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Abbott Laboratories Ireland Limited

4051 Kingswood Drive, Citywest Business Campus, Dublin 24, Ireland
Telephone: +353 1 4691500
Medical Information Direct Line: +44 (0)1628 773 355
Medical Information e-mail: medinfo.shl@abbott.com


Summary of Product Characteristics last updated on medicines.ie: 20/02/2013
SPC Klacid 250mg/5ml Granules for Oral Suspension



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1. NAME OF THE MEDICINAL PRODUCT

Klacid 250mg/5ml Granules for Oral Suspension


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2. QUALITATIVE AND QUANTITATIVE COMPOSITION

After reconstitution as directed, each 5ml of suspension contains 250mg clarithromycin.

Excipients: also contains 2.42g of sucrose per 5ml.

For a full list of excipients, see section 6.1.


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3. PHARMACEUTICAL FORM

Granules for oral suspension

White to off-white, free-flowing granules with an odour of fruit.


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4. CLINICAL PARTICULARS

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4.1 Therapeutic indications

Klacid Suspension is indicated for the treatment of infections caused by susceptible organisms. Indications include:

Lower respiratory tract infections.

Upper respiratory tract infections.

Skin and skin structure infections.

Acute otitis media.

Klacid 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, Haemophilus parainfluenzae, Moraxella (Branhamella) catarrhalis, Neisseria gonorrhoeae; Legionella pneumophila, Bordetella pertussis, Helicobacter pylori; Campylobacter jejuni.

Mycoplasma: Mycoplasma pneumoniae; Ureaplasma urealyticum.

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

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

Klacid Suspension has bactericidal activity against several bacterial strains. These organisms include Haemophilus influenzae, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Moraxella (Branhamella) catarrhalis, Neisseria gonorrhoeae, Helicobacter pylori and Campylobacter species.

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

Clarithromycin suspension is indicated in children, 6 months to 12 years.

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


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4.2 Posology and method of administration

Children under 12 years: Clinical trials have been conducted using clarithromycin paediatric suspension in children 6 months to 12 years of age. Therefore, children under 12 years of age should use clarithromycin paediatric suspension (granules for oral suspension).

Recommended doses and dosage schedules:

The usual duration of treatment is for 5 to 10 days depending on the pathogen involved and the severity of the condition. The recommended daily dosage of Klacid Suspension 250mg/5ml in children is given in the following table and is based on a 7.5mg/kg b.i.d. dosage regimen. Doses up to 500mg b.i.d. have been used in the treatment of severe infections.

KLACID SUSPENSION 250MG/5ML

DOSAGE IN CHILDREN

Dosage Based on Body Weight (kg)

Weight *

(kg)

Approx Age

(yrs)

Dosage

(ml)

bid

8-11

1 - 2

1.25

12-19

3 - 6

2.5

20-29

7 - 9

3.75

30-40

10 - 12

5

* Children < 8 kg should be dosed on a per kg basis (approx. 7.5 mg/kg bid)

In patients with renal impairment with creatinine clearance less than 30 ml/min, the dosage of clarithromycin should be reduced by one-half. Treatments should not be continued beyond 14 days in these patients.

Preparation for use: For instructions on the preparation of the suspension, see section 6.6.


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4.3 Contraindications

Clarithromycin is contraindicated in patients with known hypersensitivity to macrolide antibiotic drugs or any of its excipients.

Concomitant administration of clarithromycin and any of the following drugs is contraindicated: astemizole, cisapride, pimozide or terfenadine as this may result in QT prolongation and cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation, and torsades de pointes (see section 4.5). Concomitant administration of clarithromycin and ergotamine or dihydroergotamine is contraindicated, as this may result in ergot toxicity. Concomitant administration of clarithromycin with lovastatin or simvastatin is also contraindicated.

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

Clarithromycin should not be used concomitantly with HMG-CoA reductase inhibitors (statins) that are extensively metabolised by CYP3A4, (lovastatin or simvastatin), due to the increased risk of myopathy, including rhabdomyolysis (see section 4.4).

Colchicine is contraindicated in patients with renal or hepatic impairment who are taking P-glycoprotein or a strong CYP3A4 inhibitor.

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

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


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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). If clarithromycin is considered for patients of post-pubertal age, the physician should carefully weigh the benefits against the risk when pregnancy is either suspected or confirmed.

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

Hepatic dysfunction, including increased liver enzymes, and hepatocellular and/or cholestatic hepatitis, with or without jaundice, has been reported with clarithromycin. This hepatic dysfunction may be severe and is usually reversible. In some instances, hepatic failure with fatal outcome has been reported and generally has been associated with serious underlying diseases and/or concomitant medications. Discontinue clarithromycin immediately if signs and symptoms of hepatitis occur, such as anorexia, jaundice, dark urine, pruritus, or tender abdomen.

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

Exacerbation of symptoms of myasthenia gravis has been reported in patients receiving clarithromycin therapy.

There have been post-marketing reports of colchicine toxicity with concomitant use of clarithromycin and colchicine, especially in the elderly, some of which occurred in patients with renal insufficiency. Deaths have been reported in some such patients (see section 4.5). If concomitant administration of colchicine and clarithromycin is necessary, patients should be monitored for clinical symptoms of colchicine toxicity.

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

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

Due to the risk for QT prolongation, clarithromycin should be used with caution in patients with a medical condition associated with an increased tendency toward QT prolongation and torsades de pointes.

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

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

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

Clarithromycin should be used with caution when administered concurrently with medications that induce the cytochrome CYP3A4 enzyme (see section 4.5).

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

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

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

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

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

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

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

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.


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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, Contraindications).

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, Contraindications). 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.

Ergotamine/dihydroergotamine

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

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 (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 creatinine clearance 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. For patients with creatinine clearance <30 mL/min the dose of clarithromycin should be decreased by 75%. Doses of clarithromycin greater than 1000 mg/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

CY3A4-based interactions

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

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

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

Antiarrhythmics

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

Omeprazole

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

Sildenafil, tadalafil and vardenafil

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

Theophylline, carbamazepine

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

Tolterodine

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

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

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

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

Other drug interactions

Colchicine

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

Digoxin

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

Zidovudine

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

Phenytoin and valproate

There have been spontaneous or published reports of interactions of CYP3A inhibitors, including clarithromycin with drugs not thought to be metabolised by CYP3A (e.g. phenytoin and valproate). Serum level determinations are recommended for these drugs when administered concomitantly with clarithromycin. Increased serum levels have been reported.

Bi-directional drug interactions

Atazanavir

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

Itraconazole

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

Saquinavir

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

Verapamil

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


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4.6 Fertility, pregnancy and lactation

Pregnancy

The safety of clarithromycin during pregnancy has not been established. Therefore, use during pregnancy is not advised without carefully weighing the benefits against risk.

Lactation

The safety of clarithromycin use during breast-feeding of infants has not been established. Clarithromycin is excreted into human breast milk.


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4.7 Effects on ability to drive and use machines

There are no data 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.


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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 paediatric populations are abdominal pain, diarrhoea, nausea, vomiting and taste perversion. These adverse reactions are usually mild in intensity and are consistent with the known safety profile of macrolide antibiotics. (see 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; frequency 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 Known

(*cannot be estimated from the available data)

Infections and infestations

 

 

Cellulitis1, candidiasis, gastroenteritis2,infection3, vaginal infection

Pseudomembranous colitis, erysipelas, erythrasma

Blood and lymphatic system

 

 

Leukopenia, neutropenia4, thrombocythemia3, eosinophilia4

Agranulocytosis, thrombocytopenia

Immune system disorders

 

 

Anaphylactoid reaction1, hypersensitivity

Anaphylactic reaction

Metabolism and nutrition disorders

 

 

Anorexia, decreased appetite

Hypoglycaemia

Psychiatric disorders

 

Insomnia

Anxiety, nervousness3, screaming3

Psychotic disorder, confusional state, depersonalisation, depression, disorientation, hallucination, abnormal dreams

Nervous system disorders

 

Dysgeusia, headache, taste perversion

Loss of consciousness1, dyskinesia1, dizziness, somnolence, 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

Torsades de pointes, ventricular tachycardia

Vascular disorders

 

Vasodilation1

 

Haemorrhage

Respiratory, thoracic and mediastinal disorder

 

 

Asthma1, epistaxis2, pulmonary embolism1

 

Gastrointestinal disorders

 

Diarrhoea, vomiting, dyspepsia, nausea, abdominal pain

Oesophagitis1, gastrooesophageal reflux disease2, gastritis, proctalgia2, stomatitis, glossitis, abdominal distension4, constipation, dry mouth, eructation, flatulence,

Pancreatitis acute, tongue discolouration, tooth discolouration

Hepatobiliary disorders

 

Liver function test abnormal

Cholestasis4, hepatitis4, alanine aminotransferase increased, aspartate aminotransferase increased, gamma-glutamyl transferase increased4

Hepatic failure, jaundice hepatocellular

Skin and subcutaneous tissue disorders

 

Rash, hyperhidrosis

Dermatitis bullous1, pruritus, urticaria, rash maculo-papular3

Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS), acne, Henoch-Schonlein purpura

Musculoskeletal and connective tissue disorders

 

 

Muscle spasms3, musculoskeletal stiffness1, myalgia2

Rhabdomyolysis2**, myopathy

Renal and urinary disorders

 

 

Blood creatinine increased1, blood urea increased1

Renal failure, nephritis interstitial

General disorders and administration site conditions

Injection site phlebitis1

Injection site pain1, injection site inflammation1

Malaise4, pyrexia3, asthenia, chest pain4, chills4, fatigue4

 

Investigations

 

 

Albumin globulin ratio abnormal1, blood alkaline phosphatase increased4, blood lactate dehydrogenase increased4

International normalised ratio increased, prothrombin time prolonged, urine colour abnormal

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

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

1 ADRs reported only for the Powder for Solution for Injection formulation

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

c. Description of selected adverse reactions

There have been post-marketing reports of colchicine toxicity with concomitant use of clarithromycin and colchicine, especially in the elderly and/or patients with renal insufficiency, some with a fatal outcome. (see sections 4.4 Warnings and Precautions and 4.5 Interaction with other medicinal products and other forms of interaction).

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.

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 of clarithromycin were: nausea, vomiting, taste perversion, abdominal pain, diarrhoea, rash, flatulence, headache, constipation, hearing disturbance, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) elevations. Additional low-frequency events included dyspnoea, insomnia and dry mouth.

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 of clarithromycin daily had seriously abnormal elevated levels of AST and ALT, and abnormally low white blood cell and platelet counts. A lower percentage of patients also had elevated Blood Urea Nitrogen levels.


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4.9 Overdose

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

Adverse reactions accompanying overdosage should be treated by 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.


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5. PHARMACOLOGICAL PROPERTIES

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5.1 Pharmacodynamic properties

Clarithromycin is a semi-synthetic derivative of erythromycin A. It exerts its anti-bacterial action by binding to the 50S ribosomal sub-unit of susceptible bacteria and suppresses protein synthesis. Clarithromycin demonstrates excellent invitro activity against standard strains of clinical isolates. It is highly potent against a wide variety of aerobic and anaerobic gram-positive and gram-negative organisms. The minimum inhibitory concentrations (MICs) of clarithromycin are generally two-fold lower than the MICs of erythromycin.

The 14-(R)-hydroxy metabolite of clarithromycin formed in man by first pass metabolism also has anti-microbial activity. The MICs of this metabolite are equal or two-fold higher than the MICs of the parent compound, except for Haemophilus influenzae where the 14-hydroxy metabolite is two-fold more active than the parent compound. Clarithromycin is also bactericidal against several bacterial strains.

Clarithromycin is usually active against the following organisms in vitro: Please see below for table of MIC breakpoints.

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, Haemophilus parainfluenzae, Moraxella (Branhamella) catarrhalis, Neisseria gonorrhoeae; Legionella pneumophila, Bordetella pertussis, Helicobacter pylori; Campylobacter jejuni.

Mycoplasma: Mycoplasma pneumoniae; Ureaplasma urealyticum.

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

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

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

Breakpoints

The following breakpoints for clarithromycin, separating susceptible organisms from resistant organisms, have been established by the European Committee for Antimicrobial Susceptibility Testing (EUCAST).

Breakpoints (MIC, μg/ml)

Microorganism

Susceptible (≤)

Resistant (>)

Streptococcus spp.

0.25 mcg/ml

0.5 mcg/ml

Staphylococcus spp.

1 mcg/ml

2 mcg/ml

Haemophilus spp.

1 mcg/ml

32 mcg/ml

Moraxella catarrhalis

0.25 mcg/ml

0.5 mcg/ml

Clarithromycin is used for the eradication of H. pylori; minimum inhibitory concentration (MIC) ≤ 0.25 mcg/ml which has been established as the susceptible breakpoint by the Clinical and Laboratory Standards Institute (CLSI).


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5.2 Pharmacokinetic properties

Clarithromycin is rapidly and well absorbed from the gastro-intestinal tract after oral administration. The microbiologically active 14(R)-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. Although the pharmacokinetics of clarithromycin are non linear, steady state is attained within 2 days of dosing. 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. Five to 10% of the parent drug is recovered from the faeces.

Clarithromycin provides tissue concentrations that are several times higher than circulating drug level. 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.

Klacid Suspension does not contain tartrazine or other azo dyes, lactose or gluten.


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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.


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6. PHARMACEUTICAL PARTICULARS

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6.1 List of excipient(s)

Carbomers (Carbopol 974P) Ph.Eur.

Povidone K90,

Hypromellose phthalate (HP-55)

Castor oil

Silicon dioxide

Sucrose

Xanthan gum

Flavour - fruit punch

Potassium sorbate

Citric acid

Titanium dioxide

Maltodextrin.


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6.2 Incompatibilities

Not applicable


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6.3 Shelf life

Dry granules: 2 years. Once reconstituted, Klacid suspension should be used within 14 days.


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6.4 Special precautions for storage

Store below 25°C. Do not refrigerate. Keep bottle tightly closed.


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6.5 Nature and contents of container

Granules for reconstitution in a HDPE bottle with a polypropylene cap with LDPE liner. Pack sizes of 50, 70, 100 and 140ml are available.

Not all pack sizes may be marketed.


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6.6 Special precautions for disposal and other handling

Preparation for use:

140ml bottle: 74ml of water should be added to the granules in the bottle and shaken to yield 140ml of reconstituted suspension. The concentration of clarithromycin in the reconstituted suspension is 250mg per 5ml.

100ml bottle: 53ml of water should be added to the granules in the bottle and shaken to yield 100ml of reconstituted suspension. The concentration of clarithromycin in the reconstituted suspension is 250mg per 5ml.

70ml bottle: 37ml of water should be added to the granules in the bottle and shaken to yield 70ml of reconstituted suspension. The concentration of clarithromycin in the reconstituted suspension is 250mg per 5ml.

50ml bottle: 27ml of water should be added to the granules in the bottle and shaken to yield 50ml of reconstituted suspension. The concentration of clarithromycin in the reconstituted suspension is 250mg per 5ml.

On reconstitution product forms an opaque, white to off-white suspension with an odour of fruit.

Any unused product or waste material should be disposed of in accordance with local requirements.


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7. MARKETING AUTHORISATION HOLDER

Abbott Laboratories Ireland Limited

4051 Kingswood Drive,

Citywest Business Campus,

Dublin 24,

Ireland


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8. MARKETING AUTHORISATION NUMBER(S)

PA 38/51/9


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9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 26 June 1998

Date of last renewal: 26 June 2008


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10. DATE OF REVISION OF THE TEXT

February 2013



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Active Ingredients

 
   Clarithromycin