2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains Clarithromycin 500mg
Excipients with known effect: lactose and sodium
Each tablet contains 115mg lactose monohydrate and per tablet
Tablet sodium content: 15.3mg sodium per tablet
For the full list of excipients, see section 6.1.

4.3 Contraindications
Hypersensitivity to macrolide antibiotic drugs or any of its the excipients listed in (see section 6.1).

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).
Caution is advised in patients with severe renal insufficiency (see section 4.2).
Clarithromycin is principally excreted metabolized 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 (see also section 4.3).

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

4.8 Undesirable effects

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
Blood and lymphatic system			Leukopenia, neutropenia4, thrombocythemia3, eosinophilia4	Agranulocytosis, thrombocytopenia
Immune system disorders			Anaphylactoid reaction1, hypersensitivity	Anaphylactic reaction, angioedema
Metabolism and nutrition disorders			Anorexia, decreased appetite
Psychiatric disorders		Insomnia	Anxiety, nervousness3	Psychotic disorder, confusional state5, depersonalisation, depression, disorientation, hallucination, abnormal dreams, mania
Nervous system disorders		Dysgeusia, headache taste perversion	Loss of consciousness1, dyskinesia1, dizziness, somnolence5, tremor	Convulsion, ageusia, parosmia, anosmia ,paraesthesia
Ear and labyrinth disorders			Vertigo, hearing impaired, tinnitus	Deafness
Cardiac disorders			Cardiac arrest1, atrial fibrillation1, electrocardiogram QT prolonged, extrasystoles1, palpitations	Torsade de pointes, ventricular tachycardia, ventricullar fibrillation
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-glutamyltransferase increased4	Hepatic failure, jaundice hepatocellular
Skin and subcutaneous tissue disorders		Rash, hyperhidrosis	Dermatitis bullous1, pruritus, urticaria, rash maculo-papular3	Severe cutaneous adverse reactions (SCAR) (e.g. Acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS)), acne
Musculoskeletal and connective tissue disorders			Muscle spasms3, musculoskeletal stiffness1, myalgia2	Rhabdomyolysis2,6, 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 color abnormal

 

10. DATE OF REVISION OF THE TEXT
June 2017 January 2018

7. MARKETING AUTHORISATION HOLDER
Mylan IRE Healthcare Limited
Unit 35/36
Grange Parade
Baldoyle Industrial Estate
Dublin 13
BGP Products Ireland Limited
4051 Kingswood Drive
Citywest Business Campus
Dublin 24

10. DATE OF REVISION OF THE TEXT
February 2017June 2017

Section 4.2 - Update to text for patients with renal impairment
Section 4.3 - Deletion of contraindication for patients with creatinine clearance less than 30ml/min. also minor text updates.
Section 4.8 - Deletion of text relating to the IV formulation.

Changes include:


Section 4.1: change to the wording but no additional information added

Section 4.3:

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

Section 4.4:

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

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;

·         Due to the risk for QT prolongation, clarithromycin should be used with caution in patients Patients with coronary artery disease, severe cardiac insufficiency, hypomagnesemia, conduction disturbances or clinically relevant bradycardia (<50 bpm),

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

·         or Patients concomitantly taking when co-administered with other medicinal products associated with QT prolongation (see section 4.5). 

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

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

 

Oral anticoagulants:

Each tablet contatins 15.3mg (0.665mmol) of sodium. If patients receive two modified release tablets once daily, the resulting sodium amount (in total 30.6 mg per dose) should To be taken into consideration by for patients on a controlled sodium diet.

Section 4.5: Additional info:

Oral Midazolam

When midazolam was co-administered with clarithromycin tablets (500mg 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)

CYP3A-based Interactions

The following drugs or drug classes are known or suspected to be metabolized by the same CYP3A isozyme: alprazolam, astemizole, carbamazepine, cilostazol, cisapride, cyclosporine, disopyramide, ergot alkaloids, lovastatin, methylprednisolone, midazolam, omeprazole, oral anticoagulants (e.g. warfarin), atypical antipsychotics (e.g. quetiapine), pimozide, quinidine, rifabutin, sildenafil, simvastatin, sirolimus, tacrolimus, terfenadine, triazolam and vinblastine, but this list is not comprehensive. Drugs interacting by similar mechanisms through other isozymes within the cytochrome P450 system include phenytoin, theophylline and valproate

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

When midazolam was co-administered with clarithromycin tablets (500 mg twice daily), midazolam AUC was increased 2.7‑fold after intravenous administration of midazolam. and 7‑fold after oral administration.  Concomitant administration of oral midazolam and clarithromycin should be avoided. If intravenous midazolam is co-administered with clarithromycin, the patient must be closely monitored to allow dose adjustment. Drug delivery of midazolam via oromucosal route, which could bypass pre-systemic elimination of the drug, will likely result in a similar interaction to that observed after intravenous midazolam rather than oral administration. The same precautions should also apply to other benzodiazepines that are metabolised by CYP3A, including triazolam and alprazolam. For benzodiazepines which are not metabolised by CYP3A (temazepam, nitrazepam, lorazepam) a clinically important interaction with clarithromycin is unlikely.

Other Interactions

Aminoglycosides

Caution is advised regarding concomitant administration of clarithromycin with other ototoxic drugs, especially with aminoglycosides. ( Ssee section 4.4).

Colchicine

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

Section 4.8:
Changes to the MedRA table of AE's in section Psychiatric disorders, cardiac disorders, skin disorders, musculoskeletal disorders
Addition of AE reporting details toHPRA

- Section 7: Update of Marketing Authorisation Holder from Abbott Laboratories Ireland Limited to BGP Products Ireland Limited
- Section 8: Update of PA number

Section 2: Editorial changes to excipient details
Section 4.3: Contraindication for oral midazolam added, other minor amendments
Section 4.4: Clarification regarding intravenous midazolam, deletion of information "Use of any antimicrobial therapy, such as clarithromycin, to treat H. pylori infection may select for drug resistant organisms"
Section 4.5: Minor editorial changes
Section 4.8: Addition of adverse reaction 'mania'
Section 5.1: Amendment of pharmacotherapeutic group
Section 6.1: Addition of headings 'Tablet Core' and 'Coating Solution'

Section 4.3:

– Additoin of text “Concomitant administration with ticagrelor or ranolazine is contraindicated.”

- Update to information regarding colchicine

Section 4.4:

- Update to information regarding colchicine, HMG-CoA Reductase Inhibitors (statins), oral hypoglycaemic agents/insulin.

- Other minor updates

Section 4.5:

- Update to information regarding HMG-CoA Reductase Inhibitors (statins), antiarrhythmics, oral hypoglycaemic agents/insulin, aminoglycosides, calcium channel blockers, verapamil

- Other minor updates

Section 4.8:

- Addition of undesirable effect: Angioedema.  Deletion of undesirable effects: erythrasma, hypoglycaemia, Henoch-Schonlein purpura. Deletion of additonal text following ADR table.

 

 

Section 4.2: Change to text for children younger than 12 years
Section 4.3: Change to text re HMG-CoA reductase inhibitors and text re colchicine
Section 4.4: Addition of warning re DRESS and Henoch-Schonlein purpura. Change to text re HMG-CoA reductase inhibitors
Section 4.5: Addition of information re Etravirine
Section 4.6: Format change to text re pregnancy and breast-feeding
Section 4.8: Addition of side effects paraesthesia, Henoch-Schonlein purpura. Addition of footnotes to table

Multiple changes to various sections of the SPC - updates to sections 2, 4.1, 4.2, 4.3, 4.4, 4.5, 4.7 and 4.8 of the SPC.

Section 7 - Correction to MA Holder name and address

5.1       Pharmacodynamic properties

General Properties

ATC classification

Pharmacotherapeutic group: Anti-infectious, ATC code: J01FA09.

Mode of Action  

Clarithromycin is an antibiotic belonging to the macrolide antibiotics group. It exerts its antibacterial action by inhibiting the intracellular protein synthesis of susceptible bacteria. It selectively binds to the 50S subunit of bacterial ribosomes and thus prevents the translocation of activated amino acids.

Clarithromycin has relevant bactericidal activity against several bacterial strains. 
The organisms include H. influenzae, S. pneumoniae, S. pyogenes, S. aureus, M. catarrhalis, H. pylori, C. pneumoniae, M. pneumoniae, L. pneumophila, M. avium, and M. intracellulare.

The 14(R)-hydroxy metabolite of clarithromycin, a product of parent drug metabolism in humans, also has antimicrobial activity. The metabolite is less active than the parent compound for most organisms, including Mycobacterium spp.  An exception is Haemophilus influenzae against which the metabolite is 1 to 2 times more active than the parent compound. Clarithromycin combined with the metabolite showed a strain-dependent additive or synergistic effect both in vitro and in vivo.

PK/PD Relationship

Clarithromycin is extensively distributed in body tissues and fluids. Because of high tissue penetration, intracellular concentrations are higher than serum concentrations.

Clarithromycin concentrations in tonsil and whole lung tissue are 2‑ to 6‑fold higher than those observed in the serum. Tissue and serum concentrations observed in Abbott studies with immediate-release (IR) tablets are presented below.

The pharmacokinetics of orally administered modified-release (MR) clarithromycin tablets have been studied in adult humans (refer to section 5.2) and compared with clarithromycin 250 mg and 500 mg IR tablets.  The extent of absorption – area under curve (AUC) – was found to be equivalent when equal total daily doses were administered. The equivalent AUCs would be expected to drive tissue levels equivalent to those observed for clarithromycin IR tablets.

In a study in healthy volunteers, it was shown that the concentrations of clarithromycin in epithelial lining fluid (ELF) following administration of the MR formulation remained above 1 µg/ml for 24 hours and above 10 µg/ml for up to 18 hours.  In most subjects, the concentrations of clarithromycin in ELF were approximately 30 times greater than those in plasma, and the ratio appeared to be independent of formulation and time of assessment.  A peak tissue concentration above 40 µg/ml was observed for the MR formulation, demonstrating extensive uptake of clarithromycin into lung tissue.  This level is well above the minimum inhibitory concentration (MIC) values of all common community-acquired respiratory pathogens.

Clarithromycin accumulated extensively in the alveolar macrophages (AM), with AM levels approximately 100‑ to 600‑fold higher than those in plasma and 4‑ to 18‑fold higher than those in ELF for most subjects. While concentrations of 14(R)-hydroxy-clarithromycin in AM were not quantifiable in some subjects and were rather variable, the AM levels were generally similar for the MR and IR tablets.  The concentrations in AM were greater than those in plasma, but accumulation was less for the metabolite than for parent clarithromycin.

Mechanism of Resistance

Acquired macrolide resistance in S. pneumoniae, S. pyogenes, and S. aureus is mediated primarily by the presence of one of two mechanisms (i.e. erm and mef or msr).
Ribosomal binding of the antimicrobial is prevented through methylation of the ribosome by an enzyme (erm). Alternatively an efflux mechanism (mef or msr) can prevent the antimicrobial from reaching its ribosomal target by pumping the antimicrobial out of the cell.  No acquired resistance mechanisms have been identified in Moraxella or Haemophilus spp.  Macrolide resistance mechanisms are equally effective against 14- and 15-membered macrolides including erythromycin, clarithromycin, roxithromycin, and azithromycin.  The mechanisms for penicillin resistance and macrolide resistance are unrelated.

Attention should be paid to the erm-mediated cross-resistance between macrolides such as clarithromycin and lincosamides such as lincomycin and clindamycin.

Clarithromycin antagonises the bacterial effects of beta-lactam antibiotics.  Also the effects of lincomycin and clindamycin are antagonised, at least in vitro.

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, mg/ml)
Microorganism	Susceptible (£)	Resistant (>)
Streptococcus spp.	0.25 mg/ml	0.5 mg/ml
Staphylococcus spp.	1 mg/ml	2mg/ml
Haemophilus spp.*	1 mg/ml	32 mg/ml
Moraxella catarrhalis	0.25 mg/ml	0.5 mg/ml

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

 

The prevalence of acquired resistance rates may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections.  As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of an agent in at least some types of infections is questionable.

Clarithromycin has a pronounced effect against a wide variety of aerobic, anaerobic, Gram‑positive, Gram-negative, and acid-resistant bacteria.
The activity of 14(R)-hydroxy-clarithromycin is greater than that of clarithromycin against Haemophilus influenzae. Studies done in vitro have suggested an additive activity of the 14(R)‑hydroxy‑clarithromycin and the parent molecule against H. influenzae.

Category 1: susceptible organisms
Gram-positive	Gram-negative	Others
Listeria monocytogenes Clostridium perfringens Peptococcus niger Proprionibacterium acnes Streptococcus group F	Bordetella pertussis Haemophilus influenzae§ Legionella pneumophila Moraxella catarrhalis Pasteurella multocida	Borrelia burgdorferi Chlamydia pneumoniae (TWAR) Chlamydia trachomatis Mycobacterium avium Mycobacterium chelonae Mycobacterium fortuitum Mycobacterium intracellulare Mycobacterium kansasii Mycobacterium leprae Mycoplasma pneumoniae
Category 2: organisms for which acquired resistance may be problematic#
Staphylococcus aureus (resistant or susceptible* to methicillin) + Staphylococcus coagulase negative + Streptococcus pneumoniae *+ Streptococcus pyogenes * Streptoccoccus group B, C, G Streptococcus spp.
Category 3: intrinsic resistant organisms
Enterobacteriaceae Non-lactose fermenting Gram negative rods
* species against which efficacy has been demonstrated in clinical investigations (if susceptible)
§ Breakpoints for macrolides and related antibiotics were set to categorise wild type H. influenzae as intermediate
+  Indicates species for which a high rate of resistance (i.e. greater than 50%) has been observed in one or more area/country/region(s) of the EU
# ≥ 10% resistance in at least one country of the European Union

 

4.3   Contraindications

Clarithromycin is contra-indicated in patients with known hypersensitivity to macrolide antibiotic drugs.

Concomitant administration of clarithromycin and any of the following drugs is contraindicated: astemizole, cisapride, pimozide, terfenadine, and ergotamine or dihydroergotamine.
(see section 4.5).

As the dose cannot be reduced from 500 mg daily, Klacid LA is contraindicated in patients with creatinine clearance less than 30 ml/min.

Clarithromycin should not be given to patients with hypokalaemia (QT interval prolongation). 

4.4    Special warnings and precautions for use

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 (see also section 4.3).

There have been post-marketing reports of colchicine toxicity with concomitant use of clarithromycin and colchicine, especially in elderly and/or patients with renal insufficiency, some with a fatal outcome (see sections 4.5 and 4.8).

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

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including clarithromycin, 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. 

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

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

Each tablet contains 115 mg of lactose.  Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5              Interaction with other medicinal products and other forms of interaction

The use of the following drugs is strictly contraindicated due to the potential for severe drug interaction effects:

Cisapride, pimozide, astemizole and terfenadine

Clarithromycin has been reported to elevate plasma levels of cisapride, pimozide, astemizole, and terfenadine.  Increased levels of these drugs may result in increased risk of ventricular rhythm disorders, especially torsades de pointes.
Concomitant administration of clarithromycin and any of these medicinal products is contraindicated (see section 4.3).

Ergotamine/dihydroergotamine

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

Effect of other medicinal products on clarithromycin

The following drugs are known or suspected to affect circulating concentrations of clarithromycin; clarithromycin dosage adjustment or consideration of alternative treatments may be required:

Fluconazole

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

Ritonavir

Coadministration of clarithromycin and ritonavir increases the area under the curve (AUC), maximum concentration (C_max) and the minimum concentration (C_min) of clarithromycin.  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, such as {Klacid®}, immediate release tablets, or {Klacid®}, sachet, or {Klacid®}, paediatric suspensions  (not all presentations may be marketed).
Doses of clarithromycin greater than 1000 mg per day should not be coadministered with protease inhibitors (see section 4.2).
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, bidirectional pharmacokinetic interactions).

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(R)-hydroxy-clarithromycin, a metabolite that is also microbiologically active. Since the microbiological activities of clarithromycin and 14(R)-hydroxy-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers.

Effect of clarithromycin on other medicinal products

CYP3A-based Interactions

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

Antiarrhythmics

There have been post-marketing reports of torsade de pointes occurring with concurrent use of clarithromycin and quinidine or disopyramide.  Electrocardiograms should be monitored for QTc prolongation during coadministration of clarithromycin with these drugs.  Serum concentrations of these medications should also be monitored.

Carbamazepine

During therapy with clarithromycin, the metabolism of carbamazepine may be inhibited.
Consequently the serum concentrations of carbamazepine may be increased, and dose reduction may need to be considered.

HMG-CoA Reductase Inhibitors (e.g., lovastatin, simvastatin)

Clarithromycin inhibits the metabolization of a number of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors. This may result in elevated plasma levels of these drugs.

In rare cases, the occurrence of rhabdomyolysis was reported with concomitant administration of clarithromycin and HMG-CoA reductase inhibitors (statins), such as lovastatin or simvastatin. 

Patients should be monitored for signs and symptoms of myopathy.  Adjustment of the statin dosage or use of a statin that is less dependent on CYP3A metabolism, e.g., pravastatin, should be considered.

Oral anticoagulants (e.g., warfarin, acenocoumarol)

In isolated cases, patients receiving combination therapy with clarithromycin and oral anticoagulants may experience increased pharmacologic effects and even toxic effects of these drugs.
International normalized ratio (INR) or Prothrombin times should be carefully monitored while patients are simultaneously receiving clarithromycin and oral anticoagulants.

Sildenafil, tadalafil, and vardenafil

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

Theophylline

During therapy with clarithromycin, the metabolism of theophylline may be inhibited.
Consequently the serum concentrations of theophylline may be increased, and dose reduction may need to be considered.

Tolterodine

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

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

When midazolam was co-administered with clarithromycin tablets (500 mg twice daily), midazolam AUC was increased 2.7‑fold after intravenous administration of midazolam and 7‑fold after oral administration.  Concomitant administration of oral midazolam and clarithromycin should be avoided. If intravenous midazolam is 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 metabolised by CYP3A (temazepam, nitrazepam, lorazepam) an interaction with clarithromycin is unlikely.

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

Omeprazole

The AUC of omeprazole is increased by 89% when administered concomitantly with clarithromycin for H. pylori eradication; however the change in the mean 24-hour gastric pH value from 5.2 (omeprazole alone) to 5.7 (omeprazole + clarithromycin) is not considered clinically significant.

There are no in-vivo human data available describing an interaction between clarithromycin and the following drugs: aprepitant, eletriptan, halofantrine, and ziprasidone. However, because in vitro data suggest these drugs are CYP3A substrates, caution should be used when they are co-administered with clarithromycin.
Eletriptan should not be coadministered with CYP3A inhibitors such as clarithromycin.

There have been spontaneous or published reports of drug interactions of CYP3A inhibitors, including clarithromycin, with cyclosporine, tacrolimus, methylprednisolone, vinblastine, and cilostazol.

Other 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).

Digoxin

Digoxin is 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

Due to reduced gastrointestinal absorption of zidovudine in the presence of clarithromycin, reduced serum levels of zidovudine were observed in adults during concomitant therapy with clarithromycin and zidovudine.
Because clarithromycin appears to interfere with the absorption of simultaneously administered oral zidovudine, patients should observe a 4-hour interval between taking these two drugs.

This interaction does not appear to occur in pediatric HIV-infected patients taking clarithromycin suspension with zidovudine.  This interaction is unlikely when clarithromycin is administered via intravenous infusion.

Phenytoin and Valproate

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

Bidirectional pharmacokinetic 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(R)-hydroxy-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, such as {Klacid®}, immediate release tablets, or {Klacid®}, sachet, or {Klacid®}, paediatric suspensions (not all presentations may be marketed).
Doses of clarithromycin greater than 1000 mg per day should not be coadministered with protease inhibitors (see also section 4.2).

Itraconazole

Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A, leading to a bidirectional drug interaction:  Clarithromycin may increase the plasma levels of itraconazole, while itraconazole may increase the plasma levels of clarithromycin.

Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged pharmacologic effect.

Saquinavir

Both clarithromycin and saquinavir are substrates and inhibitors of CYP3A, and there is evidence of a bidirectional drug interaction.
Concomitant administration of clarithromycin (500 mg bid) and saquinavir (soft gelatin capsules, 1200 mg tid) to 12 healthy volunteers resulted in steady-state area under the curve (AUC) and maximum concentration (C_max) values of saquinavir which were 177% and 187% higher than those seen with saquinavir alone.
Clarithromycin AUC and C_max values were approximately 40% higher than those seen with clarithromycin alone.
No dose adjustment is required when the two drugs are co-administered for a limited time at the doses/formulations studied.
Observations from drug interaction studies using the soft gelatin capsule formulation may not be representative of the effects seen using the saquinavir hard gelatin capsule.
Observations from drug interaction studies done with unboosted saquinavir 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, effect of other medicinal products on clarithromycin).

4.8 Undesirable effects

Clinical experience

The most commonly reported ADR were gastro-intestinal disorders (nausea, diarrhoea, dyspepsia, abdominal pain).

 

*      Common: Frequency from ³1/100 (1%) to <1/10 (10%)         Uncommon: Frequency from ³1/1000 (0.1%) to £1/100 (1%).

 

System Organ Class	Frequency*	Adverse Drug Reactions
Infections and infestations	Uncommon	Gastroenteritis Oral candidiasis Rash pustular Rhinitis Vaginal candidiasis Vaginal infection
Blood and the lymphatic system disorders	Uncommon	Anaemia Eosinophilia Hypochromic anaemia Leukopenia Thrombocythaemia White blood cell disorders
Metabolism and nutrition disorders	Uncommon	Anorexia Hyperchloraemia Hyperuricaemia Hypocalcaemia Increased appetite
Psychiatric disorders	Uncommon	Depression Insomnia Nervousness Somnolence
Nervous system disorders	Common	Dysgeusia
	Uncommon	Dizziness Headache Tremor
Eye disorders	Uncommon	Conjunctivitis Visual disturbance
Ear and labyrinth disorders	Uncommon	Ear disorder Tinnitus Vertigo
Vascular disorders	Uncommon	Vasodilatation
Respiratory, thoracic and mediastinal disorders	Uncommon	Asthma Dyspnoea Lung disorder
Gastrointestinal disorders	Common	Abdominal pain Diarrhoea Dyspepsia Nausea
Gastrointestinal disorders	Uncommon	Abdominal distension Constipation Dry mouth Eructation Flatulence Gastrointestinal disorder Gastrointestinal haemorrhage Stomatitis Tongue discolouration Vomiting
Hepato-biliary disorders	Uncommon	Hyperbilirubinaemia
Skin and subcutaneous tissue disorders	Uncommon	Dry skin Eczema Hyperhidrosis Pruritus Rash Rash maculo-papular Urticaria
Musculoskeletal and connective tissue disorders	Uncommon	Back Pain
Renal and urinary disorders	Uncommon	Albuminuria Haematuria Pyuria
Reproductive system and breast disorders	Uncommon	Genital discharge
General disorders and administration site conditions	Uncommon	Asthenia Chest pain Drug interaction Face oedema Malaise Pain Thirst
Investigations	Uncommon	Alanine aminotransferase increased Alkaline phosphate increased Aspartate aminotransferase increased Blood creatinine increased Blood lactate dehydrogenase increased Blood urea increased Laboratory test abnormal Liver function test abnormal Prothrombin decreased

 

Post-Marketing Experience

The ADR reported are consistent with those observed in clinical studies.  

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.

Infection and infestations:                   Oral candidiasis.

Blood and lymphatic system disorders:           Leukopenia, thrombocytopenia.

Immune system disorders:                   Anaphylactic reaction, hypersensitivity.

Metabolism and nutrition disorders:    Hypoglycaemia.

Psychiatric disorders:                          Abnormal dreams, anxiety, confusional state, depersonalization, disorientation, hallucination, insomnia, psychotic disorder.

Nervous system disorders:                   Convulsions, dizziness, dysgeusia, ageusia, anosmia, parosmia.

Ear and labyrinth disorders:               Deafness, tinnitus, vertigo.

Cardiac disorders:                               Electrocardiogram QT prolonged, torsades de pointes, ventricular tachycardia.

Gastrointestinal disorders:                   Glossitis, pancreatitis acute, stomatitis, tongue discolouration, tooth discolouration.

Hepatobiliary disorders:                      Hepatic failure, hepatic function abnormal, hepatitis, hepatitis cholestatic, jaundice cholestatic, jaundice hepatocellular.

Skin and subcutaneous tissue disorders: Rash, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria.

Renal and urinary disorders:              Interstitial nephritis.

Investigations:                                     Blood creatinine increase, hepatic enzyme increased.

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

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including clarithromycin, and may range in severity from mild to life threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhoea subsequent to the administration of antibacterial agents.

There have been post-marketing reports of colchicine toxicity with concomitant use of clarithromycin and colchicine, especially in elderly and/or patients with renal insufficiency, some with a fatal outcome. (see sections 4.5 and 4.4).

 

5.1 Pharmacodynamic properties

General Properties

ATC classification

Pharmacotherapeutic group: Anti-infectious, ATC code: J01FA09.

Mode of Action  

Clarithromycin is an antibiotic belonging to the macrolide antibiotics group. It exerts its antibacterial action by inhibiting the intracellular protein synthesis of susceptible bacteria. It selectively binds to the 50S subunit of bacterial ribosomes and thus prevents the translocation of activated amino acids.

Clarithromycin has relevant bactericidal activity against several bacterial strains. 
The organisms include H. influenzae, S. pneumoniae, S. pyogenes, S. aureus, M. catarrhalis, H. pylori, C. pneumoniae, M. pneumoniae, L. pneumophila, M. avium, and M. intracellulare.

The 14(R)-hydroxy metabolite of clarithromycin, a product of parent drug metabolism in humans, also has antimicrobial activity. The metabolite is less active than the parent compound for most organisms, including Mycobacterium spp.  An exception is Haemophilus influenzae against which the metabolite is 1 to 2 times more active than the parent compound. Clarithromycin combined with the metabolite showed a strain-dependent additive or synergistic effect both in vitro and in vivo.

PK/PD Relationship

Clarithromycin is extensively distributed in body tissues and fluids. Because of high tissue penetration, intracellular concentrations are higher than serum concentrations.

Clarithromycin concentrations in tonsil and whole lung tissue are 2‑ to 6‑fold higher than those observed in the serum. Tissue and serum concentrations observed in Abbott studies with immediate-release (IR) tablets are presented below.

Mean Clarithromycin Concentration [250mg BID]
Tissue Type	Tissue	Serum
Tonsil	1.6 μg/g	0.8 μg/ml
Lung	8.8 μg/g	1.7 μg/ml

The pharmacokinetics of orally administered modified-release (MR) clarithromycin tablets have been studied in adult humans (refer to section 5.2) and compared with clarithromycin 250 mg and 500 mg IR tablets.  The extent of absorption – area under curve (AUC) – was found to be equivalent when equal total daily doses were administered. The equivalent AUCs would be expected to drive tissue levels equivalent to those observed for clarithromycin IR tablets.

In a study in healthy volunteers, it was shown that the concentrations of clarithromycin in epithelial lining fluid (ELF) following administration of the MR formulation remained above 1 µg/ml for 24 hours and above 10 µg/ml for up to 18 hours.  In most subjects, the concentrations of clarithromycin in ELF were approximately 30 times greater than those in plasma, and the ratio appeared to be independent of formulation and time of assessment.  A peak tissue concentration above 40 µg/ml was observed for the MR formulation, demonstrating extensive uptake of clarithromycin into lung tissue.  This level is well above the minimum inhibitory concentration (MIC) values of all common community-acquired respiratory pathogens.

Clarithromycin accumulated extensively in the alveolar macrophages (AM), with AM levels approximately 100‑ to 600‑fold higher than those in plasma and 4‑ to 18‑fold higher than those in ELF for most subjects. While concentrations of 14(R)-hydroxy-clarithromycin in AM were not quantifiable in some subjects and were rather variable, the AM levels were generally similar for the MR and IR tablets.  The concentrations in AM were greater than those in plasma, but accumulation was less for the metabolite than for parent clarithromycin.

Mechanism of Resistance

Acquired macrolide resistance in S. pneumoniae, S. pyogenes, and S. aureus is mediated primarily by the presence of one of two mechanisms (i.e. erm and mef or msr).
Ribosomal binding of the antimicrobial is prevented through methylation of the ribosome by an enzyme (erm). Alternatively an efflux mechanism (mef or msr) can prevent the antimicrobial from reaching its ribosomal target by pumping the antimicrobial out of the cell.  No acquired resistance mechanisms have been identified in Moraxella or Haemophilus spp.  Macrolide resistance mechanisms are equally effective against 14- and 15-membered macrolides including erythromycin, clarithromycin, roxithromycin, and azithromycin.  The mechanisms for penicillin resistance and macrolide resistance are unrelated.

Attention should be paid to the erm-mediated cross-resistance between macrolides such as clarithromycin and lincosamides such as lincomycin and clindamycin.

Clarithromycin antagonises the bacterial effects of beta-lactam antibiotics.  Also the effects of lincomycin and clindamycin are antagonised, at least in vitro.

Breakpoints

The following breakpoints for clarithromycin, separating susceptible organisms from intermediately susceptible organisms and intermediately susceptible organisms from resistant organisms, have been established by the Clinical and Laboratory Standards Institute (CLSI)European Committee for Antimicrobial Susceptibility Testing (EUCAST).

Breakpoints (MIC, μg/ml)
Microorganism	Susceptible (£)	Intermediate	Resistant (>)
Streptococcus spp.	0.25 mg/ml	0.5 mg/ml	0.5 1.0 mg/ml
Staphylococcus spp.	12 mg/ml	4 mg/ml	28 mg/ml
Haemophilus spp.*	18 mg/ml	16 mg/ml	32 mg/ml
Moraxella catarrhalis	0.25 mg/ml		0.5 mg/ml
Clarithromycin is used for the eradication of H. pylori; minimum inhibitory concentration (MIC) ≤ 0.25 mg/ml which has been established as the susceptible breakpoint by the Clinical and Laboratory Standards Institute (CLSI).*      These values take into account the additive/synergistic effect of the 14(R)-hydroxy-clarithromycin metabolite.

 

The prevalence of acquired resistance rates may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections.  As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of an agent in at least some types of infections is questionable.

Clarithromycin has a pronounced effect against a wide variety of aerobic, anaerobic, Gram‑positive, Gram-negative, and acid-resistant bacteria.
The activity of 14(R)-hydroxy-clarithromycin is greater than that of clarithromycin against Haemophilus influenzae. Studies done in vitro have suggested an additive activity of the 14(R)‑hydroxy‑clarithromycin and the parent molecule against H. influenzae.

 

Category 1: susceptible organisms
Gram-positive	Gram-negative	Others
Listeria monocytogenes Clostridium perfringens Peptococcus niger Proprionibacterium acnes Streptococcus group F	Bordetella pertussis Haemophilus influenzae§ Legionella pneumophila Moraxella catarrhalis Pasteurella multocida	Borrelia burgdorferi Chlamydia pneumoniae (TWAR) Chlamydia trachomatis Mycobacterium avium Mycobacterium chelonae Mycobacterium fortuitum Mycobacterium intracellulare Mycobacterium kansasii Mycobacterium leprae Mycoplasma pneumoniae
Category 2: organisms for which acquired resistance may be problematic#
Staphylococcus aureus (resistant or susceptible* to methicillin) + Staphylococcus coagulase negative + Streptococcus pneumoniae *+ Streptococcus pyogenes * Streptoccoccus group B, C, G Streptococcus spp.
Category 3: intrinsic resistant organisms
Enterobacteriaceae Non-lactose fermenting Gram negative rods
* species against which efficacy has been demonstrated in clinical investigations (if susceptible)
§ species with intermediate natural susceptibility Breakpoints for macrolides and related antibiotics were set to categorise wild type H. influenzae as intermediate
+  Indicates species for which a high rate of resistance (i.e. greater than 50%) has been observed in one or more area/country/region(s) of the EU
# ≥ 10% resistance in at least one country of the European Union

 

10. DATE OF REVISION OF THE TEXT

May 2008

Extensive updates to sections 4.3, 4.4, 4.5, 4.8 and 5.1.