Ibuprofen MK

Ibuprofen MK may be available in the countries listed below.

Ingredient matches for Ibuprofen MK

Ibuprofen

Ibuprofen is reported as an ingredient of Ibuprofen MK in the following countries:

• Romania

International Drug Name Search

Reference

Reference may be available in the countries listed below.

Ingredient matches for Reference

Gemfibrozil

Gemfibrozil is reported as an ingredient of Reference in the following countries:

• Colombia

International Drug Name Search

Klaz

Klaz may be available in the countries listed below.

Ingredient matches for Klaz

Clarithromycin

Clarithromycin is reported as an ingredient of Klaz in the following countries:

• Philippines

International Drug Name Search

Malton E

Malton E may be available in the countries listed below.

Ingredient matches for Malton E

Tocopherol, α-

Tocopherol, α- is reported as an ingredient of Malton E in the following countries:

• Germany

International Drug Name Search

Multigram

Multigram may be available in the countries listed below.

Ingredient matches for Multigram

Tetracycline

Tetracycline hydrochloride (a derivative of Tetracycline) is reported as an ingredient of Multigram in the following countries:

• Brazil

International Drug Name Search

Tredemine

Tredemine may be available in the countries listed below.

Ingredient matches for Tredemine

Niclosamide

Niclosamide is reported as an ingredient of Tredemine in the following countries:

• Greece

International Drug Name Search

PMS-Nizatidine

PMS-Nizatidine may be available in the countries listed below.

Ingredient matches for PMS-Nizatidine

Nizatidine

Nizatidine is reported as an ingredient of PMS-Nizatidine in the following countries:

• Canada

International Drug Name Search

Pénicilline bénéthamine

Pénicilline bénéthamine may be available in the countries listed below.

Ingredient matches for Pénicilline bénéthamine

Benzylpenicillin

Pénicilline bénéthamine (DCF) is also known as Benzylpenicillin (Rec.INN)

International Drug Name Search

Glossary

DCF	Dénomination Commune Française
Rec.INN	Recommended International Nonproprietary Name (World Health Organization)

Click for further information on drug naming conventions and International Nonproprietary Names.

Polimod

Polimod may be available in the countries listed below.

Ingredient matches for Polimod

Pidotimod

Pidotimod is reported as an ingredient of Polimod in the following countries:

• Greece


• Italy

International Drug Name Search

Bisacodyl PCH

Bisacodyl PCH may be available in the countries listed below.

Ingredient matches for Bisacodyl PCH

Bisacodyl

Bisacodyl is reported as an ingredient of Bisacodyl PCH in the following countries:

• Netherlands

International Drug Name Search

Tamoneprin

Tamoneprin may be available in the countries listed below.

Ingredient matches for Tamoneprin

Tamoxifen

Tamoxifen citrate (a derivative of Tamoxifen) is reported as an ingredient of Tamoneprin in the following countries:

• Romania

International Drug Name Search

Flucostan

Flucostan may be available in the countries listed below.

Ingredient matches for Flucostan

Fluconazole

Fluconazole is reported as an ingredient of Flucostan in the following countries:

• Bangladesh

International Drug Name Search

Fulcro

Fulcro may be available in the countries listed below.

Ingredient matches for Fulcro

Fenofibrate

Fenofibrate is reported as an ingredient of Fulcro in the following countries:

• Italy

International Drug Name Search

Loratadin Sandoz

Loratadin Sandoz may be available in the countries listed below.

Ingredient matches for Loratadin Sandoz

Loratadine

Loratadine is reported as an ingredient of Loratadin Sandoz in the following countries:

• Estonia


• Finland


• Germany


• Norway


• Sweden

International Drug Name Search

Tamoxifen Mylan

Tamoxifen Mylan may be available in the countries listed below.

Ingredient matches for Tamoxifen Mylan

Tamoxifen

Tamoxifen citrate (a derivative of Tamoxifen) is reported as an ingredient of Tamoxifen Mylan in the following countries:

• Belgium


• Sweden

International Drug Name Search

Gelcen

Gelcen may be available in the countries listed below.

Ingredient matches for Gelcen

Capsaicin

Capsaicin is reported as an ingredient of Gelcen in the following countries:

• Greece


• Spain

International Drug Name Search

Biso-Hennig

Biso-Hennig may be available in the countries listed below.

Ingredient matches for Biso-Hennig

Bisoprolol

Bisoprolol fumarate (a derivative of Bisoprolol) is reported as an ingredient of Biso-Hennig in the following countries:

• Germany

International Drug Name Search

Edemid

Edemid may be available in the countries listed below.

Ingredient matches for Edemid

Furosemide

Furosemide is reported as an ingredient of Edemid in the following countries:

• Bosnia & Herzegowina


• Croatia (Hrvatska)


• Slovenia


• Venezuela

International Drug Name Search

Torasemid Hexal

Torasemid Hexal may be available in the countries listed below.

Ingredient matches for Torasemid Hexal

Torasemide

Torasemide is reported as an ingredient of Torasemid Hexal in the following countries:

• Austria


• Estonia


• Germany


• Latvia


• Lithuania


• Luxembourg

International Drug Name Search

Methysilox

Methysilox may be available in the countries listed below.

In some countries, this medicine may only be approved for veterinary use.

Ingredient matches for Methysilox

Simeticone

Simeticone is reported as an ingredient of Methysilox in the following countries:

• Germany

International Drug Name Search

Amisulpride Teva

Amisulpride Teva may be available in the countries listed below.

Ingredient matches for Amisulpride Teva

Amisulpride

Amisulpride is reported as an ingredient of Amisulpride Teva in the following countries:

• France

International Drug Name Search

Chymotrypsine

Chymotrypsine may be available in the countries listed below.

Ingredient matches for Chymotrypsine

Chymotrypsin

Chymotrypsine (DCF) is known as Chymotrypsin in the US.

International Drug Name Search

Glossary

DCF	Dénomination Commune Française

Click for further information on drug naming conventions and International Nonproprietary Names.

Insulina Humulin 70 / 30

Insulina Humulin 70/30 may be available in the countries listed below.

Ingredient matches for Insulina Humulin 70/30

Insulin Injection, Biphasic Isophane

Insulin Injection, Biphasic Isophane human (a derivative of Insulin Injection, Biphasic Isophane) is reported as an ingredient of Insulina Humulin 70/30 in the following countries:

• Argentina


• Chile

International Drug Name Search

Lamepil

Lamepil may be available in the countries listed below.

Ingredient matches for Lamepil

Lamotrigine

Lamotrigine is reported as an ingredient of Lamepil in the following countries:

• Estonia


• Latvia


• Lithuania

International Drug Name Search

Coroval

Coroval may be available in the countries listed below.

Ingredient matches for Coroval

Amlodipine

Amlodipine besilate (a derivative of Amlodipine) is reported as an ingredient of Coroval in the following countries:

• Argentina

International Drug Name Search

Claritromicina Zocid

Claritromicina Zocid may be available in the countries listed below.

Ingredient matches for Claritromicina Zocid

Clarithromycin

Clarithromycin is reported as an ingredient of Claritromicina Zocid in the following countries:

• Portugal

International Drug Name Search

Ibuprofen HTP

Ibuprofen HTP may be available in the countries listed below.

Ingredient matches for Ibuprofen HTP

Ibuprofen

Ibuprofen is reported as an ingredient of Ibuprofen HTP in the following countries:

• Netherlands

International Drug Name Search

Flozul

Flozul may be available in the countries listed below.

Ingredient matches for Flozul

Lovastatin

Lovastatin is reported as an ingredient of Flozul in the following countries:

• Portugal

International Drug Name Search

Pipurin

Pipurin may be available in the countries listed below.

Ingredient matches for Pipurin

Pipemidic Acid

Pipemidic Acid trihydrate (a derivative of Pipemidic Acid) is reported as an ingredient of Pipurin in the following countries:

• Italy

International Drug Name Search

Reyataz

In the US, Reyataz (atazanavir systemic) is a member of the drug class protease inhibitors and is used to treat HIV Infection and Nonoccupational Exposure.

US matches:

• Reyataz

UK matches:

• Reyataz 150 mg, 200 mg and 300mg Hard Capsules (SPC)

Ingredient matches for Reyataz

Atazanavir

Atazanavir is reported as an ingredient of Reyataz in the following countries:

• Argentina


• Belgium


• Chile


• Colombia


• Russian Federation

Atazanavir sulfate (a derivative of Atazanavir) is reported as an ingredient of Reyataz in the following countries:

• Australia


• Austria


• Bulgaria


• Canada


• Czech Republic


• Denmark


• Finland


• France


• Germany


• Hong Kong


• Hungary


• Iceland


• Indonesia


• Ireland


• Italy


• Japan


• Luxembourg


• Mexico


• Netherlands


• New Zealand


• Norway


• Portugal


• Romania


• Singapore


• Slovakia


• Slovenia


• South Africa


• Spain


• Sweden


• Switzerland


• Taiwan


• Thailand


• United Kingdom


• United States

International Drug Name Search

Glossary

SPC	Summary of Product Characteristics (UK)

Click for further information on drug naming conventions and International Nonproprietary Names.

Hotemin

Hotemin may be available in the countries listed below.

Ingredient matches for Hotemin

Piroxicam

Piroxicam is reported as an ingredient of Hotemin in the following countries:

• Bulgaria


• Czech Republic


• Hungary


• Lithuania


• Poland


• Romania


• Slovakia


• Vietnam


• Yemen

International Drug Name Search

Paroxetina Mundogen

Paroxetina Mundogen may be available in the countries listed below.

Ingredient matches for Paroxetina Mundogen

Paroxetine

Paroxetine hydrochloride (a derivative of Paroxetine) is reported as an ingredient of Paroxetina Mundogen in the following countries:

• Spain

International Drug Name Search

Acido Alendronico Sandoz

Acido Alendronico Sandoz may be available in the countries listed below.

Ingredient matches for Acido Alendronico Sandoz

Alendronic Acid

Alendronic Acid is reported as an ingredient of Acido Alendronico Sandoz in the following countries:

• Portugal

International Drug Name Search

Azibiot

Azibiot may be available in the countries listed below.

Ingredient matches for Azibiot

Azithromycin

Azithromycin is reported as an ingredient of Azibiot in the following countries:

• Bulgaria


• Croatia (Hrvatska)

Azithromycin dihydrate (a derivative of Azithromycin) is reported as an ingredient of Azibiot in the following countries:

• Mexico


• Poland


• Slovenia

International Drug Name Search

Bemetrazole

Bemetrazole may be available in the countries listed below.

Ingredient matches for Bemetrazole

Metronidazole

Metronidazole is reported as an ingredient of Bemetrazole in the following countries:

• South Africa

International Drug Name Search

Folicron

Folicron may be available in the countries listed below.

Ingredient matches for Folicron

Ferrous Sulfate

Ferrous Sulfate is reported as an ingredient of Folicron in the following countries:

• Bahrain


• Oman

Folic Acid

Folic Acid is reported as an ingredient of Folicron in the following countries:

• Bahrain


• Oman

Metoclopramide

Metoclopramide is reported as an ingredient of Folicron in the following countries:

• Japan

International Drug Name Search

Iwacohol E

Iwacohol E may be available in the countries listed below.

Ingredient matches for Iwacohol E

Chlorhexidine

Chlorhexidine digluconate (a derivative of Chlorhexidine) is reported as an ingredient of Iwacohol E in the following countries:

• Japan

International Drug Name Search

Adalat SL

Adalat SL may be available in the countries listed below.

Ingredient matches for Adalat SL

Nifedipine

Nifedipine is reported as an ingredient of Adalat SL in the following countries:

• Georgia


• Russian Federation

International Drug Name Search

Isosorbide Mononitrate Schwarz

Isosorbide Mononitrate Schwarz may be available in the countries listed below.

Ingredient matches for Isosorbide Mononitrate Schwarz

Isosorbide Mononitrate

Isosorbide Mononitrate is reported as an ingredient of Isosorbide Mononitrate Schwarz in the following countries:

• Singapore

International Drug Name Search

Glycol Salicylate

Scheme

JAN

CAS registry number (Chemical Abstracts Service)

0000087-28-5

Chemical Formula

C9-H10-O4

Molecular Weight

182

Therapeutic Categories

Analgesic, antipyretic and anti-inflammatory agent

Non-steroidal anti-inflammatory drug, NSAID

Antirheumatic agent, topical

Chemical Name

Benzoic acid, 2-hydroxy-, 2-hydroxyethyl ester

Foreign Names

• Ethylenglycoli salicylas (Latin)
• Hydroxyethylsalicylat (German)
• Hydroxyéthyle (salicylate d') (French)

Generic Names

• Ethylenglycoli salicylas (IS)
• Ethylenglycolsalicylat (IS)
• GL-7 (IS)
• Glysal (IS)
• Spirosal (IS)
• Hydroxyethyl Salicylate (PH: BP 2010, Ph. Eur. 6)
• Hydroxyéthyle (salicylate d') (PH: Ph. Eur. 6)
• Hydroxyethylis salicylas (PH: Ph. Eur. 6)
• Hydroxyethylsalicylat (PH: Ph. Eur. 6)

Brand Names

• Balsamo Sifcamina (Glycol Salicylate and Nicotinic Acid)
  Teofarma, Italy



• Cortisal (Glycol Salicylate and Prednisolone)
  Dexo, France



• Dolo-Arthrosenex
  Riemser, Germany



• Salhumin
  Bastian, Germany

International Drug Name Search

Glossary

IS	Inofficial Synonym
JAN	Japanese Accepted Name
PH	Pharmacopoeia Name

Click for further information on drug naming conventions and International Nonproprietary Names.

Rinelon Nasal

Rinelon Nasal may be available in the countries listed below.

Ingredient matches for Rinelon Nasal

Mometasone

Mometasone 17-(2-furoate) (a derivative of Mometasone) is reported as an ingredient of Rinelon Nasal in the following countries:

• Spain

International Drug Name Search

Gastrofrenal

Gastrofrenal may be available in the countries listed below.

Ingredient matches for Gastrofrenal

Cromoglicic Acid

Cromoglicic Acid disodium salt (a derivative of Cromoglicic Acid) is reported as an ingredient of Gastrofrenal in the following countries:

• Italy

International Drug Name Search

Inexium Orifarm

Inexium Orifarm may be available in the countries listed below.

Ingredient matches for Inexium Orifarm

Esomeprazole

Esomeprazole magnesium, trihydrate (a derivative of Esomeprazole) is reported as an ingredient of Inexium Orifarm in the following countries:

• Denmark

International Drug Name Search

Mefacit

Mefacit may be available in the countries listed below.

Ingredient matches for Mefacit

Mefenamic Acid

Mefenamic Acid is reported as an ingredient of Mefacit in the following countries:

• Poland

International Drug Name Search

Passagen

Passagen may be available in the countries listed below.

Ingredient matches for Passagen

Xylometazoline

Xylometazoline hydrochloride (a derivative of Xylometazoline) is reported as an ingredient of Passagen in the following countries:

• Denmark

International Drug Name Search

Calcort

Calcort may be available in the countries listed below.

UK matches:

• Calcort 1mg, 6mg and 30mg
• Calcort 6mg Tablets (SPC)

Ingredient matches for Calcort

Deflazacort

Deflazacort is reported as an ingredient of Calcort in the following countries:

• Antigua & Barbuda


• Aruba


• Bahamas


• Barbados


• Bermuda


• Brazil


• Cayman Islands


• Costa Rica


• Dominican Republic


• Ecuador


• El Salvador


• Germany


• Guatemala


• Guyana


• Haiti


• Honduras


• Jamaica


• Luxembourg


• Mexico


• Netherlands Antilles


• Nicaragua


• Panama


• Peru


• Saint Lucia


• Saint Vincent & The Grenadines


• Switzerland


• Trinidad & Tobago


• United Kingdom


• Venezuela

International Drug Name Search

Glossary

SPC	Summary of Product Characteristics (UK)

Click for further information on drug naming conventions and International Nonproprietary Names.

Roxyrol

Roxyrol may be available in the countries listed below.

Ingredient matches for Roxyrol

Roxithromycin

Roxithromycin is reported as an ingredient of Roxyrol in the following countries:

• India

International Drug Name Search

RutinaC

RutinaC may be available in the countries listed below.

Ingredient matches for RutinaC

Ascorbic Acid

Ascorbic Acid is reported as an ingredient of RutinaC in the following countries:

• Poland

Rutoside

Rutoside is reported as an ingredient of RutinaC in the following countries:

• Poland

International Drug Name Search

Metformine Biogaran

Metformine Biogaran may be available in the countries listed below.

Ingredient matches for Metformine Biogaran

Metformin

Metformin hydrochloride (a derivative of Metformin) is reported as an ingredient of Metformine Biogaran in the following countries:

• France

International Drug Name Search

Pro Ampi

Pro Ampi may be available in the countries listed below.

Ingredient matches for Pro Ampi

Pivampicillin

Pivampicillin is reported as an ingredient of Pro Ampi in the following countries:

• Luxembourg

International Drug Name Search

Melitracen Hydrochloride

Melitracen Hydrochloride may be available in the countries listed below.

Ingredient matches for Melitracen Hydrochloride

Melitracen

Melitracen Hydrochloride (USAN) is also known as Melitracen (Rec.INN)

International Drug Name Search

Glossary

Rec.INN	Recommended International Nonproprietary Name (World Health Organization)
USAN	United States Adopted Name

Click for further information on drug naming conventions and International Nonproprietary Names.

KSR

KSR may be available in the countries listed below.

Ingredient matches for KSR

Potassium Chloride

Potassium Chloride is reported as an ingredient of KSR in the following countries:

• Indonesia

International Drug Name Search

Riketron

Riketron may be available in the countries listed below.

In some countries, this medicine may only be approved for veterinary use.

Ingredient matches for Riketron

Sulfadimidine

Sulfadimidine sodium salt (a derivative of Sulfadimidine) is reported as an ingredient of Riketron in the following countries:

• Austria


• Germany

Trimethoprim

Trimethoprim is reported as an ingredient of Riketron in the following countries:

• Austria


• Germany

International Drug Name Search

Apo-Clobazam

Apo-Clobazam may be available in the countries listed below.

Ingredient matches for Apo-Clobazam

Clobazam

Clobazam is reported as an ingredient of Apo-Clobazam in the following countries:

• Canada

International Drug Name Search

Bezachole

Bezachole may be available in the countries listed below.

Ingredient matches for Bezachole

Bezafibrate

Bezafibrate is reported as an ingredient of Bezachole in the following countries:

• South Africa

International Drug Name Search

Tiroxin

Tiroxin may be available in the countries listed below.

Ingredient matches for Tiroxin

Levothyroxine

Levothyroxine sodium salt (a derivative of Levothyroxine) is reported as an ingredient of Tiroxin in the following countries:

• Colombia

International Drug Name Search

Co-Beneldopa

Co-Beneldopa may be available in the countries listed below.

Ingredient matches for Co-Beneldopa

Benserazide

Benserazide hydrochloride (a derivative of Benserazide) is reported as an ingredient of Co-Beneldopa in the following countries:

• United Kingdom

Levodopa

Levodopa is reported as an ingredient of Co-Beneldopa in the following countries:

• United Kingdom

International Drug Name Search

Glipressina

Glipressina may be available in the countries listed below.

Ingredient matches for Glipressina

Terlipressin

Terlipressin diacetate (a derivative of Terlipressin) is reported as an ingredient of Glipressina in the following countries:

• Italy

International Drug Name Search

Fénofibrate Zydus

Fénofibrate Zydus may be available in the countries listed below.

Ingredient matches for Fénofibrate Zydus

Fenofibrate

Fenofibrate is reported as an ingredient of Fénofibrate Zydus in the following countries:

• France

International Drug Name Search

Polyod

Polyod may be available in the countries listed below.

Ingredient matches for Polyod

Povidone Iodine

Povidone-Iodine is reported as an ingredient of Polyod in the following countries:

• Turkey

International Drug Name Search

Acivir

Acivir may be available in the countries listed below.

Ingredient matches for Acivir

Acyclovir

Aciclovir is reported as an ingredient of Acivir in the following countries:

• Australia


• Denmark


• Ethiopia


• India


• Israel


• Japan


• Latvia


• Oman


• Switzerland

Aciclovir sodium salt (a derivative of Aciclovir) is reported as an ingredient of Acivir in the following countries:

• Germany

International Drug Name Search

Levobac

Levobac may be available in the countries listed below.

Ingredient matches for Levobac

Levofloxacin

Levofloxacin is reported as an ingredient of Levobac in the following countries:

• Bangladesh

International Drug Name Search

Pravastatina Normon

Pravastatina Normon may be available in the countries listed below.

Ingredient matches for Pravastatina Normon

Pravastatin

Pravastatin is reported as an ingredient of Pravastatina Normon in the following countries:

• Spain

International Drug Name Search

Gastrosedol

Gastrosedol may be available in the countries listed below.

Ingredient matches for Gastrosedol

Ranitidine

Ranitidine hydrochloride (a derivative of Ranitidine) is reported as an ingredient of Gastrosedol in the following countries:

• Argentina

International Drug Name Search

Escar-T

Escar-T may be available in the countries listed below.

Ingredient matches for Escar-T

Neomycin

Neomycin is reported as an ingredient of Escar-T in the following countries:

• Peru

International Drug Name Search

Katrasic

Katrasic may be available in the countries listed below.

Ingredient matches for Katrasic

Tramadol

Tramadol hydrochloride (a derivative of Tramadol) is reported as an ingredient of Katrasic in the following countries:

• Indonesia

International Drug Name Search

Miravelle

Miravelle may be available in the countries listed below.

Ingredient matches for Miravelle

Desogestrel

Desogestrel is reported as an ingredient of Miravelle in the following countries:

• Colombia

Ethinylestradiol

Ethinylestradiol is reported as an ingredient of Miravelle in the following countries:

• Colombia

International Drug Name Search

Kétoconazole Sandoz

Kétoconazole Sandoz may be available in the countries listed below.

Ingredient matches for Kétoconazole Sandoz

Ketoconazole

Ketoconazole is reported as an ingredient of Kétoconazole Sandoz in the following countries:

• France

International Drug Name Search

Enalapril Helvepharm

Enalapril Helvepharm may be available in the countries listed below.

Ingredient matches for Enalapril Helvepharm

Enalapril

Enalapril maleate (a derivative of Enalapril) is reported as an ingredient of Enalapril Helvepharm in the following countries:

• Switzerland

International Drug Name Search

Perdix

Perdix may be available in the countries listed below.

UK matches:

• Perdix 7.5 mg and 15 mg
• Perdix 15 mg film-coated tablets (SPC)
• Perdix 7.5 mg film-coated tablets (SPC)

Ingredient matches for Perdix

Moexipril

Moexipril hydrochloride (a derivative of Moexipril) is reported as an ingredient of Perdix in the following countries:

• Israel


• Oman


• United Kingdom

International Drug Name Search

Glossary

SPC	Summary of Product Characteristics (UK)

Click for further information on drug naming conventions and International Nonproprietary Names.

Lucebanol

Lucebanol may be available in the countries listed below.

Ingredient matches for Lucebanol

Idebenone

Idebenone is reported as an ingredient of Lucebanol in the following countries:

• Mexico

International Drug Name Search

Promet

Promet may be available in the countries listed below.

Ingredient matches for Promet

Cimetidine

Cimetidine is reported as an ingredient of Promet in the following countries:

• Myanmar


• Thailand

Metoclopramide

Metoclopramide is reported as an ingredient of Promet in the following countries:

• India

International Drug Name Search

Alfuzosine EG L. P

Alfuzosine EG L.P. may be available in the countries listed below.

Ingredient matches for Alfuzosine EG L.P.

Alfuzosin

Alfuzosin hydrochloride (a derivative of Alfuzosin) is reported as an ingredient of Alfuzosine EG L.P. in the following countries:

• France

International Drug Name Search

Fosen

Fosen may be available in the countries listed below.

Ingredient matches for Fosen

Sodium Phosphate

Sodium Phosphate Dibasic (a derivative of Sodium Phosphate) is reported as an ingredient of Fosen in the following countries:

• Indonesia

Sodium Phosphate Monobasic (a derivative of Sodium Phosphate) is reported as an ingredient of Fosen in the following countries:

• Indonesia

International Drug Name Search

Clo-Kit

Clo-Kit may be available in the countries listed below.

Ingredient matches for Clo-Kit

Chloroquine

Chloroquine phosphate (a derivative of Chloroquine) is reported as an ingredient of Clo-Kit in the following countries:

• India

International Drug Name Search

Lincohem

Lincohem may be available in the countries listed below.

Ingredient matches for Lincohem

Lincomycin

Lincomycin is reported as an ingredient of Lincohem in the following countries:

• Serbia

International Drug Name Search

Fexofenadine Ratiopharm

Fexofenadine Ratiopharm may be available in the countries listed below.

Ingredient matches for Fexofenadine Ratiopharm

Fexofenadine

Fexofenadine hydrochloride (a derivative of Fexofenadine) is reported as an ingredient of Fexofenadine Ratiopharm in the following countries:

• Netherlands

International Drug Name Search

Cromogen Easi-Breath

Cromogen Easi-Breath may be available in the countries listed below.

Ingredient matches for Cromogen Easi-Breath

Cromoglicic Acid

Cromoglicic Acid disodium salt (a derivative of Cromoglicic Acid) is reported as an ingredient of Cromogen Easi-Breath in the following countries:

• Ireland

International Drug Name Search

Regumate

Regumate may be available in the countries listed below.

In some countries, this medicine may only be approved for veterinary use.

Ingredient matches for Regumate

Altrenogest

Altrenogest is reported as an ingredient of Regumate in the following countries:

• Australia


• Austria


• Belgium


• Finland


• France


• Germany


• Ireland


• Italy


• Luxembourg


• Netherlands


• New Zealand


• Portugal


• South Africa


• Switzerland


• United Kingdom

International Drug Name Search

Teraumon

Teraumon may be available in the countries listed below.

Ingredient matches for Teraumon

Terazosin

Terazosin hydrochloride (a derivative of Terazosin) is reported as an ingredient of Teraumon in the following countries:

• Latvia


• Spain


• Turkey

International Drug Name Search

Hinews

Hinews may be available in the countries listed below.

Ingredient matches for Hinews

Clemastine

Clemastine fumarate (a derivative of Clemastine) is reported as an ingredient of Hinews in the following countries:

• Japan

International Drug Name Search

Hartil

Hartil may be available in the countries listed below.

Ingredient matches for Hartil

Ramipril

Ramipril is reported as an ingredient of Hartil in the following countries:

• Czech Republic


• Georgia


• Hungary


• Latvia


• Lithuania


• Romania


• Russian Federation


• Slovakia

International Drug Name Search

Azeclear

Azeclear may be available in the countries listed below.

Ingredient matches for Azeclear

Azelaic Acid

Azelaic Acid is reported as an ingredient of Azeclear in the following countries:

• Oman

International Drug Name Search

Atropine Sulfate Fuso

Atropine Sulfate Fuso may be available in the countries listed below.

Ingredient matches for Atropine Sulfate Fuso

Atropine

Atropine sulfate (a derivative of Atropine) is reported as an ingredient of Atropine Sulfate Fuso in the following countries:

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International Drug Name Search

Rapamune

1. Name Of The Medicinal Product

Rapamune^® 0.5 mg coated tablets

Rapamune^® 1 mg coated tablets

Rapamune^® 2 mg coated tablets

Rapamune^® 1 mg/ml oral solution

2. Qualitative And Quantitative Composition

Each 0.5 mg coated tablet contains 0.5 mg sirolimus.

Each 1 mg coated tablet contains 1 mg sirolimus.

Each 2 mg coated tablet contains 2 mg sirolimus.

Each ml contains 1 mg sirolimus.

Each 60 ml bottle contains 60 mg sirolimus.

Excipients:

Rapamune Tablets:

Each 0.5 mg tablet contains 86.4 mg of lactose monohydrate and 215.7 mg of sucrose.

Each 1 mg tablet contains 86.4 mg of lactose monohydrate and 215.8 mg of sucrose.

Each 2 mg tablet contains 86.4 mg of lactose monohydrate and 214.4 mg of sucrose.

Rapamune Oral Solution:

Each ml contains 20 mg of ethanol and 20 mg of soya oil.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Coated tablet (tablet).

0.5 mg: Tan-coloured, triangular-shaped coated tablet marked "RAPAMUNE 0.5 mg" on one side.

1 mg: White-coloured, triangular-shaped coated tablet marked "RAPAMUNE 1 mg" on one side.

2 mg: Yellow to beige-coloured, triangular-shaped coated tablet marked "RAPAMUNE 2 mg" on one side.

or

Oral solution.

Pale yellow to yellow solution

4. Clinical Particulars

4.1 Therapeutic Indications

Rapamune is indicated for the prophylaxis of organ rejection in adult patients at low to moderate immunological risk receiving a renal transplant. It is recommended that Rapamune be used initially in combination with ciclosporin microemulsion and corticosteroids for 2 to 3 months. Rapamune may be continued as maintenance therapy with corticosteroids only if ciclosporin microemulsion can be progressively discontinued (see sections 4.2 and 5.1).

4.2 Posology And Method Of Administration

Treatment should be initiated by and remain under the guidance of an appropriately qualified specialist in transplantation.

Posology

Initial therapy (2 to 3 months post-transplantation)

The usual dose regimen for Rapamune is a 6 mg single oral loading dose, administered as soon as possible after transplantation, followed by 2 mg once daily until results of therapeutic monitoring of the medicinal product are available (see Therapeutic monitoring of the medicinal product and dose adjustment). The Rapamune dose should then be individualised to obtain whole blood trough levels of 4 to 12 ng/ml (chromatographic assay). Rapamune therapy should be optimised with a tapering regimen of steroids and ciclosporin microemulsion. Suggested ciclosporin trough concentration ranges for the first 2-3 months after transplantation are 150-400 ng/ml (monoclonal assay or equivalent technique) (see section 4.5).

To minimise variability, Rapamune should be taken at the same time in relation to ciclosporin, 4 hours after the ciclosporin dose, and consistently either with or without food (see section 5.2).

Maintenance therapy

Ciclosporin should be progressively discontinued over 4 to 8 weeks, and the Rapamune dose should be adjusted to obtain whole blood trough levels of 12 to 20 ng/ml (chromatographic assay; see Therapeutic monitoring of the medicinal product and dose adjustment). Rapamune should be given with corticosteroids. In patients for whom ciclosporin withdrawal is either unsuccessful or cannot be attempted, the combination of ciclosporin and Rapamune should not be maintained for more than 3 months post-transplantation. In such patients, when clinically appropriate, Rapamune should be discontinued and an alternative immunosuppressive regimen instituted.

Therapeutic monitoring of the medicinal product and dose adjustment

Whole blood sirolimus levels should be closely monitored in the following populations:

(1) in patients with hepatic impairment

(2) when inducers or inhibitors of CYP3A4 are concurrently administered and after their discontinuation (see section 4.5) and/or

(3) if ciclosporin dosing is markedly reduced or discontinued, as these populations are most likely to have special dosing requirements.

Therapeutic monitoring of the medicinal product should not be the sole basis for adjusting sirolimus therapy. Careful attention should be made to clinical signs/symptoms, tissue biopsies, and laboratory parameters.

Most patients who received 2 mg of Rapamune 4 hours after ciclosporin had whole blood trough concentrations of sirolimus within the 4 to 12 ng/ml target range (expressed as chromatographic assay values). Optimal therapy requires therapeutic concentration monitoring of the medicinal product in all patients.

Optimally, adjustments in Rapamune dose should be based on more than a single trough level obtained more than 5 days after a previous dosing change.

Patients can be switched from Rapamune oral solution to the tablet formulation on a mg per mg basis. It is recommended that a trough concentration be taken 1 or 2 weeks after switching formulations or tablet strength to confirm that the trough concentration is within the recommended target range.

Following the discontinuation of ciclosporin therapy, a target trough range of 12 to 20 ng/ml (chromatographic assay) is recommended. Ciclosporin inhibits the metabolism of sirolimus, and consequently sirolimus levels will decrease when ciclosporin is discontinued, unless the sirolimus dose is increased. On average, the sirolimus dose will need to be 4-fold higher to account for both the absence of the pharmacokinetic interaction (2-fold increase) and the augmented immunosuppressive requirement in the absence of ciclosporin (2-fold increase). The rate at which the dose of sirolimus is increased should correspond to the rate of ciclosporin elimination.

If further dose adjustment(s) are required during maintenance therapy (after discontinuation of ciclosporin), in most patients these adjustments can be based on simple proportion: new Rapamune dose = current dose x (target concentration/current concentration). A loading dose should be considered in addition to a new maintenance dose when it is necessary to considerably increase sirolimus trough concentrations: Rapamune loading dose = 3 x (new maintenance dose - current maintenance dose). The maximum Rapamune dose administered on any day should not exceed 40 mg. If an estimated daily dose exceeds 40 mg due to the addition of a loading dose, the loading dose should be administered over 2 days. Sirolimus trough concentrations should be monitored at least 3 to 4 days after a loading dose(s).

The recommended 24-hour trough concentration ranges for sirolimus are based on chromatographic methods. Several assay methodologies have been used to measure the whole blood concentrations of sirolimus. Currently in clinical practice, sirolimus whole blood concentrations are being measured by both chromatographic and immunoassay methodologies. The concentration values obtained by these different methodologies are not interchangeable. All sirolimus concentrations reported in this Summary of Product Characteristics were either measured using chromatographic methods or have been converted to chromatographic method equivalents. Adjustments to the targeted range should be made according to the assay being utilised to determine the sirolimus trough concentrations. Since results are assay and laboratory dependent, and the results may change over time, adjustment to the targeted therapeutic range must be made with a detailed knowledge of the site-specific assay used. Physicians should therefore remain continuously informed by responsible representatives for their local laboratory on the performance of the locally used method for concentration determination of sirolimus.

Special populations

Black population

There is limited information indicating that Black renal transplant recipients (predominantly African-American) require higher doses and trough levels of sirolimus to achieve the same efficacy as observed in non-Black patients. Currently, the efficacy and safety data are too limited to allow specific recommendations for use of sirolimus in Black recipients.

Elderly population (above 65 years)

Clinical studies with Rapamune oral solution did not include a sufficient number of patients above 65 years of age to determine whether they will respond differently than younger patients (see section 5.2).

Renal impairment

No dose adjustment is required (see section 5.2).

Hepatic impairment

The clearance of sirolimus may be reduced in patients with impaired hepatic function (see section 5.2). In patients with severe hepatic impairment, it is recommended that the maintenance dose of Rapamune be reduced by approximately one-half.

It is recommended that sirolimus whole blood trough levels be closely monitored in patients with impaired hepatic function (see Therapeutic monitoring of the medicinal product and dose adjustment). It is not necessary to modify the Rapamune loading dose.

In patients with severe hepatic impairment, monitoring should be performed every 5 to 7 days until 3 consecutive trough levels have shown stable concentrations of sirolimus after dose adjustment or after loading dose due to the delay in reaching steady-state because of the prolonged half-life.

Paediatric population

The safety and efficacy of Rapamune in children and adolescents less than 18 years of age have not been established. Currently available data are described in sections 4.8, 5.1 and 5.2, but no recommendation on a posology can be made.

Method of administration

Rapamune is for oral use only.

Bioavailability has not been determined for tablets after they have been crushed, chewed or split, and therefore this cannot be recommended.

To minimise variability, Rapamune should consistently be taken either with or without food.

Grapefruit juice should be avoided (see section 4.5).

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

Multiples of 0.5 mg tablets should not be used as a substitute for the 1 mg tablet or for other strengths (see section 5.2).

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.

Rapamune oral solution contains soya oil. Patients allergic to peanut or soya must not take this medicine.

4.4 Special Warnings And Precautions For Use

Rapamune has not been adequately studied in patients at high immunological risk, therefore use is not recommended in this group of patients (see section 5.1).

In patients with delayed graft function, sirolimus may delay recovery of renal function.

Hypersensitivity reactions

Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, angioedema, exfoliative dermatitis, and hypersensitivity vasculitis, have been associated with the administration of sirolimus (see section 4.8).

Concomitant therapy

Immunosuppressive agents

Sirolimus has been administered concurrently with the following agents in clinical studies: tacrolimus, ciclosporin, azathioprine, mycophenolate mofetil, corticosteroids and cytotoxic antibodies. Sirolimus in combination with other immunosuppressive agents has not been extensively investigated.

Renal function should be monitored during concomitant administration of Rapamune and ciclosporin. Appropriate adjustment of the immunosuppression regimen should be considered in patients with elevated serum creatinine levels. Caution should be exercised when co-administering other agents that are known to have a deleterious effect on renal function.

Patients treated with ciclosporin and Rapamune beyond 3 months had higher serum creatinine levels and lower calculated glomerular filtration rates compared to patients treated with ciclosporin and placebo or azathioprine controls. Patients who were successfully withdrawn from ciclosporin had lower serum creatinine levels and higher calculated glomerular filtration rates, as well as lower incidence of malignancy, compared to patients remaining on ciclosporin. The continued co-administration of ciclosporin and Rapamune as maintenance therapy cannot be recommended.

Based on information from subsequent clinical studies, the use of Rapamune, mycophenolate mofetil, and corticosteroids, in combination with IL-2 receptor antibody (IL2R Ab) induction, is not recommended in the de novo renal transplant setting (see section 5.1).

Periodic quantitative monitoring of urinary protein excretion is recommended. In a study evaluating conversion from calcineurin inhibitors to Rapamune in maintenance renal transplant patients, increased urinary protein excretion was commonly observed at 6 to 24 months after conversion to Rapamune (see section 5.1). New onset nephrosis (nephrotic syndrome) was also reported in 2% of the patients in the study (see section 4.8). The safety and efficacy of conversion from calcineurin inhibitors to Rapamune in maintenance renal transplant patients have not been established.

The concomitant use of Rapamune with a calcineurin inhibitor may increase the risk of calcineurin inhibitor-induced haemolytic uraemic syndrome/thrombotic thrombocytopaenic purpura/thrombotic microangiopathy (HUS/TTP/TMA).

HMG-CoA reductase inhibitors

In clinical studies, the concomitant administration of Rapamune and HMG-CoA reductase inhibitors and/or fibrates was well-tolerated. During Rapamune therapy with or without CsA, patients should be monitored for elevated lipids, and patients administered an HMG-CoA reductase inhibitor and/or fibrate should be monitored for the possible development of rhabdomyolysis and other adverse reactions, as described in the respective Summary of Product Characteristics of these agents.

Cytochrome P450 isozymes

Co-administration of sirolimus with strong inhibitors of CYP3A4 (such as ketoconazole, voriconazole, itraconazole, telithromycin or clarithromycin) or inducers of CYP3A4 (such as rifampin, rifabutin) is not recommended (see section 4.5).

Angiotensin-converting enzyme inhibitors (ACE)

The concomitant administration of sirolimus and angiotensin-converting enzyme inhibitors has resulted in angioneurotic oedema-type reactions.

Vaccination

Immunosuppressants may affect response to vaccination. During treatment with immunosuppressants, including Rapamune, vaccination may be less effective. The use of live vaccines should be avoided during treatment with Rapamune.

Malignancy

Increased susceptibility to infection and the possible development of lymphoma and other malignancies, particularly of the skin, may result from immunosuppression (see section 4.8). As usual for patients with increased risk for skin cancer, exposure to sunlight and UV light should be limited by wearing protective clothing and using a sunscreen with a high protection factor.

Infections

Oversuppression of the immune system can also increase susceptibility to infection, including opportunistic infections (bacterial, fungal, viral and protozoal), fatal infections, and sepsis.

Among these conditions are BK virus-associated nephropathy and JC virus-associated progressive multifocal leukoencephalopathy (PML). These infections are often related to a high total immunosuppressive burden and may lead to serious or fatal conditions that physicians should consider in the differential diagnosis in immunosuppressed patients with deteriorating renal function or neurological symptoms.

Cases of Pneumocystis carinii pneumonia have been reported in patients not receiving antimicrobial prophylaxis. Therefore, antimicrobial prophylaxis for Pneumocystis carinii pneumonia should be administered for the first 12 months following transplantation.

Cytomegalovirus (CMV) prophylaxis is recommended for 3 months after transplantation, particularly for patients at increased risk for CMV disease.

Hepatic impairment

In hepatically impaired patients, it is recommended that sirolimus whole blood trough levels be closely monitored. In patients with severe hepatic impairment, reduction in maintenance dose by one half is recommended based on decreased clearance (see sections 4.2 and 5.2). Since half-life is prolonged in these patients, therapeutic monitoring of the medicinal product after a loading dose or a change of dose should be performed for a prolonged period of time until stable concentrations are reached (see sections 4.2 and 5.2).

Lung and liver transplant populations

The safety and efficacy of Rapamune as immunosuppressive therapy have not been established in liver or lung transplant patients, and therefore such use is not recommended.

In two clinical studies in de novo liver transplant patients, the use of sirolimus plus ciclosporin or tacrolimus was associated with an increase in hepatic artery thrombosis, mostly leading to graft loss or death.

A clinical study in liver transplant patients randomised to conversion from a calcineurin inhibitor (CNI)-based regimen to a sirolimus-based regimen versus continuation of a CNI-based regimen 6-144 months post-liver transplantation failed to demonstrate superiority in baseline-adjusted GFR at 12 months (-4.45 ml/min and -3.07 ml/min, respectively). The study also failed to demonstrate non-inferiority of the rate of combined graft loss, missing survival data, or death for the sirolimus conversion group compared to the CNI continuation group. The rate of death in the sirolimus conversion group was higher than the CNI continuation group, although the rates were not significantly different. The rates of premature study discontinuation, adverse events overall (and infections, specifically), and biopsy-proven acute liver graft rejection at 12 months were all significantly greater in the sirolimus conversion group compared to the CNI continuation group.

Cases of bronchial anastomotic dehiscence, most fatal, have been reported in de novo lung transplant patients when sirolimus has been used as part of an immunosuppressive regimen.

Systemic effects

There have been reports of impaired or delayed wound healing in patients receiving Rapamune, including lymphocele and wound dehiscence. Patients with a body mass index (BMI) greater than 30 kg/m² may be at increased risk of abnormal wound healing based on data from the medical literature.

There have also been reports of fluid accumulation, including peripheral oedema, lymphoedema, pleural effusion and pericardial effusions (including haemodynamically significant effusions in children and adults), in patients receiving Rapamune.

The use of Rapamune in renal transplant patients was associated with increased serum cholesterol and triglycerides that may require treatment. Patients administered Rapamune should be monitored for hyperlipidaemia using laboratory tests and if hyperlipidaemia is detected, subsequent interventions such as diet, exercise, and lipid-lowering agents should be initiated. The risk/benefit should be considered in patients with established hyperlipidaemia before initiating an immunosuppressive regimen, including Rapamune. Similarly the risk/benefit of continued Rapamune therapy should be re-evaluated in patients with severe refractory hyperlipidaemia.

Sucrose and lactose

Sirolimus tablets contain sucrose and lactose.

Sucrose

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

Lactose

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Ethanol

Rapamune oral solution contains up to 2.5 vol % ethanol (alcohol). A 6 mg loading dose contains up to 150 mg of alcohol which is equivalent to 3 ml beer or 1.25 ml wine. This dose could potentially be harmful for those suffering from alcoholism and should be taken into account in children and high-risk groups such as patients with liver disease or epilepsy.

Maintenance doses of 4 mg or less contain small amounts of ethanol (100 mg or less) that are likely to be too low to be harmful.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Sirolimus is extensively metabolised by the CYP3A4 isozyme in the intestinal wall and liver. Sirolimus is also a substrate for the multidrug efflux pump, P-glycoprotein (P-gp) located in the small intestine. Therefore, absorption and the subsequent elimination of sirolimus may be influenced by substances that affect these proteins. Inhibitors of CYP3A4 (such as ketoconazole, voriconazole, itraconazole, telithromycin, or clarithromycin) decrease the metabolism of sirolimus and increase sirolimus levels. Inducers of CYP3A4 (such as rifampin or rifabutin) increase the metabolism of sirolimus and decrease sirolimus levels. Co-administration of sirolimus with strong inhibitors of CYP3A4 or inducers of CYP3A4 is not recommended (see section 4.4).

Rifampicin (CYP3A4 inducer)

Administration of multiple doses of rifampicin decreased sirolimus whole blood concentrations following a single 10 mg dose of Rapamune oral solution. Rifampicin increased the clearance of sirolimus by approximately 5.5-fold and decreased AUC and C_max by approximately 82% and 71%, respectively. Co-administration of sirolimus and rifampicin is not recommended (see section 4.4).

Ketoconazole (CYP3A4 inhibitor)

Multiple-dose ketoconazole administration significantly affected the rate and extent of absorption and sirolimus exposure from Rapamune oral solution as reflected by increases in sirolimus C_max, t_max, and AUC of 4.4-fold, 1.4-fold, and 10.9-fold, respectively. Co-administration of sirolimus and ketoconazole is not recommended (see section 4.4).

Voriconazole (CYP3A4 inhibitor)

Co-administration of sirolimus (2 mg single dose) with multiple-dose administration of oral voriconazole (400 mg every 12 hours for 1 day, then 100 mg every 12 hours for 8 days) in healthy subjects has been reported to increase sirolimus C_max and AUC by an average of 7-fold and 11-fold, respectively. Co-administration of sirolimus and voriconazole is not recommended (see section 4.4).

Diltiazem (CYP3A4 inhibitor)

The simultaneous oral administration of 10 mg of Rapamune oral solution and 120 mg of diltiazem significantly affected the bioavailability of sirolimus. Sirolimus C_max, t_max, and AUC were increased 1.4-fold, 1.3-fold, and 1.6-fold, respectively. Sirolimus did not affect the pharmacokinetics of either diltiazem or its metabolites desacetyldiltiazem and desmethyldiltiazem. If diltiazem is administered, sirolimus blood levels should be monitored and a dose adjustment may be necessary.

Verapamil (CYP3A4 inhibitor)

Multiple-dose administration of verapamil and sirolimus oral solution significantly affected the rate and extent of absorption of both medicinal products. Whole blood sirolimus C_max, t_max, and AUC were increased 2.3-fold, 1.1-fold, and 2.2-fold, respectively. Plasma S-(-) verapamil C_max and AUC were both increased 1.5-fold, and t_max was decreased 24%. Sirolimus levels should be monitored, and appropriate dose reductions of both medicinal products should be considered.

Erythromycin (CYP3A4 inhibitor)

Multiple-dose administration of erythromycin and sirolimus oral solution significantly increased the rate and extent of absorption of both medicinal products. Whole blood sirolimus C_max, t_max, and AUC were increased 4.4-fold, 1.4-fold, and 4.2-fold, respectively. The C_max, t_max, and AUC of plasma erythromycin base were increased 1.6-fold, 1.3-fold, and 1.7-fold, respectively. Sirolimus levels should be monitored and appropriate dose reductions of both medicinal products should be considered.

Ciclosporin (CYP3A4 substrate)

The rate and extent of sirolimus absorption was significantly increased by ciclosporin A (CsA). Sirolimus administered concomitantly (5 mg), and at 2 hours (5 mg) and 4 hours (10 mg) after CsA (300 mg), resulted in increased sirolimus AUC by approximately 183%, 141% and 80%, respectively. The effect of CsA was also reflected by increases in sirolimus C_max and t_max. When given 2 hours before CsA administration, sirolimus C_max and AUC were not affected. Single-dose sirolimus did not affect the pharmacokinetics of ciclosporin (microemulsion) in healthy volunteers when administered simultaneously or 4 hours apart. It is recommended that Rapamune be administered 4 hours after ciclosporin (microemulsion).

Oral contraceptives

No clinically significant pharmacokinetic interaction was observed between Rapamune oral solution and 0.3 mg norgestrel/0.03 mg ethinyl estradiol. Although the results of a single-dose interaction study with an oral contraceptive suggest the lack of a pharmacokinetic interaction, the results cannot exclude the possibility of changes in the pharmacokinetics that might affect the efficacy of the oral contraceptive during long-term treatment with Rapamune.

Other possible interactions

Moderate and weak inhibitors of CYP3A4 may decrease the metabolism of sirolimus and increase sirolimus blood levels (e.g., calcium channel blockers: nicardipine; antifungal agents: clotrimazole, fluconazole; antibiotics: troleandomycin; other substances: bromocriptine, cimetidine, danazol, protease inhibitors).

Inducers of CYP3A4 may increase the metabolism of sirolimus and decrease sirolimus blood levels (e.g., St. John's Wort (Hypericum perforatum), anticonvulsants: carbamazepine, phenobarbital, phenytoin).

Although sirolimus inhibits human liver microsomal cytochrome P₄₅₀ CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5 in vitro, the active substance is not expected to inhibit the activity of these isozymes in vivo since the sirolimus concentrations necessary to produce inhibition are much higher than those observed in patients receiving therapeutic doses of Rapamune. Inhibitors of P-gp may decrease the efflux of sirolimus from intestinal cells and increase sirolimus levels.

Grapefruit juice affects CYP3A4-mediated metabolism, and should therefore be avoided.

Pharmacokinetic interactions may be observed with gastrointestinal prokinetic agents, such as cisapride and metoclopramide.

No clinically significant pharmacokinetic interaction was observed between sirolimus and any of the following substances: acyclovir, atorvastatin, digoxin, glibenclamide, methylprednisolone, nifedipine, prednisolone, and trimethoprim/sulphamethoxazole.

4.6 Pregnancy And Lactation

Women of childbearing potential

Effective contraception must be used during Rapamune therapy and for 12 weeks after Rapamune has been stopped (see section 4.5)

Pregnancy

There are no adequate data from the use of sirolimus in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Rapamune should not be used during pregnancy unless clearly necessary. Effective contraception must be used during Rapamune therapy and for 12 weeks after Rapamune has been stopped.

Breast-feeding

Following administration of radiolabelled sirolimus, radioactivity is excreted in the milk of lactating rats. It is not known whether sirolimus is excreted in human milk. Because of the potential for adverse reactions in breast-fed infants from sirolimus, breast-feeding should be discontinued during therapy.

Fertility

Impairments of sperm parameters have been observed among some patients treated with Rapamune. These effects have been reversible upon discontinuation of Rapamune in most cases (see section 5.3).

4.7 Effects On Ability To Drive And Use Machines

Rapamune has no known influence on the ability to drive and use machines. No studies on the effects on the ability to drive and use machines have been performed.

4.8 Undesirable Effects

The most commonly reported adverse reactions (occurring in >10% of patients) are thrombocytopaenia, anaemia, pyrexia, hypertension, hypokalaemia, hypophosphataemia, urinary tract infection, hypercholesterolaemia, hyperglycaemia, hypertriglyceridaemia, abdominal pain, lymphocoele, peripheral oedema, arthralgia, acne, diarrhoea, pain, constipation, nausea, headache, increased blood creatinine, and increased blood lactate dehydrogenase (LDH).

The incidence of any adverse reaction(s) may increase as the trough sirolimus level increases.

The following list of adverse reactions is based on experience from clinical studies and on postmarketing experience.

Within the system organ classes, adverse reactions are listed under headings of frequency (number of patients expected to experience the reaction), using the following categories: very common (

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Most patients were on immunosuppressive regimens, which included Rapamune in combination with other immunosuppressive agents.

System Organ Class	Very common	Common	Uncommon	Rare	Not known
Infections and infestations	Urinary tract infection	Sepsis Pneumonia Pyelonephritis Herpes simplex Fungal, viral, and bacterial infections (such as mycobacterial infections, including tuberculosis, Epstein-Barr virus, CMV, and Herpes zoster)			Clostridium difficile enterocolitis
Neoplasms benign, malignant and unspecified (including cysts and polyps)		Skin cancer*	Lymphoma*/post-transplant lymphoproli-ferative disorder
Blood and lymphatic system disorders	Thrombocytopaenia Anaemia	Thrombotic Thrombocytopaenic purpura/haemolytic uraemic syndrome Leukopaenia Neutropaenia	Pancytopaenia
Immune system disorders				Hypersensitivity reactions, including anaphylactic/ anaphylactoid reactions, angioedema, exfoliative dermatitis, and hypersensitivity vasculitis (see section 4.4)
Metabolism and nutrition disorders	Hypokalaemia Hypophosphataemia Hypercholesterolaemia Hyperglycaemia Hypertriglyceridaemia	Diabetes mellitus
Nervous system disorders	Headache
Cardiac disorders		Tachycardia	Pericardial effusion (including haemody-namically significant effusions in children and adults)
Vascular disorders	Lymphocele Hypertension	Deep vein thrombosis	Pulmonary embolism	Lymphoedema
Respiratory, thoracic, and mediastinal disorders		Pneumonitis* Pleural effusion Epistaxis	Pulmonary haemorrhage	Alveolar proteinosis
Gastrointestinal disorders	Abdominal pain Diarrhoea Constipation Nausea	Stomatitis Ascites	Pancreatitis
Hepatobiliary disorders		Liver function tests abnormal			Liver failure*
Skin and subcutaneous tissue disorders	Acne	Rash
Musculoskeletal and connective tissue disorders	Arthralgia	Osteonecrosis
Renal and urinary disorders		Proteinuria	Nephrotic syndrome (see section 4.4)		Focal segmental glomerulosclerosis*
General disorders and administration site conditions	Oedema peripheral Pyrexia Pain	Impaired healing* Oedema
Investigations	Blood lactate dehydrogenase increased Blood creatinine increased	Aspartate aminotransferase increased Alanine aminotransfer-ase increased

*See section below.

Description of selected adverse reactions

Immunosuppression increases the susceptibility to the development of lymphoma and other malignancies, particularly of the skin (see section 4.4).

Cases of BK virus-associated nephropathy, as well as cases of JC virus-associated progressive multifocal leukoencephalopathy (PML), have been reported in patients treated with immunosuppressants, including Rapamune.

Hepatoxicity has been reported. The risk may increase as the trough sirolimus level increases. Rare reports of fatal hepatic necrosis have been reported with elevated trough sirolimus levels.

Cases of interstitial lung disease (including pneumonitis and infrequently bronchiolitis obliterans organising pneumonia (BOOP) and pulmonary fibrosis), some fatal, with no identified infectious etiology have occurred in patients receiving immunosuppressive regimens including Rapamune. In some cases, the interstitial lung disease has resolved upon discontinuation or dose reduction of Rapamune. The risk may be increased as the trough sirolimus level increases.

Impaired healing following transplant surgery has been reported, including fascial dehiscence, incisional hernia, and anastomotic disruption (e.g., wound, vascular, airway, ureteral, biliary).

Impairments of sperm parameters have been observed among some patients treated with Rapamune. These effects have been reversible upon discontinuation of Rapamune in most cases (see section 5.3).

In patients with delayed graft function, sirolimus may delay recovery of renal function.

The concomitant use of sirolimus with a calcineurin inhibitor may increase the risk of calcineurin inhibitor-induced HUS/TTP/TMA.

Focal segmental glomerulosclerosis has been reported.

There have also been reports of fluid accumulation, including peripheral oedema, lymphoedema, pleural effusion and pericardial effusions (including haemodynamically significant effusions in children and adults) in patients receiving Rapamune.

In a study evaluating the safety and efficacy of conversion from calcineurin inhibitors to sirolimus (target levels of 12-20 ng/ml in maintenance renal transplant patients, enrollment was stopped in the subset of patients (n=90) with a baseline glomerular filtration rate of less than 40 ml/min (see section 5.1). There was a higher rate of serious adverse events, including pneumonia, acute rejection, graft loss and death, in this sirolimus treatment arm (n=60, median time post-transplant 36 months).

Paediatric population

Controlled clinical studies with posology comparable to that currently indicated for the use of Rapamune in adults have not been conducted in children or adolescents below 18 years of age.

Safety was assessed in a controlled clinical study enrolling renal transplant patients below 18 years of age considered of high immunologic risk, defined as a history of one or more acute allograft rejection episodes and/or the presence of chronic allograft nephropathy on a renal biopsy (see section 5.1). The use of Rapamune in combination with calcineurin inhibitors and corticosteroids was associated with an increased risk of deterioration of renal function, serum lipid abnormalities (including, but not limited to, increased serum triglycerides and cholesterol), and urinary tract infections. The treatment regimen studied (continuous use of Rapamune in combination with calcineurin inhibitor) is not indicated for adult or paediatric patients (see section 4.1).

In another study enrolling renal transplant patients 20 years of age and below that was intended to assess the safety of progressive corticosteroid withdrawal (beginning at six months post-transplantation) from an immunosuppressive regimen initiated at transplantation that included full-dose immunosuppression with both Rapamune and a calcineurin inhibitor in combination with basiliximab induction, of the 274 patients enrolled, 19 (6.9%) were reported to have developed post-transplant lymphoproliferative disorder (PTLD). Among 89 patients known to be EBV seronegative prior to transplantation, 13 (15.6%) were reported to have developed PTLD. All patients who developed PTLD were aged below 18 years.

There is insufficient experience to recommend the use of Rapamune in children and adolescents (see section 4.2).

4.9 Overdose

At present, there is minimal experience with overdose. One patient experienced an episode of atrial fibrillation after ingestion of 150 mg of Rapamune. In general, the adverse effects of overdose are consistent with those listed in section 4.8. General supportive measures should be initiated in all cases of overdose. Based on the poor aqueous solubility and high erythrocyte and plasma protein binding of Rapamune, it is anticipated that Rapamune will not be dialysable to any significant extent.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Immunosuppressants, selective immunosuppressants, ATC code: L04AA10.

Sirolimus inhibits T-cell activation induced by most stimuli, by blocking calcium-dependent and calcium-independent intracellular signal transduction. Studies demonstrated that its effects are mediated by a mechanism that is different from that of ciclosporin, tacrolimus, and other immunosuppressive agents. Experimental evidence suggests that sirolimus binds to the specific cytosolic protein FKPB-12, and that the FKPB 12-sirolimus complex inhibits the activation of the mammalian Target Of Rapamycin (mTOR), a critical kinase for cell cycle progression. The inhibition of mTOR results in blockage of several specific signal transduction pathways. The net result is the inhibition of lymphocyte activation, which results in immunosuppression.

In animals, sirolimus has a direct effect on T- and B-cell activation, suppressing immune-mediated reactions, such as allograft rejection.

Clinical studies

Patients at low to moderate immunological risk were studied in the phase 3 ciclosporin elimination-Rapamune maintenance study, which