway of metabolism is via CYP3A. In this population subset, inhibition of CYP3A results in significantly higher serum concentrations of tolterodine. A reduction in tolterodine dosage may be necessary in the presence of CYP3A inhibitors, such as clarithromycin in the CYP2D6 poor metabolizer population.

Triazolobenzodiazepines (e.g. alprazolam, midazolam, triazolam)

When midazolam was co-administered with clarithromycin tablets (500 mg twice daily), midazolam AUC was increased 2.7-fold after intravenous administration of midazolam and 7-fold after oral administration. Concomitant administration of oral midazolam and clarithromycin should be avoided. If intravenous midazolam is coadministered with clarithromycin, the patient must be closely monitored to allow dose adjustment. The same precautions should also apply to other benzodiazepines that are metabolized by CYP3A, including triazolam and alprazolam. For benzodiazepines which are not dependent on CYP3A for their elimination (temazepam, nitrazepam, lorazepam), a clinically important interaction with clarithromycin is unlikely.

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

Other drug interactions

Aminoglycosides

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

Colchicine

Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. When clarithromycin and colchicine are administered together, inhibition of Pgp and/or CYP3A by clarithromycin may lead to increased exposure to colchicine (see section 4.3 and 4.4).

Digoxin

Digoxin is thought to be a substrate for the efflux transporter, P-glycoprotein (Pgp). Clarithromycin is known to inhibit Pgp. When clarithromycin and digoxin are administered together, inhibition of Pgp by clarithromycin may lead to increased exposure to digoxin. Elevated digoxin serum concentrations in patients receiving clarithromycin and digoxin concomitantly have also been reported in post marketing surveillance. Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Serum digoxin concentrations should be carefully monitored while patients are receiving digoxin and clarithromycin simultaneously.

Zidovudine

Simultaneous oral administration of clarithromycin tablets and zidovudine to HIV infected adult patients may result in decreased steady-state zidovudine concentrations. Because clarithromycin appears to interfere with the absorption of simultaneously administered oral zidovudine, this interaction can be largely avoided by staggering the doses of clarithromycin and zidovudine to allow for a 4-hour interval between each medication. This interaction does not appear to occur in paediatric HIV-infected patients taking clarithromycin suspension with zidovudine or dideoxyinosine. This interaction is unlikely when clarithromycin is administered via intravenous infusion.

Phenytoin and Valproate

There have been spontaneous or published reports of interactions of CYP3A inhibitors, including clarithromycin with drugs not thought to be 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

Bi-directional drug interactions

Atazanavir

Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction. Co-administration of clarithromycin (500 mg twice daily) with atazanavir (400 mg once daily) resulted in a 2-fold increase in exposure to clarithromycin and a 70% decrease in exposure to 14-OH-clarithromycin, with a 28% increase in the AUC of atazanavir. Because of the large therapeutic window for clarithromycin, no dosage reduction should be necessary in patients with normal renal function. For patients with moderate renal function (creatinine clearance 30 to 60 mL/min), the dose of clarithromycin should be decreased by 50%. For patients with creatinine clearance <30 mL/min, the dose of clarithromycin should be decreased by 75% using an appropriate clarithromycin formulation. Doses of clarithromycin greater than 1000 mg per day should not be coadministered with protease inhibitors.

Calcium Channel Blockers

Caution is advised regarding the concomitant administration of clarithromycin and calcium channel blockers metabolized by CYP3A4 (e.g., verapamil, amlodipine, diltiazem) due to the risk of hypotension. Plasma concentrations of clarithromycin as well as calcium channel blockers may increase due to the interaction. Hypotension, bradyarrhythmias and lactic acidosis have been observed in patients taking clarithromycin and verapamil concomitantly.

Itraconazole

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

Saquinavir

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

When saquinavir is co-administered with ritonavir, consideration should be given to the potential effects of ritonavir on clarithromycin (see section 4.5).

Clarithromycin has been shown not to interact with oral contraceptives.

4.6 Fertility, pregnancy and lactation

Pregnancy

The safety of clarithromycin for use during pregnancy has not been established. Based on variable results obtained from studies in mice, rats, rabbits and monkeys, the possibility of adverse effects on embryofoetal development cannot be excluded. Therefore, use during pregnancy is not advised without carefully weighing the benefits against risk.

Breastfeeding

The safety of clarithromycin for use during breast feeding of infants has not been established. Clarithromycin and its active metabolite are excreted in breast milk.

4.7 Effects on ability to drive and use machines

There are no data available on the effect of clarithromycin on the ability to drive or use machines. The potential for dizziness, vertigo, confusion and disorientation should be taken into account before patients drive or use machines.

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, diarrhoea, nausea, vomiting and taste perversion. These adverse reactions are usually mild in intensity and are consistent with the known safety profile of macrolide antibiotics. (see 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

The following table displays adverse reactions reported in clinical trials and from post-marketing experience with clarithromycin immediate-release tablets, granules for oral suspension, powder for solution for injection, extended-release tablets and modified-release tablets.

The reactions considered at least possibly related to clarithromycin are displayed by system organ class and frequency using the following convention: very common (>1/10), common (> 1/100 to < 1/10), uncommon (>1/1,000 to < 1/100) and not known (adverse reactions from post-marketing experience; cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness when the seriousness could be assessed.

System Organ Class	Very common (>1/10	Common > 1/100 to < 1/10	Uncommon >1/1,000 to < 1/100	Not Known2 (cannot be estimated from the available data)
Infections and infestations			Cellulitis1, candidiasis, 2 3 gastroenteritis ,infection , vaginal infection	Pseudomembranous colitis, erysipelas,
Blood and lymphatic system			Leukopenia, . 4 neutropenia , 3 thrombocythemia , eosinophilia4	Agranulocytosis, thrombocytopenia
Immune system disorders5			Anaphylactoid reaction1, hypersensitivity	Anaphylactic reaction angioedema
Metabolism and nutrition disorders			Anorexia, decreased appetite
Psychiatric disorders		Insomnia	Anxiety, nervousness3	Psychotic disorder, confusional state, depersonalisation, depression, disorientation, hallucination, abnormal dreams, mania
Nervous system disorders		Dysgeusia, headache, taste perversion	Loss of consciousness1, dyskinesia1, dizziness, somnolence6, tremor	Convulsion, ageusia, parosmia, anosmia, paraesthesia
Ear and labyrinth disorders			Vertigo, hearing impaired, tinnitus	Deafness
Cardiac disorders			Cardiac arrest1, atrial fibrillation1, electrocardiogram QT prolonged , extrasystoles1, palpitations	Torsade de pointes7, ventricular 7 tachycardia ventricular fibrillation
Vascular disorders		Vasodilation1		Haemorrhage8
Respiratory, thoracic and			Asthma1, epistaxis2, pulmonary embolism1

¹ ADRs reported only for the Powder for Solution for Injection formulation ADRs reported only for the Extended-Release Tablets formulation

³    ADRs reported only for the Granules for Oral Suspension formulation

⁴    ADRs reported only for the Immediate-Release Tablets formulation ^5,7,9,10 See section a)

^6,8,11 See section c)

relationship to drug exposure. Patient exposure is estimated to be greater than lbillion patient treatment days for clarithromycin.

**In some of the reports of rhabdomyolysis, clarithromycin was administered concomitantly with other drugs known to be associated with rhabdomyolysis (such as statins, fibrates, colchicine or allopurinol).

c)    Description of selected adverse reactions

Injection site phlebitis, injection site pain, vessel puncture site pain, and injection site inflammation are specific to the clarithromycin intravenous formulation.

In 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 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).

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. There are insufficient data to recommend a dosage regimen for use of the clarithromycin IV formulation in patients less than 18 years of age.

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

e)    Other special populations

Immunocompromised 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 2000mg 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 1000mg and 2000mg, but were generally about 3 to 4 times as frequent for those patients who received total daily doses of 4000mg 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 1000mg or 2000mg 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 4000mg daily for all parameters except White Blood Cell.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Symptoms 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, hypokalaemia 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 overdosage should be the prompt elimination of unabsorbed drug and supportive measures. As with other macrolides, clarithromycin serum levels are not expected to be appreciably affected by haemodialysis or peritoneal dialysis. 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 PHARMACOLOGICAL PROPERTIES

Pharmacodynamic properties

Pharmacotherapeutic group: Antibacterial for systemic use, macrolides ATC code: J01FA09

Mechanism of action

Clarithromycin is an antibiotic belonging to the macrolide antibiotic group. It exerts its antibacterial action by selectively binding to the 50s ribosomal sub-unit of susceptible bacteria preventing translocation of activated amino acids. It inhibits the intracellular protein synthesis of susceptible bacteria. Clarithromycin demonstrates excellent in-vitro activity against standard strains of clinical isolates. It is highly potent against a wide variety of aerobic and anaerobic gram-positive and gramnegative organisms. The minimum inhibitory concentrations (MICs) of clarithromycin, are generally two-fold lower than the MICs of erythromycin.

The 14-hydroxy metabolite of clarithromycin, a product of parent drug metabolism also has antimicrobial activity. The metabolite is less active than the parent compound for most organisms, including mycobacterium spp. An exception is Haemophilus influenza where the 14-hydroxy metabolite is twofold more active than the parent compound.

Clarithromycin is also bactericidal against several bacterial strains.

Breakpoints

According to the EUCAST (European Committee on Antimicrobial Susceptibility Testing) the following breakpoints have been defined for clarithromycin:

Breakpoints (MIC, mg/L)
Microorganism	Susceptible (<)	Resistant (>)
Staphylococcus spp.	1 mg/L	2 mg/L
Streptococcus spp. A, B, C, G	0.25 mg/L	0.5 mg/L
Streptococcus pneumonia	0.25 mg/L	0.5 mg/L
Viridans group streptococcus	IE	IE
Haemophilus app.	1 mg/L	32 mg/L
Moraxella catarrhalis	0.25 mg/L	0.5 mg/L1
Helicobacter pylori	0.25 mg/L1	0.5 mg/L

¹ The breakpoints are based on epidemiological cut-off values (ECOFFs), which distinguish wild-type isolates from those with reduces susceptibility.

“IE" indicates that there is insufficient evidence that the species in question is a good target for therapy with the drug.

Susceptibility

The prevalence of resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections This information gives only an appropriate guidance on the probabilities whether micro-organisms will be susceptible to clarithromycin or not. As far as applicable the information on the European range of acquired resistance for the individual micro-organism is indicated in brackets.

Clarithromycin is usually active against the following organisms in vitro:

Gram-positive Bacteria: Staphylococcus aureus (methicillin susceptible); Streptococcus pyogenes ¹ (Group A beta-hemolytic streptococci); alpha-hemolytic streptococci (viridans group); Streptococcus (Diplococcus) pneumoniae; Streptococcus agalactiae; Listeria monocytogenes.

Gram-negative Bacteria: Haemophilus influenza ; Haemophilus parainfluenza; Moraxella (Branhamella) catarrhalis °; Neisseria gonorrhoeae; Legionella pneumophila°; Bordetella pertussis; Campylobacter jejuni, Helicobacter pylori . Mycoplasma: Mycoplasma pneumoniae°; Ureaplasma urealyticum.

Other Organisms: Chlamydia trachomatis; Mycobacterium avium°; Mycobacterium leprae; Mycobacterium kansasii°; Mycobacterium chelonae°; Mycobacterium fortuitum; Mycobacterium intrazellulare °; Chlamydia pneumonia°,

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 influenza ; Streptococcus pneumoniae; Streptococcus pyogenes; Streptococcus agalactiae; Moraxella (Branhamella) catarrhalis; Neisseria gonorrhoeae and Campylobacter spp.

Species for which acquired resistance may be a problem

Aerobic Gram-positive micro-organisms: Staphylococcus aureus (Methicillin-

resistant) ⁺

Inherently resistant organisms

Aerobic Gram-negative micro-organisms Escherichia coli; Klebsiella spp. And 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%.

¹    The resistance rates are in some studies >10%.

₂

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

Other information

Susceptibility and resistance of Streptococcus pneumoniae and Streptococcus spp. to clarithromycin can be predicted by testing erythromycin.

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. 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.Most available clinical experience from controlled randomised clinical trials indicate that Clarithromycin Ranbaxy 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-duodenal 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 agent should be taken into the considerations for a new retreatment regimen.

5.2 Pharmacokinetic properties

Clarithromycin is rapidly and well absorbed from the gastro-intestinal tract after oral administration. The microbiologically active metabolite 14-hydroxyclarithromycin is formed by first pass metabolism. Clarithromycin may be given without regard to meals as food does not affect the extent of bioavailability. Food does slightly delay the onset of absorption of clarithromycin and formation of the 14-hydroxymetabolite. The pharmacokinetics of clarithromycin are non linear; however, steady-state is attained within 2 days of dosing. The 14-hydroxyclarithromycin is the major urinary metabolite and accounts for 10-15% of the dose. Most of the remainder of the dose is eliminated in the faeces, primarily via the bile. 5-10% of the parent drug is recovered from the faeces.

Clarithromycin provides tissue concentrations that are several times higher than the circulating drug levels. Increased levels of clarithromycin have been found in both tonsillar and lung tissue. Clarithromycin penetrates into the middle ear fluid at concentrations greater than in the serum. Clarithromycin is 80% bound to plasma proteins at therapeutic levels.

5.3 Preclinical safety data

The acute oral LD50 values for a clarithromycin suspension administered to 3-day old mice were 1290 mg/kg for males and 1230 mg/kg for females. The LD50 values in 3-day old rats were 1330 mg/kg for males and 1270 mg/kg for females. For comparison, the LD50 of orally-administered clarithromycin is about 2700 mg/kg for adult mice and about 3000 mg/kg for adult rats. These results are consistent with other antibiotics of the penicillin group, cephalosporin group and macrolide group in that the LD50 is generally lower in juvenile animals than in adults.

In both mice and rats, body weight was reduced or its increase suppressed and suckling behaviour and spontaneous movements were depressed for the first few days following drug administration. Necropsy of animals that died disclosed dark-reddish lungs in mice and about 25% of the rats; rats treated with 2197 mg/kg or more of a clarithromycin suspension were also noted to have a reddish - black substance in the intestines, probably because of bleeding. Deaths of these animals were considered due to debilitation resulting from depressed suckling behaviour or bleeding from the intestines.

Pre-weaning rats (5 days old) were administered a clarithromycin suspension formulation for two weeks at doses of 0, 15, 55 and 200 mg/kg/day. Animals from the 200 mg/kg/day group had decreased body-weight gains, decreased mean haemoglobin and haematocrit values, and increased mean relative kidney weights compared to animals from the control group. Treatment-related minimal to mild multifocal vacuolar degeneration of the intrahepatic bile duct epithelium and an increased incidence of nephritic lesions were also observed in animals from this treatment group. The "no-toxic effect" dosage for this study was 55 mg/kg/day.

An oral toxicity study was conducted in which immature rats were administered a clarithromycin suspension (granules for suspension) for 6 weeks at daily dosages of 0, 15, 50 and 150 mg base/kg/day. No deaths occurred and the only clinical sign observed was excessive salivation for some of the animals at the highest dosage from 1 to 2 hours after administration during the last 3 weeks of treatment. Rats from the 150 mg/kg dose group had lower mean body weights during the first three weeks, and were observed to have decreased mean serum albumin values and increased mean relative liver weight compared to the controls. No treatment-related gross or microscopic histopathological changes were found. A dosage of 150 mg/kg/day produced slight toxicity in the treated rats and the "no effect dosage" was considered to be 50 mg/kg/day.

Juvenile beagle dogs, 3 weeks of age, were treated orally daily for four weeks with 0, 30, 100, or 300 mg/kg of clarithromycin, followed by a 4-week recovery period. No deaths occurred and no changes in the general condition of the animals were observed. Necropsy revealed no abnormalities. Upon histological examination, fatty deposition of centrilobular hepatocytes and cell infiltration of portal areas were observed by light microscopy and an increase in hepatocellular fat droplets was noted by electron microscopy in the 300 mg/kg dose group. The toxic dose in juvenile beagle dogs was considered to be greater than 300 mg/kg and the "no effect dose" 100 mg/kg.

Fertility, Reproduction and Teratogenicity

Fertility and reproduction studies have shown daily dosages of 150-160 mg/kg/day to male and female rats caused no adverse effects on the oestrus cycle, fertility, parturition and number and viability of offspring. Two teratogenicity studies in both Wistar (p.o.) and Sprague-Dawley (p.o. and i.v.) rats, one study in New Zealand white rabbits and one study in cynomolgus monkeys failed to demonstrate any teratogenicity from clarithromycin.

PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Microcrystalline cellulose Hypromellose Hydroxypropyl cellulose Croscarmellose sodium Alginic acid

Methacrylic acid - ethyl acrylate copolymer (1:1) dispersion 30%

Macrogol 1500

Talc

Carbomer (Carbopol 974 P)

Colloidal anhydrous silica Sucrose

Aspartame (E951)

Xanthan gum Monosodium citrate Sodium benzoate (E211)

Titanium dioxide (E171)

Peppermint flavour Tutti frutti flavour Sodium chloride

6.2.    Incompatibilities

Not applicable.

6.3.    Shelf life

Granules: Two years. Reconstituted suspension: 14 days

6.4. Special precautions for storage

Granules: No special precaution for storage.

Reconstituted suspension: Do not store above 25°C. Do not refrigerate or freeze. Keep the bottle tightly closed.

6.5    Nature and contents of container

Natural translucent HDPE bottle with white, opaque, child resistant cap having induction seal liner.

Or

Natural translucent HDPE bottle with continuous ring mark for filling volume and white, opaque, child resistant cap having induction seal liner.

Natural translucent PP/HDPE dosing pipette having filling marks for weight and volume and LDPE cap adapter.

Transparent polystyrene measuring spoon with fill marks at 2.5ml and 5.0ml Pack Size - 50, 60, 70, 100 or 140 ml. Not all pack sizes may be marketed.

6.6    Special precautions for disposal

Preparation for use:

Required quantity of water should be added to the granules in the bottle and shaken well. The concentration of clarithromycin in the reconstituted suspension is 250 mg per 5 ml.

The quantity of water required for each pack is tabulated below:

Pack	Volume of water to be added
50 ml Bottle	28 ml
60 ml Bottle	34 ml
70 ml Bottle	40 ml
100 ml Bottle	55 ml
140 ml Bottle	80 ml

7    MARKETING AUTHORISATION HOLDER

Ranbaxy (UK) Limited 5th floor, Hyde Park, Hayes 3 11 Millington Road Hayes, UB3 4AZ United Kingdom

8. MARKETING AUTHORISATION NUMBER

PL 14894/0209

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

03/11/2009

10    DATE OF REVISION OF THE TEXT

27/06/2016

1

   Patients with coronary artery disease, severe cardiac insufficiency, conduction disturbances or clinically relevant bradycardia

•    Patients with electrolyte disturbances such as hypomagnesaemia. Clarithromycin must not be given to patients with hypokalaemia (see section 4.3).

•    Patients concomitantly taking other medicinal products associated with QT-prolongation (see section 4.5).

•    Concomitant administration of clarithromycin with astemizole, cisapride, pimozide and terfendine is contraindicated (see section 4.3).

2

Because these reactions are reported voluntarily from a population of uncertain

3

size, it is not always possible to reliably estimate their frequency or establish a causal