CLARITHROMYCIN 125 MG / 5ML GRANULES FOR ORAL SUSPENSION - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Clarithromycin 125 mg/5 ml granules for oral suspension

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 5 ml of the reconstituted suspension contains 125 mg clarithromycin.

Excipients with known effect:

Each 5 ml reconstituted suspension contains 3194 mg of sucrose and 1 mg of aspartame.

This medicine contains less than 1 mmol sodium (23 mg) per 5 ml suspension.

This medicine contains 10 mg sodium benzoate in each 5 ml suspension.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Granules for oral suspension

White to off-white granular powder

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Clarithromycin is indicated in children 6 months to 12 years.

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

Bacterial pharyngitis

Acute Otitis media

Acute bacterial sinusitis

Acute bacterial exacerbation of chronic bronchitis

Mild to moderate community acquired pneumonia

Skin and soft tissue infections of mild to moderate severity, for example folliculitis, cellulitis and erysipelas.

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

4.2 Posology and method of administration

Posology

Paediatric population

Clinical trials have been conducted using clarithromycin paediatric suspension in children 6 months to 12 years of age. Therefore, children under 12 years of age should use clarithromycin paediatric suspension.

Recommended doses and dosage schedules:

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 125 mg/ 5 ml granules for oral suspension in children is given in the following table and is based on an approximate 7.5 mg/ kg twice a day (b.i.d.) dosing regime up to a maximum dose of 500 mg b.i.d.

DOSAGE IN CHILDREN

*children < 8 kg should be dosed based on a per kg basis: 0.3ml/kg twice a day (approx. 7.5 mg/kg b.i.d.)

Renal Impairment

In children with creatinine clearance less than 30 ml/min/1.73 m2, the dosage of clarithromycin should be reduced by half to 7.5 mg/kg per day.

Dosage should not be continued beyond 14 days in these patients.

Method of administration

Before administration the granules must be reconstituted with water forming a white to off-white suspension.

For administration after reconstitution, an oral syringe is used. The suspension should be shaken well before each use.

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

Clarithromycin should be administered twice daily as recommended in the table above. The doses should be given at 12-hour intervals.

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

4.3 Contraindications

Hypersensitivity to the active substance, other macrolide antibiotics or to any of the excipients listed in section 6.1.

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

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

Concomitant administration of clarithromycin and any of the following active substances is contraindicated: astemizole, cisapride, domperidone, pimozide and 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 must 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.

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

Clarithromycin must not be used concomitantly with HMG-CoA reductase inhibitors (statins) that are extensively metabolized by CYP3A4, (lovastatin or simvastatin), due to the increased risk of myopathy, including rhabdomyolysis (see section 4.5).

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

Clarithromycin should not be given to patients with electrolyte disturbances (hypokalaemia or hypomagnesiaemia, due to the risk of prolongation of the QT interval).

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

4.4 Special warnings and precautions for use

The physician should not prescribe clarithromycin to pregnant women without carefully weighing the benefits against the risk, particularly during the first three months of pregnancy (see section 4.6).

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

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

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

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including macrolides, and may range in severity from mild to lifethreatening. Clostridium difficile-associated diarrhoea (CDAD) has been reported with use of nearly all antibacterial agents including clarithromycin, and may range in severity from mild diarrhoea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon, which may lead to overgrowth of C. difficile. CDAD must be considered in all patients who present with diarrhoea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. Therefore, discontinuation of clarithromycin therapy should be considered regardless of the indication. Microbial testing should be performed and adequate treatment initiated. Medicinal products inhibiting peristalsis should be avoided.

There have been post-marketing reports of colchicine toxicity with concomitant use of clarithromycin and colchicine, especially in the elderly, some of which occurred in patients with renal insufficiency. Deaths have been reported in some such patients (see section 4.5). Concomitant administration of clarithromycin and colchicine is contraindicated (see section 4.3).

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

Prolongation of the QT interval

Prolonged cardiac repolarisation and QT interval, imparting a risk of developing cardiac arrhythmia and torsades 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 torsades de pointes), clarithromycin should be used with caution in the following patients;

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

Clarithromycin must not be given to patients with hypokalaemia (see section 4.3).

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

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

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

Pneumonia: In view of the emerging resistance of Streptococcus pneumoniae to macrolides, it is important that sensitivity testing be performed when prescribing clarithromycin for community-acquired pneumonia. In hospital-acquired pneumonia, clarithromycin should be used in combination with additional appropriate antibiotics.

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

In the event of severe acute hypersensitivity reactions, such as anaphylaxis, severe cutaneous adverse reactions (SCAR) (e.g. Acute generalised exanthematous pustulosis (AGEP), Stevens-Johnson Syndrome, toxic epidermal necrolysis, and drug rash with eosinophilia and systemic symptoms (DRESS), clarithromycin therapy should be discontinued immediately and appropriate treatment should be urgently initiated.

Clarithromycin should be used with caution when administered concurrently with medications that induce cytochrome CYP3A4 enzyme (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 section 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.

Caution should be exercised when clarithromycin is co-administered with direct acting oral anticoagulants such as dabigatran, rivaroxaban and apixaban, particularly to patients at high risk of bleeding (see section 4.5).

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

Attention should also be paid to the possibility of cross resistance between clarithromycin and other macrolide medicinal products, as well as lincomycin and clindamycin.

Sucrose

5 ml suspension contain 3194 mg sucrose.

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 medicinal product.

Aspartame

This medicine contains 1 mg aspartame in each 5 ml which is equivalent to 0.2 mg/ml. This may be harmful for people with phenylketonuria. Neither non-clinical nor clinical data are available to assess aspartame use in infants below 12 weeks of age.

Sodium

This medicine contains less than 1 mmol sodium (23 mg) per 5 ml suspension, that is to say essentially ‘sodium-free’.

4.5 Interaction with other medicinal products and other forms of interaction

Astemizole, cisapride, domperidone, pimozide, 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 2– to 3-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.

Lomitapide

Concomitant administration of clarithromycin with lomitapide is contraindicated due the potential for markedly increased transaminases (see section 4.3).

Ergot alkaloids

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

Oral Midazolam

When midazolam was co-administered with clarithromycin tablets (500 mg twice daily), midazolam AUC was increased 7-fold after oral administration of midazolam. Concomitant administration of oral midazolam and clarithromycin is contraindicated (see section 4.3).

HMG-CoA Reductase Inhibitors (statins)

Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated (see section 4.3) as these statins are extensively 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

Medicinal products 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 active substances are known or suspected to affect circulating concentrations of clarithromycin; clarithromycin dosage adjustment or consideration of alternative treatments may be required.

Efavirenz, nevirapine, rifampicin, rifabutin and rifapentine

Strong inducers of the cytochrome P450 metabolism system such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine may accelerate the metabolism of clarithromycin and thus lower the plasma levels of clarithromycin, while increasing those of 14-OH-clarithromycin, a metabolite that is also microbiologically active. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers.

Etravirine

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

Fluconazole

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

Ritonavir

A pharmacokinetic study demonstrated that the concomitant administration of ritonavir 200 mg every eight hours and clarithromycin 500 mg every 12 hours resulted in a marked inhibition of the metabolism of clarithromycin. The clarithromycin Cmax increased by 31%, Cmin increased 182% and AUC increased by 77% with concomitant administration of ritonavir. An essentially complete inhibition of the formation of 14-OH-clarithromycin was noted. Because of the large therapeutic window for clarithromycin, no dosage reduction should be necessary in patients with normal renal function. However, for patients with renal impairment, the following dosage adjustments should be considered: For patients with CLCR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. For patients with CLCR < 30mL/min the dose of clarithromycin should be decreased by 75%. Doses of clarithromycin greater than 1 g/day should not be co-administered 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 active substance interactions).

Effect of clarithromycin on other medicinal products

CYP3A-based interactions

Co-administration of clarithromycin, known to inhibit CYP3A, and a medicinal product primarily metabolized by CYP3A may be associated with elevations in active substance concentrations that could increase or prolong both therapeutic and adverse effects of the concomitant medicinal product. Clarithromycin should be used with caution in patients receiving treatment with other medicinal products 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 medicinal products primarily metabolized by CYP3A should be monitored closely in patients concurrently receiving clarithromycin.

The following medicinal products or active substance classes are known or suspected to be metabolized by the same CYP3A isozyme: alprazolam, astemizole, carbamazepine, cilostazol, cisapride, cyclosporin, disopyramide, domperidone, ergot alkaloids, ibrutinib, lovastatin, methylprednisolone, midazolam, omeprazole, oral anticoagulants (e.g. warfarin, rivaroxaban, apixaban, see section 4.4), atypical antipsychotics (e.g. quetiapine), pimozide, quinidine, rifabutin, sildenafil, simvastatin, sirolimus, tacrolimus, terfenadine, triazolam and vinblastine but this list is not exhaustive. Active substances interacting by similar mechanisms through other isozymes within the cytochrome P450 system include phenytoin, theophylline and valproate.

Antiarrhythmics

There have been post-marketing reports of torsades de pointes occurring with the concurrent use of clarithromycin and quinidine or disopyramide. Electrocardiograms should be monitored for QT prolongation during coadministration of clarithromycin with these medicinal products. 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 medicinal products 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.

Direct acting oral anticoagulants (DOACs)

The DOAC dabigatran is a substrate for the efflux transporter P-gp. Rivaroxaban and apixaban are metabolised via CYP3A4 and are also substrates for P-gp. Caution should be exercised when clarithromycin is coadministered with these agents particularly to patients at high risk of bleeding (see section 4.4).

Omeprazole

Clarithromycin (500 mg every 8 hours) was given in combination with omeprazole (40 mg daily) to healthy adult subjects. The steady-state plasma concentrations of omeprazole were increased (Cmax, AUC0–24, and t1/2 increased by 30%, 89%, and 34%, respectively), by the concomitant administration of clarithromycin. The mean 24-hour gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when omeprazole was co-administered with clarithromycin.

Sildenafil, tadalafil and vardenafil

Each of these phosphodiesterase inhibitors is 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 medicinal products are co-administered with clarithromycin.

Theophylline, carbamazepine

Results of clinical studies indicate that there was a modest but statistically significant (p < 0.05) increase of circulating theophylline or carbamazepine levels when either of these medicinal products 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. If intravenous midazolam is co-administered with clarithromycin, the patient must be closely monitored to allow dose adjustment. Active substance delivery of midazolam via oromucosal route, which could bypass pre-systemic elimination of the active substance, will likely result in a similar interaction to that observed after intravenous midazolam rather than oral administration. The same precautions should also apply to other benzodiazepines that are 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 medicinal product 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 medicinal product interactions

Colchicine

Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. When clarithromycin and colchicine are administered together, inhibition of Pgp and/or CYP3A by clarithromycin may lead to increased exposure to colchicine (see sections 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 active substances not thought to be metabolized by CYP3A (e.g. phenytoin and valproate). Serum level determinations are recommended for these medicinal products when administered concomitantly with clarithromycin. Increased serum levels have been reported.

Bi-directional medicinal product interactions

Atazanavir

Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional medicinal product interaction. Coadministration 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.

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 medicinal product 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 medicinal product interaction. Concomitant administration of clarithromycin (500 mg twice daily) and saquinavir (soft gelatin capsules, 1200 mg three times daily) to 12 healthy volunteers resulted in steady-state AUC and Cmax values of saquinavir which were 177% and 187% higher than those seen with saquinavir alone.

Clarithromycin AUC and Cmax values were approximately 40% higher than those seen with clarithromycin alone. No dose adjustment is required when the two medicinal products are co-administered for a limited time at the doses/formulations studied. Observations from medicinal product interaction studies using the soft gelatin capsule formulation may not be representative of the effects seen using the saquinavir hard gelatin capsule. Observations from medicinal product 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 above: “Ritonavir”).

Patients taking oral contraceptives should be warned that if diarrhoea, vomiting or breakthrough bleeding occur there is a possibility of contraceptive failure.

4.6 Fertility, pregnancy and lactation

Pregnancy

The safety of clarithromycin for use in pregnancy has not been established. Based on variable results obtained from animal studies and experience in humans, the possibility of adverse effects on embryofoetal development cannot be excluded. Some observational studies evaluating exposure to clarithromycin during the first and second trimester have   reported an increased risk of

miscarriage compared to no antibiotic use or other antibiotic use during the same period. The available epidemiological studies on the risk of major

congenital malformations with use of macrolides including clarithromycin during pregnancy provide conflicting results.

Therefore, use during pregnancy is not advised without carefully weighing the benefits against risks.

Breast-feeding

Clarithromycin is excreted into human breast milk in small amounts. It has been estimated that an exclusively breastfed infant would receive about 1.7% of the maternal weight-adjusted dose of clarithromycin.

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 considered. The benefit of treatment of the mother should be weighed against the potential risk for the infant.

Fertility

There is no data available on the effect of clarithromycin on fertility in humans. In rats, the limited data available do not indicate any effects on fertility.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

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 below).

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 adverse 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 postmarketing 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.

2

2ADRs 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, 6 See section c)

exposure. Patient exposure is estimated to be greater than 1 billion patient treatment days for clarithromycin.

c) Description of selected adverse reactions

Injection site phlebitis, injection 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 medicinal product 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 have been rare reports of clarithromycin extended-release tablets in the stool, many of which have occurred in patients with anatomic (including ileostomy or colostomy) or functional gastrointestinal disorders with shortened GI transit times. In several reports, tablet residues have occurred in the context of diarrhoea. It is recommended that patients who experience tablet residue in the stool and no improvement in their condition should be switched to a different clarithromycin formulation (e.g. suspension) or another antibiotic.

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

d) Paediatric 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, diarrhoea, rash, flatulence, headache, constipation, hearing disturbance, Serum Glutamic Oxaloacetic Transaminase (SGOT) and Serum Glutamic Pyruvate Transaminase (SGPT) elevations. Additional low-frequency events included dyspnoea, insomnia and dry mouth. The incidences were comparable for patients treated with 1000 mg and 2000 mg, but were generally about 3 to 4 times as frequent for those patients who received total daily doses of 4000 mg of clarithromycin.

In these immunocompromised patients, evaluations of laboratory values were made by analysing those values outside the seriously abnormal level (i.e. the extreme high or low limit) for the specified test. On the basis of these criteria, about 2% to 3% of those patients who received 1000 mg or 2000 mg of clarithromycin daily had seriously abnormal elevated levels of SGOT and SGPT, and abnormally low white blood cell and platelet counts. A lower percentage of patients in these two dosage groups also had elevated Blood Urea Nitrogen levels. Slightly higher incidences of abnormal values were noted for patients who received 4000 mg daily for all parameters except White Blood Cell.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App store..

4.9 Overdose

Reports indicate that the ingestion of large amounts of clarithromycin can be expected to produce gastro-intestinal symptoms. One patient who had a history of bipolar disorder ingested 8 grams of clarithromycin and showed altered mental status, paranoid behaviour, hypokalaemia and hypoxaemia.

Adverse reactions accompanying overdose should be treated by the prompt elimination of unabsorbed active substance and supportive measures. As with other macrolides, clarithromycin serum levels are not expected to be appreciably affected by haemodialysis or peritoneal dialysis.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antibacterial for systemic use, macrolide

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.

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 influenzae where the 14-hydroxy metabolite is twofold more active than the parent compound.

Clarithromycin is also bactericidal against several bacterial strains.

Breakpoints

The following breakpoints have been established by the European Committee for Antimicrobial Susceptibility Testing (EUCAST), version 9.0.

1) Erythromycin can be used to determine susceptibility to clarithromycin.

Susceptibility

Clarithromycin is usually active against the following organisms in vitro:-

Commonly susceptible species__________­___________________

Gram-positive bacteria___________­________________________­___

Staphylococcus aureus (methicillin susceptible);_______­_________

Streptococcus pyogenes (Group A beta-haemolytic streptococci); alpha-haemolytic streptococci (viridans group)__________­_______

Streptococcus pneumoniae___________­______________________

Streptococcus agalactiae___________­________________________­___

Listeria monocytogenes_________­________________________­____

Gram-negative bacteria___________­________________________­__

Haemophilus influenzae

Haemophilus parainfluenza­e____________

Moraxella 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__________­__________

Propionibacterium acnes

Clarithromycin also has bactericidal activity against several bacterial strains. These organisms include H. influenzae, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Moraxella catarrhalis, Neisseria gonorrhoeae, Helicobacter pylori and Campylobacter species.

5.2 Pharmacokinetic properties

Absorption

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-hydroxy metabolite.

Distribution

Clarithromycin provides tissue concentrations that are several times higher than the circulating active substance 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.

Biotransformation

14-hydroxyclarit­hromycin is the major urinary metabolite and accounts for 10–15% of the dose.

Elimination

Most of the remainder of the dose is eliminated in the faeces, primarily via the bile. 5–10% of the parent active substance is recovered from the faeces.

Linearity

Although the pharmacokinetics of clarithromycin are non linear, steady state is attained within 2 days of dosing.

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 dose of 400mg/kg/day some dogs and monkeys developed corneal opacities and/or oedema.

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 2× the clinical dose in rabbit (IV) and 10× 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 mice at doses 70× the clinical dose, cleft palate occurred at varying incidence (3–30%).

Clarithromycin has been found in the milk of lactating animals.

In 3-day old mice and rats, the LD50 values were approximately half those in adult animals. Juvenile animals presented similar toxicity profiles to mature animals although enhanced nephrotoxicity in neonatal rats has been reported in some studies. Slight reductions in erythrocytes, platelets and leukocytes have also been found in juvenile animals.

Clarithromycin has not been tested for carcinogenicity.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

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

Macrogol 1500

Talc

Carbomer

Silica, Colloidal anhydrous

Sucrose

Aspartame (E951)

Xanthan gum (E415)

Monosodium citrate

Sodium benzoate (E211)

Titanium dioxide (E171)

Peppermint flavour (containing modified food starch)

Flavour Tutti-Frutti (containing waxy maize maltodextrin, nature-identical flavouring substance(s), propylene glycol (E1520), modified waxy maize starch (E1450), and artificial flavouring substances)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years.

Reconstituted suspension: 14 days

6.4 Special precautions for storage

Store below 30°C. Do not refrigerate or freeze the reconstituted suspension.

6.5 Nature and contents of container

Clarithromycin is packed in clear translucent HDPE bottles with continuous ring mark for specific fill volume, having an inner translucent PP-induction ‘lift and peel’ seal liner and a child-resistant white opaque PP-cap closure.

Each pack contains also a translucent 10 ml PP-oral syringe (with CE marking and graduated with 1.25, 2.5, 3.75, 5.0, 6.25, 7.5, 8.75 ml and 10.0 ml) with HDPE plunger and an LDPE adapter for the bottle.

The following pack sizes are available:

1 bottle with 34.72 – 38.37 g granules for preparation of 50 ml oral suspension

1 bottle with 41.66 – 46.04 g granules for preparation of 60 ml oral suspension or

1 bottle with 48.61 – 53.72 g granules for preparation of 70 ml oral suspension or

1 bottle with 69.44 – 76.75 g granules for preparation of 100 ml oral suspension or

1 bottle with 97.21 – 107.44 g granules for preparation of 140 ml oral suspension.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Instructions for Reconstitution

Step-A The bottle should be removed from the box.

Step-B The bottle should be inverted and shaken to loosen the powder until no powder is adhered to the bottom. This should be checked by holding the bottle upside down against light. The cap should be opened as instructed below and the seal should be opened by lifting the tab and then peeling off (See Figure 2).

Figure 2

Step-C The water should be added slowly up to the ring mark. If necessary, the bottle should be held against light in order to be able to recognize the correct filling level better. The bottle should be closed, inverted and shaken well for about 1 minute until no powder is adhered to the bottom (See Figure 3). This should be checked by holding the bottle upside down against light.

The suspension should be left to settle and if it would be necessary to add more water as to make it up to the ring mark, step D should be followed.

Step-D If necessary, water should be added again up to the ring mark. If necessary, the bottle should be held against light in order to be able to recognize the correct filling level better. The bottle should be closed, inverted and shaken well until no powder is adhered to the bottom (See Figure 4). This should be checked by holding the bottle upside down against light.

1. To open the bottle, the child-proof cap should be removed from the bottle by pushing down on the cap while turning it anticlockwise.

2. The plastic circular adaptor should be taken from the carton and pushed into the neck of the bottle. This should fit tightly and once it is in place it should not be removed.

3. The oral syringe should be taken out of the carton and it should be ensured that the plunger is pressed down inside the barrel as far as it will go. This gets rid of any air that may be inside the barrel.

4. The nozzle of the oral syringe should be inserted into the hole in the adaptor.

5. The bottle should be turned upside down and held in one hand and the oral syringe in the other.

6. The barrel of the oral syringe should be held steady and slowly while pulling the plunger down, until you see the medicine fill the barrel to the mark, which matches the number of ml that you need to give to the patient.

7. The bottle should be turned the correct way up. The whole oral syringe should be removed from the adaptor, keeping hold of the barrel.

8. The oral syringe tip should be placed into the patient’s mouth and the medicinal product should be dripped in by pushing down the plunger gently while still holding the barrel. The patient shouldn’t be hurried, he or she should be allowed to swallow the medicine slowly. Alternatively, the measured dose from the oral syringe should be emptied onto a spoon for the patient to take the medicinal product from.

9. After administration, the bottle should be closed with the cap.

10. The oral syringe should be washed out in warm soapy water and rinsed well. The oral syringe should be held under water and the plunger should be moved up and down several times to make sure the inside of the barrel is clean. The oral syringe should be stored in a hygienic place with the medicinal product.

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

Administration of water or juice after medicine