Clarithromycin ratiopharm GmbH

Hauptinformation

  • Handelsname:
  • Clarithromycin ratiopharm GmbH 500 mg Filmtabletten
  • Einheiten im Paket:
  • 8 Stück (PVC Blister transparent), Laufzeit: 24 Monate,10 Stück (PVC Blister transparent), Laufzeit: 24 Monate,14 Stück (PVC Bli
  • Verschreibungstyp:
  • Arzneimittel zur einmaligen Abgabe auf aerztliche Verschreibung
  • Verwenden für:
  • Menschen
  • Art der Medizin:
  • allopathic Droge

Dokumenten

Lokalisierung

  • Erhältlich in:
  • Clarithromycin ratiopharm GmbH 500 mg Filmtabletten
    Österreich
  • Sprache:
  • Deutsch

Therapeutische Informationen

  • Therapiebereich:
  • Clarithromycin
  • Produktbesonderheiten:
  • Abgabe durch eine (öffentliche) Apotheke

Weitere Informationen

Status

  • Quelle:
  • AGES
  • Zulassungsnummer:
  • 1-27343
  • Berechtigungsdatum:
  • 19-12-2007
  • Letzte Änderung:
  • 30-11-2018

Öffentlichen Beurteilungsberichts

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Public Assessment Report

Mutual Recognition Procedure

Clarithromycin 250mg Film-Coated Tablets

Clarithromycin 500mg Film-Coated Tablets

AT/H/0921/001-002/

former: UK/H/0798/01-02

UK licence no: PL 00289/0457-8

Approved Prescription Services Limited

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Clarithromycin 250mg Film-Coated Tablets

Clarithromycin 500mg Film-Coated Tablets

LAY SUMMARY

Austria, Belgium, Czech Republic, Finland, Germany, Hungary, Italy, Lithuania, Norway,

Poland, Portugal, Slovak Republic and Sweden today granted Approved Prescription

Services Limited Marketing Authorisations (licences) for the medicinal products

Clarithromycin 250mg Film-Coated Tablets (PL 00289/0457) and Clarithromycin 500mg

Film-Coated Tablets (PL 00289/0458). These are prescription only medicines (POM) for the

treatment of acute and chronic bacterial infections, when caused by clarithromycin-

susceptible bacteria.

Clarithromycin Film-Coated Tablets contain the active ingredient clarithromycin, which

belongs to a group of drugs called macrolide antibiotics.

No new or unexpected safety concerns arose from these applications and it was therefore

judged that the benefits of taking Clarithromycin 250mg and 500mg Film-Coated Tablets

outweigh the risks, hence Marketing Authorisations have been granted.

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TABLE OF CONTENTS

Module 1: Information about initial procedure

Page 4

Module 2: Summary of Product Characteristics

Page 5

Module 3: Product Information Leaflets

Page 23

Module 4: Labelling

Page 25

Module 5: Scientific Discussion

Page 29

1 Introduction

2 Quality aspects

3 Non-clinical aspects

4 Clinical aspects

5 Overall conclusions

Module 6

Steps take after initial procedure

Not applicable

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Module 1

Product Name

Clarithromycin 250mg Film-Coated Tablets

Clarithromycin 500mg Film-Coated Tablets

Type of Application

Generic, Article 10.1(a)(iii), first paragraph

Active Substance

Clarithromycin

Form

Film-Coated Tablets

Strength

250mg and 500mg Film-Coated Tablets

MA Holder

Approved Prescription Services Limited, Brampton Road,

Hampden Park, Eastbourne, East Sussex, BN22 9AG

RMS

CMS

Austria, Belgium, Czech Republic, Finland, Germany, Hungary,

Italy, Lithuania, Norway, Poland, Portugal, Slovak Republic and

Sweden

Procedure Number

UK/H/0798/01-02

Timetable

Day 90 – 16

November 2005

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Module 2

Summary of Product Characteristics

European Summary of Product Characteristics

1.

NAME OF THE MEDICINAL PRODUCT

[Trade name of the product]

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 250 mg clarithromycin.

For a full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Film-coated tablet.

Yellow, film-coated oval shaped tablet, debossed with “93” on one side and “7157” on the other.

Clinical Particulars

4.1

Therapeutic Indications

Clarithromycin is indicated for the treatment of acute and chronic bacterial infections, when caused by

clarithromycin-susceptible bacteria.

Infections of the upper respiratory tract such as pharyngitis and sinusitis.

Infections of the lower respiratory tract, such as acute exacerbation of chronic bronchitis, and

community-acquired pneumonia.

Skin and soft tissue infections of mild to moderate severity.

In appropriate combination with antibacterial therapeutic regimens and an appropriate ulcer-healing

agent for the eradication of

H. pylori

in patients with

H. pylori-

associated ulcers. See section 4.2.

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

4.2

Posology and Method of Administration

The dosage of clarithromycin depends on the clinical condition of the patient and has to be defined in

any case by the physician.

250 and 500 mg tablets are available.

Adults and adolescents

The usual dose is 250 mg twice daily.

In severe infections, the dose may be increased to 500 mg twice daily.

In respiratory infections, owing to the high level of resistance of some pathogenic microorganisms (e.g.

S. pneumoniae

), penicillin remains the antibiotic of first choice. Clarithromycin may be used in patients

with known hypersensitivity to penicillin or when penicillin would be inappropriate for other reasons.

Children

Clarithromycin tablets are not suitable for children under 12 years of age weighing less than 30 kg.

Other pharmaceutical forms are more adapted for these patients.

Elderly

As for adults.

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Eradication of

H. pylori

in adults

In patients with peptic ulcers due to

H. pylori

infection, clarithromycin can be administered in a dose of

500 mg twice daily in combination with other appropriate antimicrobe treatment and proton-pump

inhibitors.

Renal impairment

Dosage adjustments are not usually required except in patients with severe renal impairment (creatinine

clearance <30 ml/min). If adjustment is necessary, the total daily dosage should be reduced by half, e.g.

250 mg once daily or 250 mg twice daily in more severe infections. The duration of treatment should

not exceed 14 days in these patients.

Duration of therapy

The duration of therapy with clarithromycin depends on the clinical condition of the patient and in any

case shall be determined by the physician.

The usual duration of treatment is 7 to 14 days.

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

infections caused

Streptococcus

pyogenes

(group

A beta-haemolytic

streptococci),

duration should be at least 10 days.

Combination therapy for the eradication of

H. pylori

infection, e.g. clarithromycin 500 mg (two 250 mg

tablets or one 500 mg tablet) twice daily in combination with amoxicillin 1,000 mg twice daily and

omeprazole 20 mg twice daily, should be continued for 7 days.

Method of administration

Clarithromycin may be given without regard to food intake (see section 5.2).

4.3

Contra-indications

Hypersensitivity to the active substance clarithromycin, to other macrolides, or to any of the

excipients.

Concomitant administration with ergot derivatives (see section 4.5).

Concomitant administration with cisapride, pimozide and terfenadine. Elevated cisapride, pimozide

and terfenadine levels may result in QT prolongation and cardiac arrhythmias including ventricular

tachycardia, ventricular fibrillation and torsade de pointes. Similar effects have been observed with

concomitant administration of astemizole and other macrolides (see section 4.5).

Hypokalaemia (risk of prolongation of QT-time).

4.4

Special Warnings and Special Precautions for Use

Clarithromycin is mainly excreted by the liver. Therefore, caution should be taken in administering

clarithromycin to patients with impaired hepatic function or those concomitantly receiving potentially

hepatotoxic products.

As with other antibiotics when renal function is poor, dosage of clarithromycin should be suitably

reduced depending on the degree of the impairment (see section 4.2). In elderly patients, the

possibility of renal impairment should be considered.

Clarithromycin therapy for

H. pylori

may select for substance-resistant organisms.

Patients

hypersensitive

lincomycin

clindamycin

also

hypersensitive

clarithromycin. Therefore, caution is required when prescribing clarithromycin for such patients.

Prolonged

repeated

clarithromycin

result

superinfections

with

insusceptible

organisms. In case of superinfection, clarithromycin therapy should be stopped.

Pseudomembranous colitis has been reported with the use of broad-spectrum antibiotics. Therefore, it

is important to consider its diagnosis in patients who develop severe diarrhoea during or after therapy

with clarithromycin.

As known for other macrolides, clarithromycin may cause exacerbation or aggravation of myasthenia

gravis and should therefore be used with caution in patients with myasthenia gravis.

Due to a risk of increased QT-interval, clarithromycin should be used with caution in patients with a

coronary

vessel

disease,

history

ventricular

arrhythmia,

severe

cardiac

insufficiency,

non-

compensated hypokalemia and/or hypomagnesemia, bradycardia (<50 bpm), or when co-administered

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with other medicinal products with a QT-prolonging effect. Clarithromycin should not be used in

patients with congenital or documented acquired QT prolongation (see section 4.5).

Clarithromycin should be used with caution whenever indicated for use in patients receiving treatment

with an inducer of CYP3A4 (see section 4.5).

Clarithromycin is an inhibitor of CYP3A4, and concomitant use with other medicinal products that are

metabolised to a large extent by this enzyme should be restricted to situations where it is clearly

indicated (see section 4.5).

Clarithromycin inhibits the metabolism of some HMG-CoA reductase inhibitors, which results in

increased plasma concentrations of these medicinal products (see section 4.5).

This medicinal product contains tartrazine and may cause allergic reactions.

4.5

Interaction with Other Medicinal Products and Other Forms of Interaction

Contraindicated combinations

Concomitant administration of clarithromycin and terfenadine, cisapride, pimozide and ergot alkaloids

is contraindicated.

The effect of other medicinal products on clarithromycin tablets

Clarithromycin is metabolised by the enzyme CYP3A4. Hence, strong inhibitors of this enzyme may

inhibit

metabolism

clarithromycin,

resulting

increased

plasma

concentrations

clarithromycin.

Although the plasma concentrations of clarithromycin and omeprazole may be increased when they are

administered concurrently, no adjustment to the dosage is necessary. Increased plasma concentrations

of clarithromycin may also occur when it is co-administered with antacids or ranitidine. No adjustment

to the dosage is necessary.

Ritonavir (200 mg tid) has been shown to inhibit the metabolism of clarithromycin (500 mg bid), with

an increase in C

, C

and AUC of 31, 182 and 77%, respectively, when co-administered with

ritonavir. Formation of the active 14-OH-hydroxy metabolite was almost completely inhibited. A

general dose reduction is probably not required in patients with normal renal function, but the daily

dose of clarithromycin should not exceed 1 g. Dose reduction should be considered in patients with

renal impairment. For patients with a creatinine clearance of 30 to 60 ml/min, the clarithromycin dose

should be reduced with 50%, and at a creatinine clearance of <30 ml/min, the dose should be reduced

with 75%.

Products that are inducers of CYP3A4 (eg 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. When clarithromycin is clearly indicated it might be

necessary to increase the dose of clarithromycin and monitor its efficacy and safety carefully.

Furthermore monitoring the plasma levels of the CYP3A4 inducer might be necessary because the

latter could be increased owing to the inhibition of CYP3A4 by clarithromycin (see also the relevant

product information for the CYP3A4 inhibitor administered). Concomitant administration of rifabutin

and clarithromycin resulted in an increase and decrease, respectively, in serum levels, followed by an

increased risk of uveitis.

The effect of clarithromycin on other medicinal products

Clarithromycin is an inhibitor of the metabolising enzyme CYP3A4 and the transport protein P-

glycoprotein. The degree of inhibition with different CYP3A4 substrates is difficult to predict. Hence,

clarithromycin should not be used during treatment with other medicinal products that are substrates

for CYP3A4, unless plasma levels, therapeutic effect or adverse events of the CYP3A4 substrate can be

closely monitored. A dose reduction may be necessary for medicinal products that are substrates for

CYP3A4 if co-administered with clarithromycin. Alternatively, treatment with these products may be

interrupted during clarithromycin treatment.

Medicinal products with a potential to prolong QT-interval

Clarithromycin has been reported to inhibit the metabolism of cisapride and terfenadine, with a 2 to 3-

fold increase in plasma levels reported for terfenadine. This has been associated with QT-prolongation

and cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation and torsades de

pointes. Similar symptoms have been described for patients treated with pimozide when combined with

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clarithromycin. Concomitant administration of clarithromycin and terfenadine, cisapride of pimozide is

contraindicated (see section 4.3).

Cases with torsades de pointes has been reported in patients where clarithromycin has been co-

administered with quinidine or disopyramide. These combinations should therefore be avoided, or

plasma levels of quinidine or disopyramide closely monitored to allow dose adjustment. Caution is

warranted when clarithromycin is administered to patients treated taking other medicinal products with

the potential to prolong QT (see section 4.4).

HMG-CoA reductase inhibitors

Clarithromycin inhibits the metabolism of some HMG-CoA reductase inhibitors, which results in

increased plasma concentrations of these medicinal products. Rhabdomyolysis in association with

increased plasma concentrations have in rare cases been reported in patients treated with clarithromycin

and simvastatin or lovastatin. Clarithromycin may produce a similar interaction with atorvastatin and a

lesser interaction with either cerivastatin. When treatment with clarithromycin is indicated in patients

receiving treatment with either simvastatin or lovastatin or atorvastatin or cerivastatin patients should

be monitored for signs and symptoms of myopathy.

Ergot vasoconstrictors (eg dihydroergotamine, ergotamine)

Cases of ergotism due to increased plasma levels of ergot alkaloids have been reported when these

products have been co-administered with macrolides. The combination is contraindicated (see section

4.3).

Benzodiazepines

When midazolam was co-administered with clarithromycin tablets (250 mg bid), 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 mohnitored to allow

dose adjustment. The same precautions should also apply to other benzodiazepines that are metabolised

by CYP3A4, especially triazolam but also alprazolam. For benzodiazepines which are not metabolised

by CYP3A4 (temazepam, nitrazepam, lorazepam) an interaction with clarithromycin is unlikely.

Cyclosporin, tacrolimus and sirolimus

Concomitant use of oral clarithromycin and cyclosporin or tacrolimus have results in more than a 2-

fold increase of the C

levels of both cyclosporin and tacrolimus. Similar effects are also expected for

sirolimus. When initiating treatment with clarithromycin in patients already receiving any of these

immunosuppressive

agents,

cyclosporin,

tacrolimus

sirolimus

plasma

levels

must

closely

monitored and their doses decreased as necessary. When clarithromycin is discontinued in these

patients, close monitoring of plasma levels of cyclosporin, tacrolimus or sirolimus is again necessary to

guide dose adjustment.

Digoxin

The concentration of digoxin may be increased when co-administered with clarithromycin. Monitoring

of plasma levels of digoxin should be considered when co-treatment with clarithromycin is initiated or

terminated since a dose adjustment may be warranted.

Theophylline

The administration of clarithromycin to patients who are receiving theophylline has been associated

with an increase in serum theophylline levels and potential theophylline toxicity.

Warfarin

The use of clarithromycin in patients receiving warfarin may result in potentiation of the effects of

warfarin. Prothrombin time should be frequently monitored in these patients.

Zidovudine

Simultaneous oral administration of clarithromycin tablets and zidovudine to HIV-infected adult

patients may result in decreased steady-state zidovudine levels. This can be largely avoided by

staggering the doses of clarithromycin and zidovudine by 1-2 hours. No such reaction has been

reported in children.

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4.6

Pregnancy and Lactation

Pregnancy

Data on the use of clarithromycin during the first trimester of more than 200 pregnancies show no clear

evidence of teratogenic effects, or of adverse effects or on the health of and neonate. Data from a

limited number of pregnant women exposed in the first trimester indicate a possible increased risk of

abortions. To date no other relevant epidemiological data are available. Data from animal studies have

shown reproductive toxicity (see section 5.3). The risk for humans is unknown. Clarithromycin should

only be given to pregnant women after a careful benefit/risk assessment.

Lactation

Clarithromycin and its active metabolite are excreted in breast milk. Therefore, diarrhoea and fungus

infection of the mucous membranes could occur in the breast-fed infant, so that nursing might have to

be discontinued. The possibility of sensitisation should be borne in mind. The benefit of treatment of

the mother should be weighed against the potential risk for the infant.

4.7

Effects on Ability to Drive and Use Machines

There are no data available on the effect of clarithromycin on the ability to drive or use machines.

When performing these activities the possible occurrence of the adverse reactions dizziness, vertigo,

confusion and disorientation should be taken into account.

4.8

Undesirable Effects

The most frequently reported undesirable effects in adults taking clarithromycin tablets were diarrhoea

(3%), nausea (3%), abnormal taste (3%), dyspepsia (2%), abdominal pain/discomfort (2%) and

headache (2%).

In this section undesirable effects are defined as follows:

Very common (>1/10), common (>1/100, <1/10), uncommon (>1/1000, <1/100), rare (>1/10000,

<1/1000), very rare (<1/10000).

Infections and infestations

Common:

Oral monilia

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

Blood and the lymphatic system disorders

Uncommon:

Decreased leucocyte levels

Very rare:

Thrombocytopenia

Immune system disorders

Uncommon:

Allergic reactions ranging from urticaria and mild skin eruptions to anaphylaxis

Psychiatric disorders

Very rare:

Anxiety, insomnia, hallucinations, psychosis, disorientation, depersonalisation, bad

dreams and confusion

Nervous system disorders

Common:

Headache, smell alteration

Very rare:

Dizziness, vertigo, paraesthesia, convulsions

Ear and labyrinth disorders

Rare:

Tinnitus

Very rare:

Reversible hearing loss

Cardiac disorders

Very rare:

QT prolongation, ventricular tachycardia and Torsades de Pointes.

Gastrointestinal disorders

Common:

Nausea,

diarrhoea,

vomiting,

abdominal

pain,

dyspepsia,

stomatitis,

glossitis,

reversible tooth and tongue discoloration, and taste perversion, i.e. metallic or bitter

taste.

Very rare:

Pancreatitis.

Pseudomembranous

colitis

been

reported

very

rarely

with

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

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Hepato-biliary disorders

Uncommon:

Hepatic

dysfunction,

which

usually

transient

reversible,

hepatitis

cholestasis with or without jaundice.

Very rare:

Fatal hepatic failure has been reported particularly in patients with pre-existing liver

disease or taking other hepatotoxic medicinal products.

Skin and subcutaneous tissue disorders

Very rare:

Stevens-Johnson syndrome and toxic epidermal necrolysis

Musculoskeletal, connective tissue and bone disorders

Uncommon:

Arthralgia, myalgia.

Renal and urinary disorders

Very rare:

Interstitial nephritis, renal failure.

Investigations

Common:

Elevated BUN

Uncommon:

Prolongation of prothrombin time, elevated serum creatinine, altered liver function

tests (increased transaminase levels).

Very rare:

Hypoglycaemia has been observed especially after concomitant administration with

antidiabetic medicinal products and insulin

4.9.

Overdose

Symptoms of intoxication:

Reports indicate that the ingestion of large amounts of clarithromycin can be expected to produce

gastrointestinal symptoms. Symptoms of overdose may largely correspond to the profile of adverse

reactions. One patient who had a history of bipolar disorder ingested 8 grams of clarithromycin and

showed altered mental status, paranoid behaviour, hypokaliaemia and hypoxaemia.

Therapy of intoxication:

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

haemodialysis or peritoneal dialysis.

Adverse reactions accompanying overdosage should be treated by gastric lavage and supportive

measures. Severe acute allergic reactions may be seen very rarely, e.g. anaphylactic shock. At the first

signs of hypersensitivity reactions therapy with clarithromycin must be discontinued and the required

measures should be initiated immediately.

5

Pharmacological Properties

5.1.

Pharmacodynamic Properties

Pharmacotherapeutic group: Macrolides

ATC code: J01F A09

Mechanism of action

Clarithromycin is a semi-synthetic derivative of erythromycin A. It exerts its antibacterial action by

binding to the 50s ribosomal sub-unit of susceptible bacteria and suppresses protein synthesis. It is

highly potent against a wide variety of aerobic and anaerobic gram-positive and gram-negative

organisms. The minimum inhibitory concentrations (MICs) of clarithromycin are generally two-fold

lower than the MICs of erythromycin.

The 14-hydroxy metabolite of clarithromycin also has antimicrobial activity. The MICs of this

metabolite are equal or two-fold higher than the MICs of the parent compound, except for

H.

influenzae

where the 14-hydroxy metabolite is two-fold more active than the parent compound.

Mechanisms of resistance

Resistance mechanisms against macrolide antibiotics include alteration of the target site of the

antibiotic

based

modification

and/or

active

efflux

antibiotic.

Resistance

development can be mediated via chromosomes or plasmids, be induced or exist constitutively.

Macrolide-resistant bacteria generate enzymes which lead to methylation of residual adenine at

ribosomal RNA and consequently to inhibition of the antibiotic binding to the ribosome. Macrolide-

resistant

organisms

generally

cross-resistant

lincosamides

streptogramin

based

methylation of the ribosomal binding site. Clarithromycin ranks among the strong inducers of this

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enzyme as well. Furthermore, macrolides have a bacteriostatic action by inhibiting the peptidyl

transferase of ribosomes.

A complete cross-resistance exists among clarithromycin, erythromycin and azithromycin. Methicillin-

resistant staphylococci and penicillin-resistant

Streptococcus pneumoniae

are resistant to macrolides

such as clarithromycin.

Breakpoints

According to the NCCLS (US National Committee on Clinical Laboratory Standards) in 2003 the

following breakpoints have been defined for clarithromycin:

Staphylococcus

spp.: ≤2 µg/ml susceptible, ≥8 µg/ml resistant

Haemophilus

spp.: ≤8 µg/ml susceptible

Streptococcus

spp. including

S. pneumoniae

: ≤0.25 µg/ml susceptible, ≥1 µg/ml resistant

Susceptibility

The prevalence of acquired resistance may vary geographically and with time for selected species and

local information on resistance is desirable, particularly when treating severe infections. As necessary,

expert advice should be sought when the local prevalence of resistance is such that the utility of the

agent in at least some types of infections is questionable.

Commonly susceptible species (ie resistance < 10 % in all EU Member States)

Aerobic, Gram-positive microorganisms

Streptococcus

group A

Streptococcus

group B

Streptococcus

group C,F,G

Aerobic, Gram-negative microorganisms

Moraxella catarrhalis

Pasteurella multocida

Legionella

spp.

Anaerobic microorganisms

Bacteroides

spp.

Peptococcus/Peptostreptococcus

spp.

Clostridium

spp., other than

C. difficile

Fusobacterium

spp.

Other microorganisms

Mycoplasma pneumoniae

Chlamydia trachomatis

Chlamydia pneumoniae

Species for which acquired resistance may be a problem (ie resistance

10 % in at least 1 EU

Member State)

Aerobic, Gram-positive microorganisms

Staphylococcus aureus,

methicillin-susceptible

Streptococcus pneumoniae*

Aerobic, Gram-negative microorganisms

Haemophilus influenzae

Helicobacter pylori

Inherently resistant microorganisms

Aerobic, Gram-positive microorganisms

Enterococcus

spp.

Staphylococcus aureus

, methicillin-resistant or erythromycin-resistant

Other microorganisms

Mycobacterium tuberculosis

*Comments regarding resistance see “Mechanisms of resistance”

5.2.

Pharmacokinetic Properties

Absorption:

Clarithromycin is rapidly and well absorbed from the gastrointestinal tract - primarily in the jejunum -

but undergoes extensive first-pass metabolism after oral administration. The absolute bioavailability of

a 250 mg clarithromycin tablet is approximately 50%. Food slightly delays the absorption but does not

affect the extent of bioavailability. Therefore, clarithromycin tablets may be given without regard to

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food. Due to its chemical structure (6-O-methylerythromycin) clarithromycin is quite resistant to

degradation by stomach acid. Peak plasma levels of 1-2 µg/ml clarithromycin were observed in adults

after oral administration of 250 mg twice daily. After administration of 500 mg clarithromycin twice

daily the peak plasma level was 2.8 µg/ml.

After administration of 250 mg clarithromycin twice daily the microbiologically active 14-hydroxy

metabolite attains peak plasma concentrations of 0.6 µg/ml. Steady state is attained within 2 days of

dosing.

Distribution:

Clarithromycin penetrates well into different compartments, with an estimated volume of distribution

of 200-400 l. Clarithromycin provides concentrations in some tissues that are several times higher than

the circulating substance levels. Increased levels have been found in both tonsils and lung tissue.

Clarithromycin also penetrates the gastric mucus.

Clarithromycin is approximately 80% bound to plasma proteins at therapeutic levels.

Biotransformation and elimination:

Clarithromycin is rapidly and extensively metabolised in the liver. Metabolism involves mainly N-

dealkylation, oxidation and stereospecific hydroxylation at position C 14.

The pharmacokinetics of clarithromycin is non-linear due to saturation of hepatic metabolism at high

doses.

elimination

half-life

increased

from

hours

following

administration

clarithromycin twice daily to 5 hours following administration of 500 mg clarithromycin twice daily.

The half-life of the active 14-hydroxy metabolite ranges between 5 to 6 hours following administration

of 250 mg clarithromycin twice daily.

After oral administration of radioactive clarithromycin 70-80% of the radioactivity was found in the

faeces. Approximately 20-30% of clarithromycin is collected as the unchanged active substance in the

urine.

This

proportion

increased

when

dose

increased.

Renal

insufficiency

increases

clarithromycin levels in plasma, if the dose is not decreased.

Total plasma clearance has been estimated to approximately 700 ml/min, with a renal clearance of

approximately 170 ml/min.

Special populations:

Renal impairment: Reduced renal function results in increased plasma levels of clarithromycin and the

active metabolite levels in plasma.

5.3

Preclinical Safety Data

In 4-week studies in animals, the toxicity of clarithromycin was found to be related to the dose and

duration of the treatment. In all species, the first signs of toxicity were observed in the liver, in which

lesions were seen within 14 days in dogs and monkeys. The systemic levels of exposure related to this

toxicity are not known in detail, but toxic doses were clearly higher than the therapeutic doses

recommended for humans.

No mutagenic effects were found in

in vitro

in vivo

studies with clarithromycin.

Studies on reproduction toxicity showed that administration of clarithromycin at doses 2x the clinical

dose in rabbit (iv) and x10 the clinical dose in monkey (po) resulted in an increased incidence of

spontaneous

abortions.

These

doses

were

related

maternal

toxicity.

embryotoxicity

teratogenicity was noted in rat studies.

However, cardiovascular malformations were observed in rats

treated with doses of 150 mg/kg/day. In mouse at doses x70 the clinical dose cleft palate occurred at

varying incidence (3-30%).

6.

PHARMACEUTICAL PARTICULARS

6.1

List of Excipients

Tablet core:

Sodium starch glycolate

Microcrystalline cellulose

Povidone (PVP K-30)

Magnesium hydroxide

Croscarmellose sodium

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Colloidal anhydrous silica

Stearic acid

Magnesium stearate

Film-coat:

Hypromellose (E464)

Titanium dioxide (E171)

Macrogol 400

Tartrazine lake (E102)

Allura Red AC Lake (E129)

Indigo Carmine Lake (E132)

Vanillin

6.2

Incompatibilities

Not applicable.

6.3

Shelf Life

2 years

6.4

Special Precautions for Storage

Do not store above 25°C. Keep container in the outer carton.

6.5

Nature and Contents of Container

Available in blister packs of transparent or white opaque PVC or PVC/PVdC lidded with aluminium

foil for 10, 12, 14, 14 calendar pack, 20 & 120 (10x12) as hospital pack.

Not all pack sizes may be marketed.

6.6

Special precautions for disposal

No special requirements

Administrative Data

7.

MARKETING AUTHORISATION HOLDER

8.

MARKETING AUTHORISATION NUMBER

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION

10.

DATE OF (PARTIAL) REVISION OF THE TEXT

PAR Clarithromycin 250 and 500mg Film-Coated Capsules

UK/H/0798/01-02

14

European Summary of Product Characteristics

1.

NAME OF THE MEDICINAL PRODUC

T

[Trade name of the product]

2.

QUALITATIVE AND QUANTITATIVE COMPOSIT

ION

Each

film-coated tablet contains 500 mg clarithromyci

For a full list of excipients, see section 6.1.

3

.

PHARM

ACEUTICAL FORM

Film-coated tablet.

ght yellow, film-coated oval shaped tablet, debossed with “93” on one side and “7158” on the othe

Clinica

l Particulars

4.1

Therapeutic Indications

Clarithromycin is indicated for the treatment of acute and chronic bacterial infections, when caused by

clarithromycin-susceptible bacteria.

Infections of the upper respiratory tract such as pharyngitis and sinu

sitis.

Infections of the lower respiratory tract, such as acute exacerbation of chronic bronchitis, and

munity-acquired pneumoni

Skin and soft tissue infections of mild to moderate seve

rity.

appropriate combination with antibacterial therapeutic regimens and an appropriate ulcer-healing

agent for the eradication of

H. pylori

in patients with

H. pylori associated

ulcers. See section 4.2.

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

4.2

Posology and Method of Administration

The dosage of clarithromycin depends on the clinical condition of the patient and has to be defined in

any case by the physician.

250 and 500 mg tablets are available.

Adults and adolescents

The usual dose is 250 mg twice daily.

In severe infections, the dose may be increased to 500 mg twice daily.

In respiratory infections, owing to the high level of resistance of some pathogenic microorganisms (e.g.

S. p

neumoniae

), penicillin remains the antibiotic of first choice. Clarithromycin may be used in patients

with known hypersensitivity to penicillin or when penicillin would be inappropriate for other reason

ildren

Clarithromycin tablets are not suitable for children under 12 years of age weighing less than 30 kg.

Other pharmaceutical forms are more adapted for these patients.

Elderly

As for adults.

Eradication of

H. pylori

in ddults

In patients with peptic ulcers due to

H. pylori

infection, clarithromycin can be administered in a dose of

500 mg twice daily in combination with other appropriate antimicrobe treatment and proton-pump

inhibitors.

Renal impairment

Dosage adjustments are not usually required except in patients with severe renal impairment (creatinine

clearance <30 ml/min). If adjustment is necessary, the total daily dosage should be reduced by half, e.g.

250 mg once daily or 250 mg twice daily in more severe infections. The duration of treatment should

not exceed 14 days in these patients.

PAR Clarithromycin 250 and 500mg Film-Coated Capsules

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15

Duration of therapy

The duration of therapy with clarithromycin depends on the clinical condition of the patient and in any

case shall be determined by the physician.

The usual duration of treatment is 7 to 14 days.

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

infections caused

Streptococcus

pyogenes

(group

A beta-haemolytic

streptococci),

duration should be at least 10 days.

Combination therapy for the eradication of

H. pylori

infection, e.g. clarithromycin 500 mg (two 250 mg

tablets or one 500 mg tablet) twice daily in combination with amoxicillin 1,000 mg twice daily and

omeprazole 20 mg twice daily, should be continued for 7 days.

Method of administration

Clarithromycin may be given without regard to food intake (see section 5.2).

4.3

Contra-indications

Hypersensitivity to the active substance clarithromycin, to other macrolides, or to any of the

excipients.

Concomitant administration with ergot derivatives (see section 4.5).

Concomitant administration with cisapride, pimozide and terfenadine. Elevated cisapride, pimozide

and terfenadine levels may result in QT prolongation and cardiac arrhythmias including ventricular

tachycardia, ventricular fibrillation and torsade de pointes. Similar effects have been observed with

concomitant administration of astemizole and other macrolides (see section 4.5).

Hypokalaemia (risk of prolongation of QT-time).

4.4

Special Warnings and Special Precautions for Use

Clarithromycin is mainly excreted by the liver. Therefore, caution should be taken in administering

clarithromycin to patients with impaired hepatic function or those concomitantly receiving potentially

hepatotoxic products.

As with other antibiotics when renal function is poor, dosage of clarithromycin should be suitably

reduced depending on the degree of the impairment (see section 4.2). In elderly patients, the

possibility of renal impairment should be considered.

Clarithromycin therapy for

H. pylori

may select for substance-resistant organisms.

Patients

hypersensitive

lincomycin

clindamycin

also

hypersensitive

clarithromycin. Therefore, caution is required when prescribing clarithromycin for such patients.

Prolonged

repeated

clarithromycin

result

superinfections

with

insusceptible

organisms. In case of superinfection, clarithromycin therapy should be stopped.

Pseudomembranous colitis has been reported with the use of broad-spectrum antibiotics. Therefore, it

is important to consider its diagnosis in patients who develop severe diarrhoea during or after therapy

with clarithromycin.

As known for other macrolides, clarithromycin may cause exacerbation or aggravation of myasthenia

gravis and should therefore be used with caution in patients with myasthenia gravis.

Due to a risk of increased QT-interval, clarithromycin should be used with caution in patients with a

coronary

vessel

disease,

history

ventricular

arrhythmia,

severe

cardiac

insufficiency,

non-

compensated hypokalemia and/or hypomagnesemia, bradycardia (<50 bpm), or when co-administered

with other medicinal products with a QT-prolonging effect. Clarithromycin should not be used in

patients with congenital or documented acquired QT prolongation (see section 4.5).

Clarithromycin should be used with caution whenever indicated for use in patients receiving treatment

with an inducer of CYP3A4 (see section 4.5).

Clarithromycin is an inhibitor of CYP3A4, and concomitant use with other medicinal products that are

metabolised to a large extent by this enzyme should be restricted to situations where it is clearly

indicated (see section 4.5).

PAR Clarithromycin 250 and 500mg Film-Coated Capsules

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16

Clarithromycin inhibits the metabolism of some HMG-CoA reductase inhibitors, which results in

increased plasma concentrations of these medicinal products (see section 4.5).

This medicinal product contains tartrazine and may cause allergic reactions.

4.5

Interaction with Other Medicinal Products and Other Forms of Interaction

Contraindicated combinations

Concomitant administration of clarithromycin and terfenadine, cisapride, pimozide and ergot alkaloids

is contraindicated.

The effect of other medicinal products on clarithromycin tablets

Clarithromycin is metabolised by the enzyme CYP3A4. Hence, strong inhibitors of this enzyme may

inhibit

metabolism

clarithromycin,

resulting

increased

plasma

concentrations

clarithromycin.

Although the plasma concentrations of clarithromycin and omeprazole may be increased when they are

administered concurrently, no adjustment to the dosage is necessary. Increased plasma concentrations

of clarithromycin may also occur when it is co-administered with antacids or ranitidine. No adjustment

to the dosage is necessary.

Ritonavir (200 mg tid) has been shown to inhibit the metabolism of clarithromycin (500 mg bid), with

an increase in C

, C

and AUC of 31, 182 and 77%, respectively, when co-administered with

ritonavir. Formation of the active 14-OH-hydroxy metabolite was almost completely inhibited. A

general dose reduction is probably not required in patients with normal renal function, but the daily

dose of clarithromycin should not exceed 1 g. Dose reduction should be considered in patients with

renal impairment. For patients with a creatinine clearance of 30 to 60 ml/min, the clarithromycin dose

should be reduced with 50%, and at a creatinine clearance of <30 ml/min, the dose should be reduced

with 75%.

Products that are inducers of CYP3A4 (eg 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. When clarithromycin is clearly indicated it might be

necessary to increase the dose of clarithromycin and monitor its efficacy and safety carefully.

Furthermore monitoring the plasma levels of the CYP3A4 inducer might be necessary because the

latter could be increased owing to the inhibition of CYP3A4 by clarithromycin (see also the relevant

product information for the CYP3A4 inhibitor administered). Concomitant administration of rifabutin

and clarithromycin resulted in an increase and decrease, respectively, in serum levels, followed by an

increased risk of uveitis.

The effect of clarithromycin on other medicinal products

Clarithromycin is an inhibitor of the metabolising enzyme CYP3A4 and the transport protein P-

glycoprotein. The degree of inhibition with different CYP3A4 substrates is difficult to predict. Hence,

clarithromycin should not be used during treatment with other medicinal products that are substrates

for CYP3A4, unless plasma levels, therapeutic effect or adverse events of the CYP3A4 substrate can be

closely monitored. A dose reduction may be necessary for medicinal products that are substrates for

CYP3A4 if co-administered with clarithromycin. Alternatively, treatment with these products may be

interrupted during clarithromycin treatment.

Medicinal products with a potential to prolong QT-interval

Clarithromycin has been reported to inhibit the metabolism of cisapride and terfenadine, with a 2 to 3-

fold increase in plasma levels reported for terfenadine. This has been associated with QT-prolongation

and cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation and torsades de

pointes. Similar symptoms have been described for patients treated with pimozide when combined with

clarithromycin. Concomitant administration of clarithromycin and terfenadine, cisapride of pimozide is

contraindicated (see section 4.3).

Cases with torsades de pointes has been reported in patients where clarithromycin has been co-

administered with quinidine or disopyramide. These combinations should therefore be avoided, or

plasma levels of quinidine or disopyramide closely monitored to allow dose adjustment. Caution is

warranted when clarithromycin is administered to patients treated taking other medicinal products with

the potential to prolong QT (see section 4.4).

PAR Clarithromycin 250 and 500mg Film-Coated Capsules

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HMG-CoA reductase inhibitors

Clarithromycin inhibits the metabolism of some HMG-CoA reductase inhibitors, which results in

increased plasma concentrations of these medicinal products. Rhabdomyolysis in association with

increased plasma concentrations have in rare cases been reported in patients treated with clarithromycin

and simvastatin or lovastatin. Clarithromycin may produce a similar interaction with atorvastatin and a

lesser interaction with either cerivastatin. When treatment with clarithromycin is indicated in patients

receiving treatment with either simvastatin or lovastatin or atorvastatin or cerivastatin patients should

be monitored for signs and symptoms of myopathy.

Ergot vasoconstrictors (eg dihydroergotamine, ergotamine)

Cases of ergotism due to increased plasma levels of ergot alkaloids have been reported when these

products have been co-administered with macrolides. The combination is contraindicated (see section

4.3).

Benzodiazepines

When midazolam was co-administered with clarithromycin tablets (250 mg bid), 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 mohnitored to allow

dose adjustment. The same precautions should also apply to other benzodiazepines that are metabolised

by CYP3A4, especially triazolam but also alprazolam. For benzodiazepines which are not metabolised

by CYP3A4 (temazepam, nitrazepam, lorazepam) an interaction with clarithromycin is unlikely.

Cyclosporin, tacrolimus and sirolimus

Concomitant use of oral clarithromycin and cyclosporin or tacrolimus have results in more than a 2-

fold increase of the C

levels of both cyclosporin and tacrolimus. Similar effects are also expected for

sirolimus. When initiating treatment with clarithromycin in patients already receiving any of these

immunosuppressive

agents,

cyclosporin,

tacrolimus

sirolimus

plasma

levels

must

closely

monitored and their doses decreased as necessary. When clarithromycin is discontinued in these

patients, close monitoring of plasma levels of cyclosporin, tacrolimus or sirolimus is again necessary to

guide dose adjustment.

Digoxin

The concentration of digoxin may be increased when co-administered with clarithromycin. Monitoring

of plasma levels of digoxin should be considered when co-treatment with clarithromycin is initiated or

terminated since a dose adjustment may be warranted.

Theophylline

The administration of clarithromycin to patients who are receiving theophylline has been associated

with an increase in serum theophylline levels and potential theophylline toxicity.

Warfarin

The use of clarithromycin in patients receiving warfarin may result in potentiation of the effects of

warfarin. Prothrombin time should be frequently monitored in these patients.

Zidovudine

Simultaneous oral administration of clarithromycin tablets and zidovudine to HIV-infected adult

patients may result in decreased steady-state zidovudine levels. This can be largely avoided by

staggering the doses of clarithromycin and zidovudine by 1-2 hours. No such reaction has been

reported in children.

4.6

Pregnancy and Lactation

Pregnancy

Data on the use of clarithromycin during the first trimester of more than 200 pregnancies show no clear

evidence of teratogenic effects, or of adverse effects or on the health of and neonate. Data from a

limited number of pregnant women exposed in the first trimester indicate a possible increased risk of

abortions. To date no other relevant epidemiological data are available. Data from animal studies have

shown reproductive toxicity (see section 5.3). The risk for humans is unknown. Clarithromycin should

only be given to pregnant women after a careful benefit/risk assessment.

Lactation

Clarithromycin and its active metabolite are excreted in breast milk. Therefore, diarrhoea and fungus

infection of the mucous membranes could occur in the breast-fed infant, so that nursing might have to

PAR Clarithromycin 250 and 500mg Film-Coated Capsules

UK/H/0798/01-02

18

be discontinued. The possibility of sensitisation should be borne in mind. The benefit of treatment of

the mother should be weighed against the potential risk for the infant.

4.7

Effects on Ability to Drive and Use Machines

There are no data available on the effect of clarithromycin on the ability to drive or use machines.

When performing these activities the possible occurrence of the adverse reactions dizziness, vertigo,

confusion and disorientation should be taken into account.

4.8

Undesirable Effects

The most frequently reported undesirable effects in adults taking clarithromycin tablets were diarrhoea

(3%), nausea (3%), abnormal taste (3%), dyspepsia (2%), abdominal pain/discomfort (2%) and

headache (2%).

In this section undesirable effects are defined as follows:

Very common (>1/10), common (>1/100, <1/10), uncommon (>1/1000, <1/100), rare (>1/10000,

<1/1000), very rare (<1/10000).

Infections and infestations

Common:

Oral monilia

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

Blood and the lymphatic system disorders

Uncommon:

Decreased leucocyte levels

Very rare:

Thrombocytopenia

Immune system disorders

Uncommon:

Allergic reactions ranging from urticaria and mild skin eruptions to anaphylaxis

Psychiatric disorders

Very rare:

Anxiety, insomnia, hallucinations, psychosis, disorientation, depersonalisation, bad

dreams and confusion

Nervous system disorders

Common:

Headache, smell alteration

Very rare:

Dizziness, vertigo, paraesthesia, convulsions

Ear and labyrinth disorders

Rare:

Tinnitus

Very rare:

Reversible hearing loss

Cardiac disorders

Very rare:

QT prolongation, ventricular tachycardia and Torsades de Pointes.

Gastrointestinal disorders

Common:

Nausea,

diarrhoea,

vomiting,

abdominal

pain,

dyspepsia,

stomatitis,

glossitis,

reversible tooth and tongue discoloration, and taste perversion, i.e. metallic or bitter

taste.

Very rare:

Pancreatitis.

Pseudomembranous

colitis

been

reported

very

rarely

with

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

Hepato-biliary disorders

Uncommon:

Hepatic

dysfunction,

which

usually

transient

reversible,

hepatitis

cholestasis with or without jaundice.

Very rare:

Fatal hepatic failure has been reported particularly in patients with pre-existing liver

disease or taking other hepatotoxic medicinal products.

Skin and subcutaneous tissue disorders

Very rare:

Stevens-Johnson syndrome and toxic epidermal necrolysis

Musculoskeletal, connective tissue and bone disorders

Uncommon:

Arthralgia, myalgia.

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Renal and urinary disorders

Very rare:

Interstitial nephritis, renal failure.

Investigations

Common:

Elevated BUN

Uncommon:

Prolongation of prothrombin time, elevated serum creatinine, altered liver function

tests (increased transaminase levels).

Very rare:

Hypoglycaemia has been observed especially after concomitant administration with

antidiabetic medicinal products and insulin

4.9

Overdose

Symptoms of intoxication:

Reports indicate that the ingestion of large amounts of clarithromycin can be expected to produce

gastrointestinal symptoms. Symptoms of overdose may largely correspond to the profile of adverse

reactions. One patient who had a history of bipolar disorder ingested 8 grams of clarithromycin and

showed altered mental status, paranoid behaviour, hypokaliaemia and hypoxaemia.

Therapy of intoxication:

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

haemodialysis or peritoneal dialysis.

Adverse reactions accompanying overdosage should be treated by gastric lavage and supportive

measures. Severe acute allergic reactions may be seen very rarely, e.g. anaphylactic shock. At the first

signs of hypersensitivity reactions therapy with clarithromycin must be discontinued and the required

measures should be initiated immediately.

5

Pharmacological Properties

5.1.

Pharmacodynamic Properties

Pharmacotherapeutic group: Macrolides

ATC code J01F A09

Mechanism of action

Clarithromycin is a semi-synthetic derivative of erythromycin A. It exerts its antibacterial action by

binding to the 50s ribosomal sub-unit of susceptible bacteria and suppresses protein synthesis. It is

highly potent against a wide variety of aerobic and anaerobic gram-positive and gram-negative

organisms. The minimum inhibitory concentrations (MICs) of clarithromycin are generally two-fold

lower than the MICs of erythromycin.

The 14-hydroxy metabolite of clarithromycin also has antimicrobial activity. The MICs of this

metabolite are equal or two-fold higher than the MICs of the parent compound, except for

H.

influenzae

where the 14-hydroxy metabolite is two-fold more active than the parent compound.

Mechanisms of resistance

Resistance mechanisms against macrolide antibiotics include alteration of the target site of the

antibiotic

based

modification

and/or

active

efflux

antibiotic.

Resistance

development can be mediated via chromosomes or plasmids, be induced or exist constitutively.

Macrolide-resistant bacteria generate enzymes which lead to methylation of residual adenine at

ribosomal RNA and consequently to inhibition of the antibiotic binding to the ribosome. Macrolide-

resistant

organisms

generally

cross-resistant

lincosamides

streptogramin

based

methylation of the ribosomal binding site. Clarithromycin ranks among the strong inducers of this

enzyme as well. Furthermore, macrolides have a bacteriostatic action by inhibiting the peptidyl

transferase of ribosomes.

A complete cross-resistance exists among clarithromycin, erythromycin and azithromycin. Methicillin-

resistant staphylococci and penicillin-resistant

Streptococcus pneumoniae

are resistant to macrolides

such as clarithromycin.

Breakpoints

According to the NCCLS (US National Committee on Clinical Laboratory Standards) in 2003 the

following breakpoints have been defined for clarithromycin:

Staphylococcus

spp.: ≤2 µg/ml susceptible, ≥8 µg/ml resistant

Haemophilus

spp.: ≤8 µg/ml susceptible

Streptococcus

spp. including

S. pneumoniae

: ≤0.25 µg/ml susceptible, ≥1 µg/ml resistant

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sceptibility

The prevalence of acquired resistance may vary geographically and with time for selected species and

local information on resistance is desirable, particularly when treating severe infections. As necessary,

expert advice should be sought when the local prevalence of resistance is such that the utility of the

agent in at least some types of infections is questionable.

Commonly susceptible species (ie resistance < 10 % in all EU Member States)

Aerobic, Gram-positive microorganisms

Streptococcus

group A

Streptococcus

group B

Streptococcus

group C,F,G

Aerobic, Gram-negative microorganisms

Moraxella catarrhalis

Pasteurella multocida

Legionella

spp.

Anaerobic microorganisms

Bacteroides

spp.

Peptococcus/Peptostreptococcus

spp.

Clostridium

spp., other than

C. difficile

Fusobacterium

spp.

Other microorganisms

Mycoplasma pneumoniae

Chlamydia trachomatis

Chlamydia pneumoniae

Species for which acquired resistance may be a problem (ie resistance

10 % in at least 1 EU

Member State)

Aerobic, Gram-positive microorganisms

Staphylococcus aureus,

methicillin-susceptible

Streptococcus pneumoniae*

Aerobic, Gram-negative microorganisms

Haemophilus influenzae

Helicobacter pylori

Inherently resistant microorganisms

Aerobic, Gram-positive microorganisms

Enterococcus

spp.

Staphylococcus aureus

, methicillin-resistant or erythromycin-resistant

Other microorganisms

Mycobacterium tuberculosis

*Comments regarding resistance see “Mechanisms of resistance”

5.

1

Pharmacokinetic Properties

Absorption:

Clarithromycin is rapidly and well absorbed from the gastrointestinal tract - primarily in the jejunum -

but undergoes extensive first-pass metabolism after oral administration. The absolute bioavailability of

a 250 mg clarithromycin tablet is approximately 50%. Food slightly delays the absorption but does not

affect the extent of bioavailability. Therefore, clarithromycin tablets may be given without regard to

food. Due to its chemical structure (6-O-methylerythromycin) clarithromycin is quite resistant to

degradation by stomach acid. Peak plasma levels of 1-2 µg/ml clarithromycin were observed in adults

after oral administration of 250 mg twice daily. After administration of 500 mg clarithromycin twice

daily the peak plasma level was 2.8 µg/ml.

After administration of 250 mg clarithromycin twice daily the microbiologically active 14-hydroxy

metabolite attains peak plasma concentrations of 0.6 µg/ml. Steady state is attained within 2 days of

dosing.

Distribution:

Clarithromycin penetrates well into different compartments, with an estimated volume of distribution

of 200-400 l. Clarithromycin provides concentrations in some tissues that are several times higher than

PAR Clarithromycin 250 and 500mg Film-Coated Capsules

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21

the circulating substance levels. Increased levels have been found in both tonsils and lung tissue.

Clarithromycin also penetrates the gastric mucus.

Clarithromycin is approximately 80% bound to plasma proteins at therapeutic levels.

Biotransformation and elimination:

Clarithromycin is rapidly and extensively metabolised in the liver. Metabolism involves mainly N-

dealkylation, oxidation and stereospecific hydroxylation at position C 14.

The pharmacokinetics of clarithromycin is non-linear due to saturation of hepatic metabolism at high

doses.

elimination

half-life

increased

from

hours

following

administration

clarithromycin twice daily to 5 hours following administration of 500 mg clarithromycin twice daily.

The half-life of the active 14-hydroxy metabolite ranges between 5 to 6 hours following administration

of 250 mg clarithromycin twice daily.

After oral administration of radioactive clarithromycin 70-80% of the radioactivity was found in the

faeces. Approximately 20-30% of clarithromycin is collected as the unchanged active substance in the

urine.

This

proportion

increased

when

dose

increased.

Renal

insufficiency

increases

clarithromycin levels in plasma, if the dose is not decreased.

Total plasma clearance has been estimated to approximately 700 ml/min, with a renal clearance of

approximately 170 ml/min.

Special populations:

Renal impairment: Reduced renal function results in increased plasma levels of clarithromycin and the

active metabolite levels in plasma.

5.3

Preclinical Safety Data

In 4-week studies in animals, the toxicity of clarithromycin was found to be related to the dose and

duration of the treatment. In all species, the first signs of toxicity were observed in the liver, in which

lesions were seen within 14 days in dogs and monkeys. The systemic levels of exposure related to this

toxicity are not known in detail, but toxic doses were clearly higher than the therapeutic doses

recommended for humans.

No mutagenic effects were found in

in vitro

in vivo

studies with clarithromycin.

Studies on reproduction toxicity showed that administration of clarithromycin at doses 2x the clinical

dose in rabbit (iv) and x10 the clinical dose in monkey (po) resulted in an increased incidence of

spontaneous

abortions.

These

doses

were

related

maternal

toxicity.

embryotoxicity

teratogenicity was noted in rat studies. However, cardiovascular malformations were observed in rats

treated with doses of 150 mg/kg/day. In mouse at doses x70 the clinical dose cleft palate occurred at

varying incidence (3-30%).

6.

PHARMACEUTICAL PARTICULARS

6.1

List of Excipients

Tablet core:

Sodium starch glycolate

Microcrystalline cellulose

Povidone (PVP K-30)

Magnesium hydroxide

Croscarmellose sodium

Colloidal anhydrous silica

Stearic acid

Magnesium stearate

Film-coat:

Hypromellose (E464)

Titanium dioxide (E171)

Macrogol 400

Tartrazine lake (E102)

Allura Red AC Lake (E129)

Indigo Carmine Lake (E132)

Vanillin

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6.2

Incompatibilities

Not applicable.

6.3

Shelf Life

2 years

6.4

Special Precautions for Storage

Do not store above 25°C. Keep container in the outer carton.

6.5

Nature and Contents of Container

Available in blister packs of transparent or white opaque PVC or PVC/PVdC lidded with aluminium

foil for 10, 14, 14 calendar pack & 30.

Not all pack sizes may be marketed.

6.6

Special precautions for disposal

No special requirements

Administrative Data

7.

MARKETING AUTHORISATION HOLDER

8

.

MARKETING

AUTHORISATION

NUMBER

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATIO

N

10

.

DATE OF (PARTIAL) REVISION OF THE TEXT

PAR Clarithromycin 250 and 500mg Film-Coated Capsules

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Module 3

Product Information Leaflet

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PAR Clarithromycin 250 and 500mg Film-Coated Capsules

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Module 4

Labelling

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PAR Clarithromycin 250 and 500mg Film-Coated Capsules

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27

PAR Clarithromycin 250 and 500mg Film-Coated Capsules

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Module 5

Scientific discussion during initial procedure

I

INTRODUCTION

Based on the review of the data on quality, safety and efficacy, the MHRA has granted a

marketing authorisation for Clarithromycin 250 and 500 mg Film-coated Tablets, from

Approved Prescription Services Ltd. for the treatment of infections caused by clarithromycin-

susceptible microorganisms.

These are applications made under Article 10.1(a)(iii), first paragraph of 2001/83 EC for

Clarithromycin

250 and

500 mg

Film-coated

Tablets,

claiming

essential

similarity

[Bioequivalence]

Klaricid®

tablets

(Abbott

Laboratories

Ltd,

that

received

authorisation in 1991 and has been in clinical use since.

Clarithromycin, is a semisynthetic derivative of erythromycin [6-O-methyl erythromycin-A],

which is a macrolide antibiotic that is active against aerobic and anaerobic bacteria both gram

positive and gram negative. Its primary efficacy is against respiratory tract infections, soft

tissue infections and

H.pylori

bacteria.

No new preclinical or clinical studies were conducted, which is acceptable given that the

application was based on essential similarity to a product that has been licensed for over 10

years. The RMS has been assured that the bioequivalence study was carried out in

accordance with Good Clinical Practice (GCP).

The RMS has also been assured that acceptable standards of GMP are in place for these

product types at all sites responsible for the manufacture and assembly of this product prior

to granting its national authorisation. For manufacturing sites outside the community, the

RMS has accepted copies of current GMP Certificates or satisfactory inspection summary

reports, ‘close-out letters’ or ‘exchange of information’ issued by the inspection services of

the competent authorities (or those countries with which the EEA has a Mutual Recognition

Agreement for their own territories) as certification that acceptable standards of GMP are in

place at those non-Community sites.

The products were granted marketed authorisations on 8

November 2004. With the UK as

Reference Member State in this Mutual Recognition

Procedure

(MRP),

marketing

authorisation holder (Approved Prescription Services Ltd.) gained approval for marketing

authorisations in Austria, Belgium, the Czech Republic, Finland, Germany, Hungary, Italy,

Lithuania, Norway, Poland, Portugal, Sweden and the Slovak Republic.

Clarithromycin 250 & 500 mg Film-coated Tablets are available on prescription.

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30

II.

ABOUT THE PRODUCT

Name of the product in the Reference Member State

Clarithromycin 250mg Film-Coated Tablets

Clarithromycin 500mg Film-Coated Tablets

Name(s) of the active substance(s) (INN)

Clarithromycin

Pharmacotherapeutic classification

(ATC code)

J01F A09

Pharmaceutical form and strength(s)

250 mg and 500 mg film-coated tablets

Reference numbers for the Mutual Recognition

Procedure

UK/H/0798/01-2

Reference Member State

United Kingdom

Member States concerned

Austria, Belgium, Czech Republic, Finland, Germany,

Hungary, Italy, Lithuania, Norway, Poland, Portugal,

Slovak Republic and Sweden

Name and address of manufacturer responsible for batch

release in the EEA

Approved Prescription Services Limited, Brampton

Road, Hampden Park, Eastbourne, East Sussex,

BN22 9AG, UK

Pharmachemie BV, Swensweg 5, Postbus 552, 2003

RN Haarlem, The Netherlands

Oy Galena Ltd, Sammokatu 10, PO Box 1450, 70500

Kuopio, Finland

Balmac SA, Poligono Malpica, Calle C, Number 4,

50016 Zaragoza, Spain

Date of first authorisation

08.11.2004

Marketing Authorisation Number(s)

PL 00289/0457-8

Date of assessment report

16/12/2005

Name and address of the

authorisation holder

Approved Prescription Services Limited, Brampton

Road, Hampden Park, Eastbourne, East Sussex, BN22

9AG, UK

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31

III

SCIENTIFIC OVERVIEW AND DISCUSSION

III.1

QUALITY ASPECTS

S.

Active substance

The active substance is clarithromycin, an established active substance described in the

European Pharmacopoeia.

The active substance specification is considered adequate to control the quality and meets the

requirements of the monograph in the Ph. Eur. The analytical methods used for quality

control of clarithromycin are appropriately described and validated. The applicant proposes a

retest period of 24 months.

P

Medicinal Product

P.1

Composition

Composition

Clarithromycin

500 mg

tablet

compositions

contain

active

substance

clarithromycin (Ph Eur and HSE) with standard pharmaceutical excipients. The core includes

croscarmellose sodium (Ph Eur), microcrystalline cellulose (Ph Eur), povidone (Ph Eur),

colloidal anhydrous silica (Ph Eur), sodium starch glycollate (Ph Eur), magnesium hydroxide

(Ph Eur), stearic acid (Ph Eur,) and magnesium stearate (Ph Eur). The coating consists of

Opadry Yellow (containing hypromellose, titanium dioxide, macrogol 400, tartrazine, indigo

carmine and allura red) and vanillin.

Container/closure system

Transparent or white opaque PVC 350µm/Al 20µm blisters or transparent or white opaque

PVC 300µm/PVdC 40g/m2/Al 20µm blisters in cardboard boxes. The opacifier is titanium

dioxide.

P.2

Pharmaceutical development

The objective of the development programme has been a globally acceptable, stable and

bioequivalent tablet dosage form of clarithromycin, comparable to Klaricid® tablets (Abbott

Laboratories Limited, UK).

A qualitative comparison of the composition of the reference product (UK) and other EU

brand leader products has shown the same formula.

The common blend was tested for bulk density, tapped density, LOD and particle size

distribution. The film-coated tablets complied with the finished product specification. Results

of early stability studies in the marketing pack were encouraging.

The dissolution method was shown to be discriminatory. Comparative dissolution studies

have been carried out with the biobatches, UK brand leader and several EU brands.

The applicant has carried out an impurity profile comparison against the brand leader. The

results show that the impurity profile of the applicant’s product appears to be comparable to

that of the brand leader.

To ensure batch to batch reproducibility, particle size distribution is measured by the active

substance manufacturer using the Malvern method.

PAR Clarithromycin 250 and 500mg Film-Coated Capsules

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32

Clinical trial formula(e)

The formulation of the batch used in the bioequivalence study is identical to that proposed for

marketing.

P.3

Method of preparation of the product

The method of manufacture is unremarkable. A satisfactory flow chart of the manufacturing

process has been provided. The equipment used for pilot batches (including the biobatch) and

commercial batches are the same.

In-process control

The critical steps to be controlled in the manufacturing process are as follows:

Granulate - moisture content

Tablets -

individual weight, average weight, thickness, hardness and friability .

Coated Tablets - description

Process validation

It is stated that the maximum batch size can be 10x the size of the pilot batch based on process

validation performed prior to launch. A process validation protocol has been provided and is

considered to be satisfactory given the batch data presented and the conventional nature of the

manufacturing procedure and the drug product.

P.4

Control of other substance(s) (excipients)

All excipients, except Opadry, comply with the specified Ph Eur monographs. Certificates of

Analysis

demonstrating

compliance

with

current

BP/PhEur

monographs

in-house

specifications have been provided. Opadry is sourced from a known supplier, Colorcon, and

Certificates

Analysis

provided

satisfactory.

finished

product

manufacturer

performs satisfactory tests as appropriate on receipt of the excipients.

Statements have been provided which confirm that no material of animal origin is used in the

manufacture of the tablets.

P.5

Control tests on the finished product

Finished Product Specification

Quality Specification for the Proposed Shelf Life:

Tests

Description

Identification

For Clarithromycin:

For colours*:

Titanium dioxide

Dissolution

Uniformity of mass

Assay

Impurities and Degradation Products

Microbial limit test*

Water Content (Granulate)**

Thickness (Cores)**

Hardness (Cores)**

Friability (Cores)**

* This is a non-routine test

**In-Process

PAR Clarithromycin 250 and 500mg Film-Coated Capsules

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33

A justification for the specification, which complies with the Ph Eur for coated tablets and

also with CPMP/ICH/367/96, has been provided.

It is stated that microbiological testing will be carried out on one batch per year. Considering

the results found where the product was shown to be bactericidal for bacteria this is

considered to be satisfactory.

Test methods have been adequately described and validated. The stability-indicating nature of

assay

method

demonstrated

stress

testing.

System

suitability

been

demonstrated and satisfactory chromatograms have been provided. Certificates of Analysis

reference

in-house

standards

have

been

provided.

reference

standard

clarithromycin complies with in-house specifications. Release of standard or batches of active

substance according to Ph Eur will be performed once the Ph Eur standard is available. The

in-house standard has been tested versus USP clarithromycin RS and its quality was found to

be satisfactory.

The limits for related substances have been based on those for the active substance, which are

in turn based on the now adopted Ph Eur monograph for clarithromycin (as above).

Dissolution testing is carried out using BP Apparatus II. The method has been satisfactorily

validated. Individual tablet results have been reported in the batch analyses.

The microbial limit test has been validated. It is stated that microbiological testing will be

carried out on one batch per year. Considering the aforementioned results this is considered to

be satisfactory.

Batch Analysis

Batch analyses for two batches of each strength have been provided. In addition, two batches

have been tested for known impurities, in accordance with Ph Eur. The results from these

batches show that active substance impurities are within the allowable limits stated in the Ph

Eur monograph.

P.6

Packaging Materials

Satisfactory specifications and Certificates of Analysis have been provided for packaging

materials, which conform with the Ph Eur. The finished product manufacturer performs

satisfactory tests, as appropriate, on receipt of the packaging components.

P.7

Stability tests on the finished product

Stability data has been generated for pilot-scale batches. Samples have been stored in the

proposed transparent PVC/PVdC/Al pack and in the proposed transparent PVC/Al pack at

25°C/60%RH for 24 months, 30°C/60%RH for 12 months and 40°C/75% RH for 3 months.

Analytical methods were the same as those described for product at release.

data

both

packs

after

months

stored

30°C/60%RH

months

25°C/60%RH have shown satisfactory stability.

A shelf-life of 24 months when the product is stored not above 30°C in the original pack

(container kept in the outer carton) is claimed. This is acceptable.

PAR Clarithromycin 250 and 500mg Film-Coated Capsules

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34

Conclusion on quality

The pharmaceutical assessor concluded that marketing authorisations may be granted for

these products.

III.2

PRE-CLINICAL ASPECTS

These applications for a generic product claim essential similarity to Klaricid 250mg and

500mg Tablets (Abbott Laboratories Limited, UK), which has been licensed within the EEA

for over 10 years.

No new preclinical data has been supplied with these applications, however, a preclinical

expert report summarising relevant non-clinical studies has been included in the MR dossier;

this is satisfactory.

III.3

CLINICAL ASPECTS

III.3.1 Clinical Pharmacology

Pharmacokinetics

Introduction and Summary:

The applicant has not submitted any new data on clinical pharmacology of clarithromycin

and none are required as per Article 10.1(a)(iii). A summary of current knowledge on

pharmacokinetics of clarithromycin is provided. Clarithromycin is absorbed after an oral dose

with ~55% bioavailability that is unaffected by concomitant food intake in a clinically

significant fashion. Clarithromycin undergoes first-pass metabolism and the major metabolite

14-hydroxy-clarithromycin is active. Approximately 20% of administered dose is excreted

unchanged in the urine and urinary recovery of the active metabolite is about 15%. It has

non-linear dose dependent kinetics with saturable metabolic pathways for both the parent

compound and the active metabolite. Clarithromycin is well distributed throughout body

tissues (volume ~250 litres with 250mg) after oral dose. It is 40-70% plasma protein bound,

the binding decreasing with increasing dose. Clarithromycin is eliminated both by renal

excretion (37%) and hepatic metabolism (60%), 40% of the latter being first pass or pre-

systemic primarily by CYP3A4 family of enzymes.

Assessor’s Comment:

It is to be noted that at high doses, the kinetics of the active metabolite are altered with

prolongation of t

1/2

, and the AUC, suggesting that the same enzymatic pathways are likely

involved in subsequent metabolism of 14 hydroxy compound as well.

Interactions

There are several important interactions of clarithromycin that arise because of the relation to

CYP3A4 enzymatic pathways involved. Well known ones include, antihistamines

(terfenadine & astemizole), Antiviral agents (Ritonavir and Zidovudine), Ergot alkaloids,

HMG CoA reductase inhibitors, and immunosuppressants (Cyclosporin, tacrolimus and

Sirolimus). Others include digoxin, warfarin and theophylline.

Assessor’s Comment:

These are highlighted adequately in the SmPC.

Special Populations

Due to its dual mode of elimination, dose adjustments are not routinely required in those with

renal or hepatic impairment. However care should be taken in those with severe renal and

hepatic impairment or those with both conditions. These aspects are detailed in the proposed

PAR Clarithromycin 250 and 500mg Film-Coated Capsules

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35

SmPC but need emphasis. Safety and efficacy in pregnancy and lactating mothers has not

been established. Therefore clarithromycin should not be used in these situations.

Pharmacodynamics

Introduction

Clarithromycin, a semisynthetic derivative of erythromycin-A is active against a wide variety

of aerobic and anaerobic gram-positive or gram-negative bacterial strains. Clarithromycin is

highly stable in the presence of β-lactamase enzymes. The predominant resistant organisms

are beta-lactamase positive, methicillin-resistant staphylococcus aureus, erythromycin-

resistant streptococcus pneumoniae and viridans group along with mycobacterium hominis

species.

Mechanism of Action

Clarithromycin binds to the ‘50s’ ribosomal subunit of the susceptible organism and

suppresses protein synthesis. It is bactericidal against its primary target species.

Primary Pharmacology

Due to its stability in presence of β-lactamase enzymes, it is likely to be effective against

penicillin- and cephalosporin-resistant organisms. Attention is drawn here to the fact that

against some organisms, even the metabolite 14-hydroxy clarithromycin is at least as active

as erythromycin and marginally less active than the parent compound. It is much less potent

in mammalian cells and in clinical doses does not affect mammalian protein synthesis. It,

however, has certain important secondary effects.

Secondary Pharmacology

The secondary pharmacology of Clarithromycin essentially involves, interaction between the

agent and the P450 enzyme system, and its effect on cardiac tissue, manifesting as changes in

QT interval. It is metabolised by the CYP3A4 enzyme systems in the liver with a first-pass

effect into bacteriologically active metabolites. The major metabolite 14-OH clarithromycin

has significant activity against

H. influenzae

, while it is similar to the parent compound

against other bacteria.

Pharmcodynamic Interactions With Other Medicinal Products.

Clarithromycin is expected to interact with other medicines metabolised by the Cytochrome

P450 enzyme system, as it is both a substrate and an enzyme depressant for this class of

enzymes. It should not, therefore, be co-administered with Cyclosporin, HMG Co-A inhibitors

(Cisapride, Pimozide, etc).

Similar to other macrolide antibiotics, clarithromycin prolongs QT interval albeit to a less

significant extent than erythromycin. It should, therefore, not be administered with other

agents that prolong QT interval or have a risk of inducing torsade, such as Astemizole,

terfenadine, Class-Ia antiarrhythmic agents, etc.

The exact effect of 14-OH clarithromycin on QT interval is not known and there is scant

information in the literature.

Assessor’s Overall Conclusions on Pharmacodynamics

The pharmacodynamics of Clarithromycin have been previously demonstrated and the

current application does not include any new data. This is acceptable for a generic application

under Article 10.1(a)(iii).

PAR Clarithromycin 250 and 500mg Film-Coated Capsules

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Bioavailability & Bioequivalence

Bioavailability

The bioavailability of the generic compound was not assessed separately, but as a part of the

bioequivalence study that is addressed below:

Bioequivalence Study

accordance

with

requirements,

applicant

submitted

bioequivalence

study

comparing 500mg tablets of the current product with the reference product. A summary is

provided below. It is stated that the study conformed to GCP guidelines.

BE Study:

Methodology

Randomised, open-label, single-dose, two-period cross-over studies

Reference Product

Klaricid 500mg tablets

Test Formulations

Clarithromycin 250mg and 500mg tablets.

Subjects

N= 60, age 19-53 years, 57 completed the study

Study-02-498: 500-mg tablets (Log-transformed data)

Analyte Clarithromycin:

Parameter

Test Product

500 mg

Reference Product

500 mg

Pt Est & CI 90% for Geom

Means

(ng/ml)

1786.64

650.44

1982.51

733.51

89.98 (

82.97- 96.92

(ng*hr/ml)

14299.77

5277.91

15625.36

6257.26

92.02 (

87.62- 96.64

(ng*hr/ml)

14716.83

5275.56

15945.9

6328.14

91.91 (

87.63- 96.40

Analyte 14 hydroxy-clarithromycin:

Parameter

Test Product

500 mg

Reference Product

500 mg

Pt Est & CI 90% for Geom.

Means

(ng/ml)

810.97

224.89

865.47

231.09

93.83 (

88.03- 100.01

(ng*hr/ml)

9171.55

1719.38

9586.69

1876.16

95.97(

92.38- 99.71

(ng*hr/ml)

9661.46

1888.04

9917.14

1942.11

97.58(

93.92-101.39

Assessor’s Conclusions:

Based on the tables it is considered that both clarithromycin and active metabolite, 14-

hydroxy clarithromycin are equivalent. It is, therefore, accepted that bioequivalence with the

reference product has been demonstrated.

It should be noted that only a single biostudy has been provided. This has been justified on

the basis that clarithromycin exhibits non-linear kinetics at doses greater than 1200mg, and

in doses less than 600mg the kinetics are believed to be linear. The applicant has provided

the biostudy at the higher dose and claims exemption for the lower dose. As the dissolution

profiles are similar and the claim is in line with the provisions of the CPMP(CHMP)

guideline on bioequivalence [CPMP/EWP/QWP/1401/98], a single biostudy is considered

acceptable.

III.3.2 Clinical Efficacy

In this generic application, no new efficacy data has been submitted and this is acceptable.

Efficacy of clarithromycin is well known and the active has been in clinical use for nearly 10

years in the EU and worldwide. The issue of development of resistance is addressed in the

SmPC and national/official guidelines on the use of antibacterial agents have been referred to

as appropriate.

III.3.3 Clinical Safety

Introduction

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37

The clinical safety of the active has again been well established and there have been no major

regulatory actions since authorisation, except for minor variations or additions. The applicant

has not submitted any new data concerning safety and this is acceptable for an application

based on essential similarity.

The adverse events experienced during the bioequivalence studies were minor and are

addressed below.

Adverse Events and Post Marketing Experience.

Twelve adverse events in seven patients (of 60; 11%) were reported during the

bioequivalence study. All these were classified as minor and all but one resolved

spontaneously. There is no post marketing experience with the current generic product.

Assessor’s Overall Conclusions on Clinical Safety

The safety of active (clarithromycin) is well established. The SmPC contains adequate

warnings.

IV

OVERALL CONCLUSION AND BENEFIT-RISK ASSESSMENT

This is a generic application based on essential similarity to an established active (brand

leader) that was authorised in 1991. The applicant has not submitted any pharmacological

data except for bioequivalence. This is acceptable.

It is accepted that bioequivalence has been demonstrated with the reference product for both

clarithromycin and the metabolite 14-hydroxy clarithromycin.

No new efficacy or safety data have been included in the dossier and none are necessary for

an application based on essential similarity.

It is accepted that risk:benefit ratio is favourable.

The product literature has been amended in-line with the current guidelines. The SmPC

includes all relevant warnings.

There are no pre-clinical concerns with these applications or with the clinical use of

clarithromycin.

Packungsbeilage: zusammensetzung, kinische angaben, nebenwirkungen, wechselwirkungen, dosierung, schwangerschaft, stillzeit

Gebrauchsinformation: Information für Anwender

Clarithromycin ratiopharm GmbH 500 mg Filmtabletten

Wirkstoff: Clarithromycin

Lesen Sie die gesamte Packungsbeilage sorgfältig durch, bevor Sie mit der Einnahme dieses

Arzneimittels beginnen, denn sie enthält wichtige Informationen.

Heben Sie die Packungsbeilage auf. Vielleicht möchten Sie diese später nochmals lesen.

Wenn Sie weitere Fragen haben, wenden Sie sich an Ihren Arzt oder Apotheker.

Dieses Arzneimittel wurde Ihnen persönlich verschrieben. Geben Sie es nicht an Dritte weiter.

Es kann anderen Menschen schaden, auch wenn diese die gleichen Beschwerden haben wie Sie.

Wenn Sie Nebenwirkungen bemerken, wenden Sie sich an Ihren Arzt oder Apotheker. Dies gilt

auch für Nebenwirkungen, die nicht in dieser Packungsbeilage angegeben sind. Siehe Abschnitt

Was in dieser Packungsbeilage steht

Was ist Clarithromycin ratiopharm GmbH und wofür wird es angewendet?

Was sollten Sie vor der Einnahme von Clarithromycin ratiopharm GmbH beachten?

Wie ist Clarithromycin ratiopharm GmbH einzunehmen?

Welche Nebenwirkungen sind möglich?

Wie ist Clarithromycin ratiopharm GmbH aufzubewahren?

Inhalt der Packung und weitere Informationen

1.

Was ist Clarithromycin ratiopharm GmbH und wofür wird es angewendet?

Clarithromycin ratiopharm GmbH gehört zu einer Gruppe von Arzneimitteln, die Makrolidantibiotika

genannt werden.

Clarithromycin ratiopharm GmbH wird zur Behandlung von Infektionen angewendet, wie:

Infektionen des Brustraums, z.B. Bronchitis und Lungenentzündung (Pneumonie)

Infektionen des Rachens und der Nebenhöhlen, z.B. Nebenhöhlenentzündung (Sinusitis) und

Rachenentzündungen (Pharyngitis)

Infektionen der Haut und der Weichteile

Helicobacter pylori Infektionen verbunden mit einem Zwölffingerdarmgeschwür.

2.

Was sollten Sie vor der Einnahme von Clarithromycin ratiopharm GmbH beachten?

Clarithromycin ratiopharm GmbH darf nicht eingenommen werden,

wenn Sie allergisch gegen Clarithromycin, alle anderen Makrolidantibiotika (z.B.

Erythromycin, Azithromycin) oder einen der in Abschnitt 6. genannten sonstigen Bestandteile

dieses Arzneimittels sind

wenn Sie Medikamente einnehmen die Terfenadin oder Astemizol (Medikamente gebräuchlich

gegen Heuschnupfen oder Allergien) oder Cisaprid (bei Magenbeschwerden) oder Pimozid

(Medikamente zur Behandlung von psychischen Erkrankungen) enthalten, da die Einnahme

dieser Arzneimittel in Kombination mit Clarithromycin schwere Herzrhythmusstörungen zur

Folge haben kann. Sprechen Sie bitte mit Ihrem Arzt, um sich über andere

Behandlungsmöglichkeiten beraten zu lassen.

wenn Ihnen Ihr Arzt mitgeteilt hat, dass Sie abnormal niedrige Kaliumwerte im Blut haben

(Hypokalämie)

wenn Sie oder Personen aus Ihrer Familie Herzrhythmusstörungen (ventrikuläre kardiale

Arrhythmie, einschließlich Torsade de pointes) oder Elektrokardiogramm-Abweichungen

(EKG, elektrische Aufzeichnung der Herzaktion) sogenanntes „langes QT-Syndrom“ in der

Vorgeschichte hatten.

wenn Sie Ergotamin-ähnliche Arzneimittel (werden üblicherweise gegen Migräne angewendet)

einnehmen

wenn Sie Arzneimittel zur Senkung des Cholesterinspiegels (Simvastatin oder Lovastatin)

einnehmen

wenn Sie Herzprobleme haben, wie beispielsweise einen unnatürlichen Herzrhythmus

wenn Sie ernste Leberprobleme in Verbindung mit Nierenproblemen haben

wenn Sie Ticagrelor (ein blutverdünnendes Arzneimittel) einnehmen

wenn Sie Ranolazin (zur Behandlung von Angina pectoris) einnehmen

wenn Sie Colchizin (zur Behandlung von Gicht) einnehmen.

Warnhinweise und Vorsichtsmaßnahmen

Bitte sprechen Sie mit Ihrem Arzt, bevor Sie Clarithromycin ratiopharm GmbH einnehmen wenn Sie,

allergisch auf die Antibiotika Lincomycin oder Clindamycin sind

Leberprobleme haben

Nierenprobleme haben

Herzprobleme haben

eine Pilzinfektion haben oder für diese anfällig sind (z.B. Soor)

Muskelprobleme haben, die als Myasthenia gravis bekannt sind

Arzneimittel zur Senkung des Blutzuckers (orale hypoglykämische Arzneimittel) oder Insulin

nehmen

einen abnormal niedrigen Magnesiumspiegel im Blut haben (Hypomagnesaemia)

in Ihrem Blut ein Salzungleichgewicht haben (Elektrolyte)

Arzneimittel einnehmen, welche bekannt für schwerwiegende Herzrhythmusstörungen sind

(Terfenadin, Astemizol, Cisaprid und Pimozid; siehe Abschnitt „Clarithromycin ratiopharm darf

nicht eingenommen werden“).

Einnahme von Clarithromycin ratiopharm GmbH zusammen mit anderen Arzneimitteln

Informieren Sie Ihren Arzt oder Apotheker, wenn Sie andere Arzneimittel einnehmen/anwenden,

kürzlich andere Arzneimittel eingenommen/angewendet haben oder beabsichtigen andere Arzneimittel

einzunehmen/anzuwenden, einschließlich solcher, die Sie ohne Verschreibung erhalten.

Nehmen Sie Clarithromycin nicht ein, wenn Sie eines der folgenden Arzneimittel einnehmen

Ergotamin oder Dihydroergotamin (zur Behandlung von Migräne)

Terfenadin oder Astemizol (zur Behandlung von Heuschnupfen und anderen Allergien)

Pimozid (zur Behandlung von mentalen Störungen)

Cisaprid (zur Behandlung von Magenproblemen)

Simvastatin oder Lovastatin (zur Senkung des Cholesterins)

andere Makrolidantibiotika, z.B. Erythromycin oder Azithromycin

Ticagrelor (ein Arzneimittel zur Blutverdünnung)

Ranolazin (zur Behandlung von Angina pectoris)

Colchizin (zur Behandlung von Gicht)

Sprechen Sie mit Ihrem Arzt, wenn Sie eines der folgenden Arzneimittel einnehmen

Cumarin-Antikoagulantien zur Verdünnung Ihres Blutes, z.B. Warfarin oder Digoxin

Arzneimittel zur Behandlung eines unregelmäßigen Herzschlages, z.B. Disopyramid oder

Chinidin

Arzneimittel zur Behandlung einer Herzinsuffizienz, z.B. Digoxin

Arzneimittel zur Behandlung von Epilepsie, z.B. Phenytoin, Valproat oder Carbamazepin

Quetiapin (ein Arzneimittel gegen Psychosen)

Theophyllin, zur Behandlung von Asthma

Benzodiazepine, die als Beruhigungsmittel eingesetzt werden, z.B. Alprazolam, Midazolam

oder Triazolam

Phenobarbital, das als Beruhigungsmittel und Krampfmittel verwendet wird

Rifabutin, Rifampicin, Rifapentin oder Aminoglykoside (z.B. Gentamicin) zur Behandlung von

einigen Infektionen

Ciclosporin, Tacrolimus oder Sirolimus, die nach Organtransplantationen verwendet werden

Arzneimittel zur Senkung des Cholesterins, z.B. Atorvastatin oder Rosuvastatin

Ritonavir, Atazanvir, Etravirin, Saquinavir, Efavirenz, Nevirapin oder Zidovudin, zur

Behandlung HIV-infizierter Patienten

Johanniskraut, zur Behandlung von Depressionen

Sildenafil, Tadalafil, Vardenafil zur Behandlung von Erektionsproblemen

Cilostazol (angewendet, um den Blutfluss in den Beinen zu verbessern)

Methylprednisolon (zur Behandlung von Entzündungen)

Vinblastin (zur Behandlung von Krebs)

Omeprazol zur Behandlung von Verdauungsstörungen

Tolterodin für die Harnhäufigkeit

Itraconazol oder Fluconazol bei Pilzinfektionen

Calcium-Kanal-Blocker, z.B. Verapamil, Amlodipin, Diltiazem (zur Behandlung von

Bluthochdruck oder Herzschlagstörungen)

Arzneimittel, die Ihren Blutzucker senken (zur Behandlung von Diabetes, z.B. Nateglinid,

Repaglinid oder Insulin)

Einnahme von Clarithromycin ratiopharm GmbH zusammen mit Nahrungsmitteln und

Getränken

Sie können Clarithromycin entweder mit oder ohne Nahrung einnehmen, je nachdem, was Sie

bevorzugen.

Schwangerschaft und Stillzeit

Wenn Sie schwanger sind oder stillen, oder wenn Sie vermuten, schwanger zu sein oder beabsichtigen,

schwanger zu werden, fragen Sie vor der Einnahme dieses Arzneimittels Ihren Arzt oder Apotheker

um Rat.

Clarithromycin ratiopharm GmbH darf nicht an schwangere oder stillende Frauen verabreicht werden,

wenn nicht der Nutzen für die Mutter die Risiken für das Baby übersteigt.

Geringe Mengen von Clarithromycin gehen in die Muttermilch über.

Verkehrstüchtigkeit und Fähigkeit zum Bedienen von Maschinen

Achtung: dieses Arzneimittel kann die Reaktionsfähigkeit und Verkehrstüchtigkeit

beeinträchtigen.

Durch Clarithromycin ratiopharm GmbH Tabletten können Sie sich müde, schwindlig oder verwirrt

fühlen. Sie dürfen sich nicht an das Steuer eines Fahrzeugs setzen und keine Maschinen bedienen,

wenn Sie betroffen sind.

Clarithromycin ratiopharm GmbH Filmtabletten enthalten Tartrazinlack und Allurarot

Aluminiumlack

Tartrazinlack (E 102) und Allurarot Aluminiumlack (E 129) können allergieartige Reaktionen

hervorrufen.

3.

Wie ist Clarithromycin ratiopharm GmbH einzunehmen?

Nehmen Sie dieses Arzneimittel immer genau nach der Absprache mit Ihrem Arzt ein. Fragen Sie bei

Ihrem Arzt oder Apotheker nach, wenn Sie sich nicht sicher sind.

Die Tabletten sollten vorzugsweise mit einem Glas Wasser geschluckt werden.

Die empfohlene Dosis beträgt:

Erwachsene, einschließlich älterer Patienten:

Bei Infektionen des Brustraumes, des Rachens oder der Nebenhöhlen, und Infektionen der

Haut und Weichteile:

Die empfohlene Dosis beträgt 250 mg zweimal täglich. Bei schweren Infektionen kann Ihr Arzt

die Dosis auf 500 mg zweimal täglich erhöhen. Die übliche Behandlungsdauer beträgt 6 bis 14

Tage. Die Behandlung sollte für mindestens 2 Tage nach Ende des Auftretens von Beschwerden

fortgesetzt werden.

Erwachsene

Zur Behandlung von Infektionen durch Helicobacter pylori verbunden mit einem

Zwölffingerdarmgeschwür:

Clarithromycin sollte, in Kombination mit anderen Arzneimitteln zur Behandlung von

Helicobacter pylori, in einer Dosis von 500 mg zweimal täglich eingenommen werden.

Ihr Arzt wird über die beste Kombinationsbehandlung für Sie entscheiden. Wenn Sie gänzlich

im Unklaren sind, welches Arzneimittel und wann es einzunehmen ist, müssen Sie mit Ihrem

Arzt sprechen.

Patienten mit Leber- oder Nierenproblemen

Wenn Sie Leberprobleme oder schwere Nierenprobleme haben, kann es notwendig sein, dass Ihr Arzt

Ihre Dosis verringert. Wenn Sie diese Probleme haben, sollte Clarithromycin nicht länger als 14 Tage

eingenommen werden.

Anwendung bei Kindern und Jugendlichen

Kinder unter 12 Jahren

Clarithromycin wird nicht empfohlen für die Anwendung bei Kindern im Alter unter 12 Jahren. Für

Kinder unter 12 Jahren stehen andere Darreichungsformen zur Verfügung, zum Beispiel in Form einer

oralen Suspension die Ihr Arzt für Kinder unter 12 Jahren verschreibt.

Kinder über 12 Jahre

Bei Infektionen des Brustraumes, des Rachens oder der Nebenhöhlen, und Infektionen der

Haut und Weichteile:

Die empfohlene Dosis beträgt 250 mg zweimal täglich. Bei schweren Infektionen kann Ihr Arzt die

Dosis auf 500 mg zweimal täglich erhöhen. Die übliche Behandlungsdauer beträgt 6 bis 14 Tage.

Die Behandlung sollte für mindestens 2 Tage nach Ende des Auftretens von Beschwerden

fortgesetzt werden.

Wenn Sie eine größere Menge Clarithromycin ratiopharm GmbH eingenommen haben als Sie

sollten

Wenn Sie (oder jemand anders) versehentlich eine größere Anzahl dieser Tabletten auf einmal

schlucken, oder wenn Sie denken, ein Kind habe eine oder mehrere Tabletten geschluckt, kontaktieren

Sie unverzüglich die Notaufnahme Ihres nächsten Krankenhauses oder Ihren Arzt.

Eine Überdosierung löst wahrscheinlich Erbrechen und Magenschmerzen aus.

Bitte nehmen Sie diese Gebrauchsinformation, jegliche verbliebene Tabletten und das Behältnis mit

sich zum Krankenhaus oder Arzt, damit diese wissen, welche Tabletten eingenommen wurden.

Wenn Sie die Einnahme von Clarithromycin ratiopharm GmbH vergessen haben

Wenn Sie die Einnahme einer Tablette vergessen haben, nehmen Sie diese ein, sobald Sie sich daran

erinnern, es sei denn, es wäre schon fast Zeit für die Einnahme der nächsten Tablette. Nehmen Sie

nicht die doppelte Menge ein, wenn Sie die vorherige Einnahme vergessen haben.

Wenn Sie die Einnahme von Clarithromycin ratiopharm GmbH abbrechen

Beenden Sie nicht die Einnahme Ihres Arzneimittels, weil Sie sich besser fühlen. Es ist wichtig, dass

Sie den verordneten Behandlungsverlauf vollenden, ansonsten kann das Problem wieder auftreten und

es kann sein, dass dieses Arzneimittel das nächste Mal weniger wirksam ist.

Wenn Sie weitere Fragen zur Einnahme dieses Arzneimittels haben, wenden Sie sich an Ihren Arzt

oder Apotheker.

4.

Welche Nebenwirkungen sind möglich?

Wie alle Arzneimittel kann Clarithromycin ratiopharm GmbH Nebenwirkungen haben, die aber nicht

bei jedem auftreten müssen.

Schwerwiegende Nebenwirkungen

Wenn Folgendes auftritt, hören Sie sofort auf Clarithromycin einzunehmen und gehen Sie sofort

zu Ihrem Arzt oder in die Notaufnahme des nächstgelegenen Krankenhauses:

Gelegentlich: kann bis zu 1 von 100 Behandelten betreffen

eine allergische Reaktion, die Schwellungen von Lippen, Gesicht, Zunge oder Rachen

hervorruft, die zu schwerer Atemnot oder schweren Haut- oder Nesselausschlägen führen

Gallenblasenprobleme (Cholestase)

Gelbfärbung der Haut (Gelbsucht), Hautreizung, heller Stuhl, dunkler Urin, druckempfindlicher

Bauch oder Appetitverlust. Diese könnten Anzeichen von Hepatitis sein (Entzündung der

Leber)

Veränderung des Herzschlags/-rhythmus (ein abnormal schneller, langsamer oder

unregelmäßiger Puls

Nicht bekannt: Häufigkeit auf Grundlage der verfügbaren Daten nicht abschätzbar

Torsades de pointes, ein lebensbedrohlicher unregelmäßiger Herzschlag

Blasenbildung von Haut, Mund, Augen und Genitalien; dies könnte durch ein Steven-Johnson-

Syndrom oder eine toxische epidermale Nekrose verursacht sein, die schwere Erkrankungen

sind.

Arzneimittelexanthem mit Eosinophilie (Erhöhung bestimmter weißer Blutzellen) und

systemischen Symptomen (DRESS)

Ein roter, schuppiger Ausschlag mit Erhebungen unter der Haut und Blasen (exanthematische

Pustulose )

Pseudomembranöse Colitis (Darminfektion mit schwerem oder längerem Durchfall, der Blut

oder Schleim enthalten kann)

Agranulozytose (ernstzunehmende Verringerung der Zahl der weißen Blutkörperchen mit einem

erhöhten Risiko für Infektionen); Diese Symptome beinhalten: erhöhte Temperatur und

Geschwüre im Mund und Rachen, unerklärliche Blutergüsse oder Blutungen

Pancreatitis (Entzündung der Bauchspeicheldrüse), Übelkeit, Erbrechen, Bauchschmerzen und

Rückenschmerzen

Anfälle

Veränderungen des Herzrhythmus (ventrikuläre Tachykardie, Kammerflimmern)

Leberversagen und Gelbsucht - Gelbfärbung von Haut und Augenweiß, mit erhöhten

Leberenzymen im Blut

Andere Nebenwirkungen:

Die folgenden Nebenwirkungen wurden mit den angegebenen annähernden Häufigkeiten berichtet:

Häufig: kann bis zu 1 von 10 Behandelten betreffen

Magenprobleme wie Übelkeit, Erbrechen, Verdauungsstörungen, Magenschmerzen oder

Durchfall

Geschmacksstörungen

Kopfschmerzen

Schlafschwierigkeiten

Veränderter Leberfunktionstest

Ausschlag, vermehrtes Schwitzen

Erweiterung der Blutgefäße (Vasodilatation)

Gelegentlich: kann bis zu 1 von 100 Behandelten betreffen

Pilzinfektionen, Vaginalinfektionen

Bluterkrankungen, wie eine Veränderung der Anzahl weißer Blutkörperchen, die Infektionen

wahrscheinlicher machen. Diese können durch Schüttelfrost, Halsentzündung, Geschwüre in

Ihrem Mund gekennzeichnet sein.

Gelenks- und Muskelschmerzen, Muskelsteifigkeit

, Muskelkrämpfe

Verlängerte Blutgerinnungszeit

, Nasenbluten

Veränderte Leber- oder Nierenfunktionstests oder Bluttests

Nesselausschlag, Juckreiz, flache , rote Stellen auf der Haut mit kleinen konfluenten

(zusammenlaufenden) Beulen bedeckt (makulopapulöser Ausschlag)

, Blasen auf der Haut, die

mit Flüssigkeit gefüllt sind (bullöse Dermatitis)

Appetitsverlust, verminderter Appetit

Angst, Nervosität

Schwindelanfall, Schläfrigkeit, Zittern (Wackeln), Bewegungsstörungen (Dyskinesie)

Schwindel (Drehschwindel), Ohrgeräusche, Hörstörung

Entzündung der Magenschleimhaut und des Dünndarms, Sodbrennen

, Blähungen,

Verstopfung, trockener Mund, Aufstoßen, Flatulenz (Winde)

, rektale Schmerzen

Entzündung der Speiseröhre (Ösophagitis)

Entzündung oder Geschwürbildung im Mund oder der Zunge, Schwächegefühl oder

Unbehagen, Bewusstseinsverlust

, allgemeines Gefühl von Unwohlsein

, Brustschmerzen,

EKG-Anomalien

Schüttelfrost, Müdigkeit, Fieber

Überempfindlichkeitsreaktionen (allergische Reaktionen)

Veränderungen verschiedener Enzyme im Blut, die sich bei einem Bluttest zeigen

Asthma

Husten und Bluthusten (Zeichen einer Lungenembolie)

Cellulitis

(Eine Infektion der Haut durch Bakterien verursacht)

Infektionen

Herzstillstand

(plötzliche Unterbrechung des Blutkreislaufes aufgrund Versagen des Herzens

wirksam zu kontrahieren)

Sehr selten: kann bis zu 1 von 10.000 Behandelten betreffen

Taubheit oder „Ameisenlaufen“ (Parästhesie)

Nicht bekannt (Häufigkeit auf Grundlage der verfügbaren Daten nicht abschätzbar)

Erysipel oder Erythrasma (Hautinfektionen)

Herabgesetzte Anzahl von Blutplättchen

Verwirrtheit, Veränderung in der Wahrnehmung von Realität und ein Gefühl von Panik,

Desorientierung, Halluzinationen

Verfärbungen der Zähne (diese können in der Regel durch professionelle Zahnreinigung

entfernt werden)

Verfärbung der Zunge

Nierenversagen, Nierenentzündung

Psychotische Störung (Geisteskrankheit), Depression, ungewöhnliche Träume, Hochgefühl

oder übermäßige Begeisterung, welche ungewöhnliches Verhalten hervorbingt

(Manie)Geschmacksverlust, Geruchssveränderung, Geruchsverlust

Hörverlust

Ungewöhnliche Blutungen oder unerklärbare Blutergüsse

Niedrige Blutzuckerspiegel oder eine „Hypo“ (Unterzucker) bei diabetischen Patienten.

Akne

Myopathie (Muskelschwäche), Rhabdomyolyse (Muskelschmerzen, Abbau von Muskelfasern)

International Normalized Ratio erhöht (verlängerte Blutgerinnungszeit)

Verlängerte Blutgerinnungszeit

Nebenwirkungen wurden nur bei bei der Darreichungsform Pulver zur Herstellung einer

Infusionslösung berichtet.

Nebenwirkungen wurden nur bei bei der Darreichungsform Tabletten mit verzögerter

Wirkstofffreisetzung.

Nebenwirkungen wurden nur bei bei der Darreichungsform Granulat zur Herstellung einer

Suspension zum Einnehmen berichtet.

Nebenwirkungen wurden nur bei bei der Darreichungsform Tabletten mit sofortiger

Wirkstofffreisetzung berichtet.

Sie können Nebenwirkungen bekommen, die Sie selbst nicht bemerken, wie beispielsweise

Veränderungen in der Zahl bestimmter Blutzellen, von anderen Blutbestandteile oder der

Leberenzyme. Ihr Arzt könnte entscheiden eine Blutuntersuchung durchzuführen um das zu

kontrollieren.

Meldung von Nebenwirkungen

Wenn Sie Nebenwirkungen bemerken, wenden Sie sich an Ihren Arzt oder Apotheker. Dies gilt auch

für Nebenwirkungen, die nicht in dieser Packungsbeilage angegeben sind. Sie können

Nebenwirkungen auch direkt über das nationale Meldesystem anzeigen:

Bundesamt für Sicherheit im Gesundheitswesen

Traisengasse 5

1200 WIEN

ÖSTERREICH

Fax: + 43 (0) 50 555 36207

Website: http://www.basg.gv.at/

Indem Sie Nebenwirkungen melden, können Sie dazu beitragen, dass mehr Informationen über die

Sicherheit dieses Arzneimittels zur Verfügung gestellt werden.

5.

Wie ist Clarithromycin ratiopharm GmbH aufzubewahren?

Bewahren Sie dieses Arzneimittel für Kinder unzugänglich auf.

Nicht über 25° C lagern. Das Behältnis im Umkarton aufbewahren. Nicht in ein anderes Behältnis

umfüllen.

Sie dürfen dieses Arzneimittel nach dem auf der Blisterpackung und dem Umkarton angegebenen

Verfalldatum nicht mehr verwenden. Das Verfalldatum bezieht sich auf den letzten Tag des

angegebenen Monats.

Entsorgen Sie Arzneimittel nicht im Abwasser oder Haushaltsabfall. Fragen Sie Ihren Apotheker, wie

das Arzneimittel zu entsorgen ist, wenn Sie es nicht mehr verwenden. Sie tragen damit zum Schutz der

Umwelt bei.

6.

Inhalt der Packung und weitere Informationen

Was Clarithromycin ratiopharm GmbH enthält

Der Wirkstoff ist: Clarithromycin. Jede Tablette enthält 500 mg Clarithromycin.

Die sonstigen Bestandteile sind: Carboxymethylstärke-Natrium, mikrokristalline Cellulose,

Povidon (PVP K-30), Magnesiumhydroxid, Croscarmellose-Natrium, hochdisperses

Siliciumdioxid, wasserfrei, Stearinsäure, Magnesiumstearat, Hypromellose (E 464), Titandioxid

(E 171), Macrogol 400, Tartrazinlack (E 102), Allurarot Aluminiumlack (E 129), Indigocarmin

(E 132) und Vanillin.

Wie Clarithromycin ratiopharm GmbH aussieht und Inhalt der Packung

Hellgelbe, ovale, Filmtablette mit der Prägung „93“ auf einer Seite und „7158“ auf der anderen.

Clarithromycin ratiopharm GmbH 500 mg ist in Packungsgrößen zu 7, 8, 10, 14, 14

(Kalenderpackung), 16, 20, 21, 30, 42 und 100 Tabletten verfügbar.

Es werden möglicherweise nicht alle Packungsgrößen in den Verkehr gebracht.

Pharmazeutischer Unternehmer

TEVA B.V.

Swensweg 5

2031 GA Haarlem

Niederlande

Tel.-Nr.: +43/1/97007-0

Fax-Nr.:+43/1/97007-66

e-mail: info@ratiopharm.at

Hersteller

Teva UK Ltd

Brampton Road, Hampden Park

Eastbourne

East Sussex

BN22 9AG

Vereinigtes Königreich

Pharmachemie B.V.

Swensweg 5

Postbus 552

2003 RN Haarlem

Niederlande

Teva Pharmaceutical Works Private Limited Company

Pallagi út 13

4042 Debrecen

Ungarn

Merckle GmbH

Ludwig-Merckle-Straβe 3

89143 Blaubeuren

Deutschland

Dieses Arzneimittel ist in den Mitgliedsstaaten des Europäischen Wirtschaftsraumes (EWR)

unter den folgenden Bezeichnungen zugelassen:

Belgien

Clarithromycine TEVA 500 mg filmomhulde tabletten

Deutschland

Clarithromycin AbZ 500 mg Filmtabletten

Italien

Claritromicina Teva 500 mg Compresse rivestite con film

Litauen

Clarithromycin-Teva 500 mg plëvele dengtos tabletës

Norwegen

Clarithromycin Teva 500 mg tabletter, filmdrasjerte

Portugal

Claritromicina Teva 500 mg Comprimidos

Tschechische Republik

Clarithromycin-Teva 500 mg

Vereinigtes Königreich

Clarithromycin 500 mg Film-coated Tablets

Z. Nr.: 1-27343

Diese Packungsbeilage wurde zuletzt überarbeitet im Februar 2018.

11-9-2018

Broschüre für den Apotheker

Broschüre für den Apotheker

Bortezomib - Bortezomib-ratiopharm® - Information für Ärzte

Deutschland - BfArM - Bundesinstitut für Arzneimittel und Medizinprodukte

11-9-2018

Poster

Poster

Bortezomib - Bortezomib-ratiopharm® - Information für Ärzte

Deutschland - BfArM - Bundesinstitut für Arzneimittel und Medizinprodukte

28-11-2018

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