Lumalia may be available in the countries listed below.
Cyproterone 17α-acetate (a derivative of Cyproterone) is reported as an ingredient of Lumalia in the following countries:
Ethinylestradiol is reported as an ingredient of Lumalia in the following countries:
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Theoplus may be available in the countries listed below.
Theophylline is reported as an ingredient of Theoplus in the following countries:
Theophylline monohydrate (a derivative of Theophylline) is reported as an ingredient of Theoplus in the following countries:
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Amikalen may be available in the countries listed below.
Amikacin is reported as an ingredient of Amikalen in the following countries:
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Menosor may be available in the countries listed below.
Mebeverine hydrochloride (a derivative of Mebeverine) is reported as an ingredient of Menosor in the following countries:
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Rec.INN
G03DC01
0000432-60-0
C21-H32-O
300
Progestin
Estr-4-en-17-ol, 17-(2-propenyl)-, (17ß)-
International Drug Name Search
Glossary
| BAN | British Approved Name |
| DCF | Dénomination Commune Française |
| DCIT | Denominazione Comune Italiana |
| IS | Inofficial Synonym |
| OS | Official Synonym |
| Rec.INN | Recommended International Nonproprietary Name (World Health Organization) |
Celovan may be available in the countries listed below.
Vancomycin hydrochloride (a derivative of Vancomycin) is reported as an ingredient of Celovan in the following countries:
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In some countries, this medicine may only be approved for veterinary use.
Rec.INN
0061570-90-9
C12-H14-N2-O3-S
266
Anthelmintic
Carbamic acid, (6-propoxy-2-benzothiazolyl)-, methyl ester
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Glossary
| IS | Inofficial Synonym |
| OS | Official Synonym |
| Rec.INN | Recommended International Nonproprietary Name (World Health Organization) |
| USAN | United States Adopted Name |
Levomepromazin-neuraxpharm may be available in the countries listed below.
Levomepromazine hydrochloride (a derivative of Levomepromazine) is reported as an ingredient of Levomepromazin-neuraxpharm in the following countries:
Levomepromazine maleate (a derivative of Levomepromazine) is reported as an ingredient of Levomepromazin-neuraxpharm in the following countries:
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Ceflong may be available in the countries listed below.
Cefalexin is reported as an ingredient of Ceflong in the following countries:
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Roflazin may be available in the countries listed below.
Ciprofloxacin is reported as an ingredient of Roflazin in the following countries:
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Flunarizine Hydrochloride may be available in the countries listed below.
Flunarizine Hydrochloride (BANM, JAN, USAN) is also known as Flunarizine (Rec.INN)
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Glossary
| BANM | British Approved Name (Modified) |
| JAN | Japanese Accepted Name |
| Rec.INN | Recommended International Nonproprietary Name (World Health Organization) |
| USAN | United States Adopted Name |
Gobbifol may be available in the countries listed below.
Propofol is reported as an ingredient of Gobbifol in the following countries:
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A-Por may be available in the countries listed below.
Clotrimazole is reported as an ingredient of A-Por in the following countries:
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Calciumfolinat Medis may be available in the countries listed below.
Calcium Folinate is reported as an ingredient of Calciumfolinat Medis in the following countries:
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Bayer Copper Capsules 4 Grams may be available in the countries listed below.
In some countries, this medicine may only be approved for veterinary use.
Copper Oxide is reported as an ingredient of Bayer Copper Capsules 4 Grams in the following countries:
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Finastéride Arrow may be available in the countries listed below.
Finasteride is reported as an ingredient of Finastéride Arrow in the following countries:
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In the US, Ceftin (cefuroxime systemic) is a member of the drug class second generation cephalosporins and is used to treat Bacterial Infection, Bladder Infection, Bone infection, Bronchitis, Epiglottitis, Gonococcal Infection - Disseminated, Gonococcal Infection - Uncomplicated, Impetigo, Joint Infection, Kidney Infections, Lyme Disease, Meningitis, Otitis Media, Peritonitis, Pneumonia, Sepsis, Sinusitis, Skin and Structure Infection, Skin Infection, Strep Throat, Surgical Prophylaxis, Tonsillitis/Pharyngitis, Upper Respiratory Tract Infection and Urinary Tract Infection.
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Cefuroxime axetil (a derivative of Cefuroxime) is reported as an ingredient of Ceftin in the following countries:
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Ciprobiot may be available in the countries listed below.
Ciprofloxacin hydrochloride (a derivative of Ciprofloxacin) is reported as an ingredient of Ciprobiot in the following countries:
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Corozell may be available in the countries listed below.
Potassium Chloride is reported as an ingredient of Corozell in the following countries:
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Loratadina Mepha may be available in the countries listed below.
Loratadine is reported as an ingredient of Loratadina Mepha in the following countries:
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Captopril Actavis may be available in the countries listed below.
Captopril is reported as an ingredient of Captopril Actavis in the following countries:
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Pipamperon Sandoz may be available in the countries listed below.
Pipamperone dihydrochloride (a derivative of Pipamperone) is reported as an ingredient of Pipamperon Sandoz in the following countries:
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Colixane may be available in the countries listed below.
Trimebutine maleate (a derivative of Trimebutine) is reported as an ingredient of Colixane in the following countries:
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Morficontin may be available in the countries listed below.
Morphine sulphate pentahydrate (a derivative of Morphine) is reported as an ingredient of Morficontin in the following countries:
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Merxil may be available in the countries listed below.
Diclofenac sodium salt (a derivative of Diclofenac) is reported as an ingredient of Merxil in the following countries:
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Coxeton may be available in the countries listed below.
Nabumetone is reported as an ingredient of Coxeton in the following countries:
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Prednisona Iqfarma may be available in the countries listed below.
Prednisone is reported as an ingredient of Prednisona Iqfarma in the following countries:
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Midazolam IBI may be available in the countries listed below.
Midazolam is reported as an ingredient of Midazolam IBI in the following countries:
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Tropicamide SDU Faure may be available in the countries listed below.
Tropicamide is reported as an ingredient of Tropicamide SDU Faure in the following countries:
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Armolev may be available in the countries listed below.
Levofloxacin is reported as an ingredient of Armolev in the following countries:
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Chricetyl may be available in the countries listed below.
Acetylcysteine is reported as an ingredient of Chricetyl in the following countries:
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Ibuprofen Actavis may be available in the countries listed below.
Ibuprofen is reported as an ingredient of Ibuprofen Actavis in the following countries:
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Elektra may be available in the countries listed below.
Enalapril maleate (a derivative of Enalapril) is reported as an ingredient of Elektra in the following countries:
Hydrochlorothiazide is reported as an ingredient of Elektra in the following countries:
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Acetaminofén may be available in the countries listed below.
Paracetamol is reported as an ingredient of Acetaminofén in the following countries:
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alpha-Vibolex may be available in the countries listed below.
Thioctic Acid is reported as an ingredient of alpha-Vibolex in the following countries:
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Texis may be available in the countries listed below.
Azithromycin dihydrate (a derivative of Azithromycin) is reported as an ingredient of Texis in the following countries:
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Tefor may be available in the countries listed below.
Levothyroxine sodium salt (a derivative of Levothyroxine) is reported as an ingredient of Tefor in the following countries:
Metformin hydrochloride (a derivative of Metformin) is reported as an ingredient of Tefor in the following countries:
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Flutamide Mylan may be available in the countries listed below.
Flutamide is reported as an ingredient of Flutamide Mylan in the following countries:
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Morphin and Antropine may be available in the countries listed below.
Atropine sulfate (a derivative of Atropine) is reported as an ingredient of Morphin and Antropine in the following countries:
Morphine hydrochloride (a derivative of Morphine) is reported as an ingredient of Morphin and Antropine in the following countries:
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Tansulosina Sandoz may be available in the countries listed below.
Tamsulosin is reported as an ingredient of Tansulosina Sandoz in the following countries:
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Polyron may be available in the countries listed below.
Iron Polymaltose is reported as an ingredient of Polyron in the following countries:
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Prednidale may be available in the countries listed below.
In some countries, this medicine may only be approved for veterinary use.
Prednisolone is reported as an ingredient of Prednidale in the following countries:
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Clorexine may be available in the countries listed below.
In some countries, this medicine may only be approved for veterinary use.
Chlorhexidine is reported as an ingredient of Clorexine in the following countries:
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Mowivit may be available in the countries listed below.
Tocopherol, α- is reported as an ingredient of Mowivit in the following countries:
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In the US, Maalox Anti-Gas (simethicone systemic) is a member of the drug class miscellaneous GI agents and is used to treat Endoscopy or Radiology Premedication, Functional Gastric Disorder, Gas and Postoperative Gas Pains.
US matches:
Simeticone is reported as an ingredient of Maalox Anti-Gas in the following countries:
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UK matches:
Trazodone Hydrochloride (BANM, JAN, USAN) is known as Trazodone in the US.
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Glossary
| BANM | British Approved Name (Modified) |
| JAN | Japanese Accepted Name |
| SPC | Summary of Product Characteristics (UK) |
| USAN | United States Adopted Name |
Litizem may be available in the countries listed below.
Diltiazem hydrochloride (a derivative of Diltiazem) is reported as an ingredient of Litizem in the following countries:
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Curoxime may be available in the countries listed below.
Cefuroxime sodium salt (a derivative of Cefuroxime) is reported as an ingredient of Curoxime in the following countries:
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In some countries, this medicine may only be approved for veterinary use.
In the US, Procainamide (procainamide systemic) is a member of the drug class group I antiarrhythmics and is used to treat Arrhythmia.
US matches:
Rec.INN
C01BA02
0000051-06-9
C13-H21-N3-O
235
Antiarrhythmic agent
Benzamide, 4-amino-N-[2-(diethylamino)ethyl]-
International Drug Name Search
Glossary
| BAN | British Approved Name |
| BANM | British Approved Name (Modified) |
| DCF | Dénomination Commune Française |
| DCIT | Denominazione Comune Italiana |
| IS | Inofficial Synonym |
| JAN | Japanese Accepted Name |
| OS | Official Synonym |
| PH | Pharmacopoeia Name |
| Rec.INN | Recommended International Nonproprietary Name (World Health Organization) |
Monocor may be available in the countries listed below.
Bisoprolol fumarate (a derivative of Bisoprolol) is reported as an ingredient of Monocor in the following countries:
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GenRX Clomiphene may be available in the countries listed below.
Clomifene citrate (a derivative of Clomifene) is reported as an ingredient of GenRX Clomiphene in the following countries:
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Povicler may be available in the countries listed below.
Povidone-Iodine is reported as an ingredient of Povicler in the following countries:
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Kainozym may be available in the countries listed below.
Diflorasone 17α,21-diacetate (a derivative of Diflorasone) is reported as an ingredient of Kainozym in the following countries:
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Clotrimazole is reported as an ingredient of Trivagizole in the following countries:
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Hidroplus may be available in the countries listed below.
Urea is reported as an ingredient of Hidroplus in the following countries:
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Glibesyn may be available in the countries listed below.
Glibenclamide is reported as an ingredient of Glibesyn in the following countries:
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Lapicrine may be available in the countries listed below.
In some countries, this medicine may only be approved for veterinary use.
Sulfadimidine sodium salt (a derivative of Sulfadimidine) is reported as an ingredient of Lapicrine in the following countries:
Sulfaquinoxaline sodium salt (a derivative of Sulfaquinoxaline) is reported as an ingredient of Lapicrine in the following countries:
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Locain may be available in the countries listed below.
Lidocaine is reported as an ingredient of Locain in the following countries:
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Minoxidil Isac may be available in the countries listed below.
Minoxidil is reported as an ingredient of Minoxidil Isac in the following countries:
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Ceclodyne may be available in the countries listed below.
Cefaclor monohydrate (a derivative of Cefaclor) is reported as an ingredient of Ceclodyne in the following countries:
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Fluticasone Furoate may be available in the countries listed below.
Fluticasone Furoate (USAN) is known as Fluticasone in the US.
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Glossary
| USAN | United States Adopted Name |
Brexic may be available in the countries listed below.
Piroxicam is reported as an ingredient of Brexic in the following countries:
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Metored may be available in the countries listed below.
Metformin hydrochloride (a derivative of Metformin) is reported as an ingredient of Metored in the following countries:
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Tinidazol Ecar may be available in the countries listed below.
Tinidazole is reported as an ingredient of Tinidazol Ecar in the following countries:
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Bipasmin may be available in the countries listed below.
Scopolamine butylbromide (a derivative of Scopolamine) is reported as an ingredient of Bipasmin in the following countries:
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Tusosedal may be available in the countries listed below.
Butamirate is reported as an ingredient of Tusosedal in the following countries:
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Pimenol may be available in the countries listed below.
Pirmenol hydrochloride (a derivative of Pirmenol) is reported as an ingredient of Pimenol in the following countries:
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Apo-Theo LA may be available in the countries listed below.
Theophylline is reported as an ingredient of Apo-Theo LA in the following countries:
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Ketoderm may be available in the countries listed below.
Ketoconazole is reported as an ingredient of Ketoderm in the following countries:
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Diphenhydramine hydrochloride (a derivative of Diphenhydramine) is reported as an ingredient of Miles in the following countries:
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Mixtard 40 Penfill may be available in the countries listed below.
Insulin Injection, Biphasic Isophane human (a derivative of Insulin Injection, Biphasic Isophane) is reported as an ingredient of Mixtard 40 Penfill in the following countries:
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Amfebutamone may be available in the countries listed below.
Amfebutamone (BAN) is known as Bupropion in the US.
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Glossary
| BAN | British Approved Name |
In the US, Ramipril (ramipril systemic) is a member of the drug class angiotensin converting enzyme inhibitors and is used to treat Diabetic Kidney Disease, Heart Attack, Heart Failure, High Blood Pressure and Left Ventricular Dysfunction.
US matches:
UK matches:
Ramipril (BAN, DCF, USAN) is known as Ramipril in the US.
Hydrochlorothiazide is reported as an ingredient of Ramipril in the following countries:
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Glossary
| BAN | British Approved Name |
| DCF | Dénomination Commune Française |
| SPC | Summary of Product Characteristics (UK) |
| USAN | United States Adopted Name |
Fenofix may be available in the countries listed below.
Fenofibrate is reported as an ingredient of Fenofix in the following countries:
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Miantrex may be available in the countries listed below.
Methotrexate is reported as an ingredient of Miantrex in the following countries:
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Ivaliten may be available in the countries listed below.
Phenothrin is reported as an ingredient of Ivaliten in the following countries:
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In the US, Hyperstat (diazoxide systemic) is a member of the following drug classes: agents for hypertensive emergencies, glucose elevating agents and is used to treat Hypertensive Emergency and Hypoglycemia.
US matches:
Diazoxide is reported as an ingredient of Hyperstat in the following countries:
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Enterobene ratiopharm may be available in the countries listed below.
Loperamide hydrochloride (a derivative of Loperamide) is reported as an ingredient of Enterobene ratiopharm in the following countries:
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Lozicum may be available in the countries listed below.
Lorazepam is reported as an ingredient of Lozicum in the following countries:
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Bemetson may be available in the countries listed below.
Betamethasone 17α-valerate (a derivative of Betamethasone) is reported as an ingredient of Bemetson in the following countries:
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Panacid may be available in the countries listed below.
Piromidic Acid is reported as an ingredient of Panacid in the following countries:
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Mitoxantron-Gry may be available in the countries listed below.
Mitoxantrone dihydrochloride (a derivative of Mitoxantrone) is reported as an ingredient of Mitoxantron-Gry in the following countries:
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Epares may be available in the countries listed below.
Epalrestat is reported as an ingredient of Epares in the following countries:
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Atenololo Almus may be available in the countries listed below.
Atenolol is reported as an ingredient of Atenololo Almus in the following countries:
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Cereton may be available in the countries listed below.
Vinpocetine is reported as an ingredient of Cereton in the following countries:
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Elkopas may be available in the countries listed below.
Aluminium Hydroxide is reported as an ingredient of Elkopas in the following countries:
Magnesium Carbonate is reported as an ingredient of Elkopas in the following countries:
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Genalen may be available in the countries listed below.
Alendronic Acid sodium trihydrate (a derivative of Alendronic Acid) is reported as an ingredient of Genalen in the following countries:
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Kantec may be available in the countries listed below.
Malotilate is reported as an ingredient of Kantec in the following countries:
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Glukosamin Copyfarm may be available in the countries listed below.
Glucosamine sulfate potassium chloride (a derivative of Glucosamine) is reported as an ingredient of Glukosamin Copyfarm in the following countries:
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Cardipen may be available in the countries listed below.
Perindopril is reported as an ingredient of Cardipen in the following countries:
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Telectol may be available in the countries listed below.
Vinpocetine is reported as an ingredient of Telectol in the following countries:
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Rec.INN
P01AX05
0000083-89-6
C23-H30-Cl-N3-O
399
Antiprotozoal agent: Antimalarial
1,4-Pentanediamine, N4-(6-chloro-2-methoxy-9-acridinyl)-N1,N1-diethyl-
International Drug Name Search
Glossary
| BAN | British Approved Name |
| BANM | British Approved Name (Modified) |
| DCF | Dénomination Commune Française |
| IS | Inofficial Synonym |
| OS | Official Synonym |
| PH | Pharmacopoeia Name |
| Rec.INN | Recommended International Nonproprietary Name (World Health Organization) |
| USAN | United States Adopted Name |
Anksen may be available in the countries listed below.
Dipotassium Clorazepate is reported as an ingredient of Anksen in the following countries:
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Rivastigmine Sandoz 4.5 mg hard capsules
Each capsule contains rivastigmine hydrogen tartrate corresponding to rivastigmine 4.5 mg.
For a full list of excipients, see section 6.1.
Hard capsule
Off-white to slightly yellow powder in a capsule with red cap and red body, with white imprint “RIV 4.5 mg” on the body.
Symptomatic treatment of mild to moderately severe Alzheimer's dementia.
Symptomatic treatment of mild to moderately severe dementia in patients with idiopathic Parkinson's disease.
Treatment should be initiated and supervised by a physician experienced in the diagnosis and treatment of Alzheimer's dementia or dementia associated with Parkinson's disease. Diagnosis should be made according to current guidelines. Therapy with rivastigmine should only be started if a caregiver is available who will regularly monitor intake of the medicinal product by the patient.
Rivastigmine should be administered twice a day, with morning and evening meals. The capsules should be swallowed whole.
Initial dose
1.5 mg twice a day.
Dose titration
The starting dose is 1.5 mg twice a day. If this dose is well tolerated after a minimum of two weeks of treatment, the dose may be increased to 3 mg twice a day. Subsequent increases to 4.5 mg and then 6 mg twice a day should also be based on good tolerability of the current dose and may be considered after a minimum of two weeks of treatment at that dose level.
If adverse reactions (e.g. nausea, vomiting, abdominal pain or loss of appetite), weight decrease or worsening of extrapyramidal symptoms (e.g. tremor) in patients with dementia associated with Parkinson's disease are observed during treatment, these may respond to omitting one or more doses. If adverse reactions persist, the daily dose should be temporarily reduced to the previous well-tolerated dose or the treatment may be discontinued.
Maintenance dose
The effective dose is 3 to 6 mg twice a day; to achieve maximum therapeutic benefit patients should be maintained on their highest well tolerated dose. The recommended maximum daily dose is 6 mg twice a day.
Maintenance treatment can be continued for as long as a therapeutic benefit for the patient exists. Therefore, the clinical benefit of rivastigmine should be reassessed on a regular basis, especially for patients treated at doses less than 3 mg twice a day. If after 3 months of maintenance dose treatment the patient's rate of decline in dementia symptoms is not altered favourably, the treatment should be discontinued. Discontinuation should also be considered when evidence of a therapeutic effect is no longer present.
Individual response to rivastigmine cannot be predicted. However, a greater treatment effect was seen in Parkinson's disease patients with moderate dementia. Similarly a larger effect was observed in Parkinson's disease patients with visual hallucinations (see section 5.1).
Treatment effect has not been studied in placebo-controlled trials beyond 6 months.
Re-initiation of therapy
If treatment is interrupted for more than several days, it should be re-initiated at 1.5 mg twice daily. Dose titration should then be carried out as described above.
Renal and hepatic impairment
Due to increased exposure in moderate renal and mild to moderate hepatic impairment, dosing recommendations to titrate according to individual tolerability should be closely followed (see section 5.2).
Patients with severe liver impairment have not been studied (see section 4.3).
Children
Rivastigmine is not recommended for use in children.
The use of this medicinal product is contraindicated in patients with
- hypersensitivity to the active substance, other carbamate derivatives or to any of the excipients used in the formulation,
- severe liver impairment, as it has not been studied in this population.
The incidence and severity of adverse reactions generally increase with higher doses. If treatment is interrupted for more than several days, it should be re-initiated at 1.5 mg twice daily to reduce the possibility of adverse reactions (e.g. vomiting).
Dose titration: Adverse reactions (e.g. hypertension and hallucinations in patients with Alzheimer's dementia and worsening of extrapyramidal symptoms, in particular tremor, in patients with dementia associated with Parkinson's disease) have been observed shortly after dose increase. They may respond to a dose reduction. In other cases, rivastigmine has been discontinued (see section 4.8).
Gastrointestinal disorders such as nausea and vomiting may occur particularly when initiating treatment and/or increasing the dose. These adverse reactions occur more commonly in women. Patients with Alzheimer's disease may lose weight. Cholinesterase inhibitors, including rivastigmine, have been associated with weight loss in these patients. During therapy patient's weight should be monitored.
In case of severe vomiting associated with rivastigmine treatment, appropriate dose adjustments as recommended in section 4.2 must be made. Some cases of severe vomiting were associated with oesophageal rupture (see section 4.8). Such events appeared to occur particularly after dose increments or high doses of rivastigmine.
Care must be taken when using rivastigmine in patients with sick sinus syndrome or conduction defects (sino-atrial block, atrio-ventricular block) (see section 4.8).
Rivastigmine may cause increased gastric acid secretions. Care should be exercised in treating patients with active gastric or duodenal ulcers or patients predisposed to these conditions.
Cholinesterase inhibitors should be prescribed with care to patients with a history of asthma or obstructive pulmonary disease.
Cholinomimetics may induce or exacerbate urinary obstruction and seizures. Caution is recommended in treating patients predisposed to such diseases.
The use of rivastigmine in patients with severe dementia of Alzheimer's disease or associated with Parkinson's disease, other types of dementia or other types of memory impairment (e.g. age-related cognitive decline) has not been investigated and therefore use in these patient populations is not recommended.
Like other cholinomimetics, rivastigmine may exacerbate or induce extrapyramidal symptoms. Worsening (including bradykinesia, dyskinesia, gait abnormality) and an increased incidence or severity of tremor have been observed in patients with dementia associated with Parkinson's disease (see section 4.8). These events led to the discontinuation of rivastigmine in some cases (e.g. discontinuations due to tremor 1.7% on rivastigmine vs 0% on placebo). Clinical monitoring is recommended for these adverse reactions.
As a cholinesterase inhibitor, rivastigmine may exaggerate the effects of succinylcholine-type muscle relaxants during anaesthesia. Caution is recommended when selecting anaesthetic agents. Possible dose adjustments or temporarily stopping treatment can be considered if needed.
In view of its pharmacodynamic effects, rivastigmine should not be given concomitantly with other cholinomimetic substances and might interfere with the activity of anticholinergic medicinal products.
No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam or fluoxetine in studies in healthy volunteers. The increase in prothrombin time induced by warfarin is not affected by administration of rivastigmine. No untoward effects on cardiac conduction were observed following concomitant administration of digoxin and rivastigmine.
According to its metabolism, metabolic interactions with other medicinal products appear unlikely, although rivastigmine may inhibit the butyrylcholinesterase mediated metabolism of other substances.
For rivastigmine no clinical data on exposed pregnancies are available. No effects on fertility or embryofoetal development were observed in rats and rabbits, except at doses related to maternal toxicity. In peri/postnatal studies in rats, an increased gestation time was observed. Rivastigmine should not be used during pregnancy unless clearly necessary.
In animals, rivastigmine is excreted into milk. It is not known if rivastigmine is excreted into human milk. Therefore, women on rivastigmine should not breast-feed.
Alzheimer's disease may cause gradual impairment of driving performance or compromise the ability to use machinery. Furthermore, rivastigmine can induce dizziness and somnolence, mainly when initiating treatment or increasing the dose. As a consequence, rivastigmine has minor or moderate influence on the ability to drive and use machines. Therefore, the ability of patients with dementia on rivastigmine to continue driving or operating complex machines should be routinely evaluated by the treating physician.
The most commonly reported adverse reactions are gastrointestinal, including nausea (38%) and vomiting (23%), especially during titration. Female patients in clinical studies were found to be more susceptible than male patients to gastrointestinal adverse reactions and weight loss.
The following adverse reactions, listed below in Table 1, have been accumulated in patients with Alzheimer's dementia treated with rivastigmine.
Adverse reactions in Table 1 are listed according to MedDRA system organ class and frequency category. Frequency categories are defined using the following convention: very common (
Table 1
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The following additional adverse reactions have been observed with rivastigmine transdermal patches: anxiety, delirium, pyrexia (common).
Table 2 shows the adverse reactions reported in patients with dementia associated with Parkinson's disease treated with rivastigmine.
Table 2
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Table 3 lists the number and percentage of patients from the specific 24-week clinical study conducted with rivastigmine in patients with dementia associated with Parkinson's disease with pre-defined adverse events that may reflect worsening of parkinsonian symptoms.
Table 3
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Symptoms
Most cases of accidental overdose have not been associated with any clinical signs or symptoms and almost all of the patients concerned continued rivastigmine treatment. Where symptoms have occurred, they have included nausea, vomiting and diarrhoea, hypertension or hallucinations. Due to the known vagotonic effect of cholinesterase inhibitors on heart rate, bradycardia and/or syncope may also occur. Ingestion of 46 mg occurred in one case; following conservative management the patient fully recovered within 24 hours.
Treatment
As rivastigmine has a plasma half-life of about 1 hour and a duration of acetylcholinesterase inhibition of about 9 hours, it is recommended that in cases of asymptomatic overdose no further dose of rivastigmine should be administered for the next 24 hours. In overdose accompanied by severe nausea and vomiting, the use of antiemetics should be considered. Symptomatic treatment for other adverse reactions should be given as necessary.
In massive overdose, atropine can be used. An initial dose of 0.03 mg/kg intravenous atropine sulphate is recommended, with subsequent doses based on clinical response. Use of scopolamine as an antidote is not recommended.
Pharmacotherapeutic group: anticholinesterases, ATC code: N06DA03
Rivastigmine is an acetyl- and butyrylcholinesterase inhibitor of the carbamate type, thought to facilitate cholinergic neurotransmission by slowing the degradation of acetylcholine released by functionally intact cholinergic neurones. Thus, rivastigmine may have an ameliorative effect on cholinergic-mediated cognitive deficits in dementia associated with Alzheimer's disease and Parkinson's disease.
Rivastigmine interacts with its target enzymes by forming a covalently bound complex that temporarily inactivates the enzymes. In healthy young men, an oral 3 mg dose decreases acetylcholinesterase (AChE) activity in CSF by approximately 40% within the first 1.5 hours after administration. Activity of the enzyme returns to baseline levels about 9 hours after the maximum inhibitory effect has been achieved. In patients with Alzheimer's disease, inhibition of AChE in CSF by rivastigmine was dose-dependent up to 6 mg given twice daily, the highest dose tested. Inhibition of butyrylcholinesterase activity in CSF of 14 Alzheimer patients treated by rivastigmine was similar to that of AChE.
Clinical studies in Alzheimer's dementia
The efficacy of rivastigmine has been established through the use of three independent, domain specific, assessment tools which were assessed at periodic intervals during 6 month treatment periods. These include the ADAS-Cog (a performance based measure of cognition), the CIBIC-Plus (a comprehensive global assessment of the patient by the physician incorporating caregiver input), and the PDS (a caregiver-rated assessment of the activities of daily living including personal hygiene, feeding, dressing, household chores such as shopping, retention of ability to orient oneself to surroundings as well as involvement in activities relating to finances, etc.).
The patients studied had an MMSE (Mini-Mental State Examination) score of 10–24.
The results for clinically relevant responders pooled from two flexible dose studies out of the three pivotal 26-week multicentre studies in patients with mild-to-moderately severe Alzheimer's Dementia, are provided in Table 4 below. Clinically relevant improvement in these studies was defined a priori as at least 4-point improvement on the ADAS-Cog, improvement on the CIBIC-Plus, or at least a 10% improvement on the PDS.
In addition, a post-hoc definition of response is provided in the same table. The secondary definition of response required a 4-point or greater improvement on the ADAS-Cog, no worsening on the CIBIC-Plus, and no worsening on the PDS. The mean actual daily dose for responders in the 6-12 mg group, corresponding to this definition, was 9.3 mg. It is important to note that the scales used in this indication vary and direct comparisons of results for different therapeutic agents are not valid.
Table 4
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*p<0.05, **p<0.01, ***p<0.001
Clinical studies in dementia associated with Parkinson's disease
The efficacy of rivastigmine in dementia associated with Parkinson's disease has been demonstrated in a 24-week multicentre, double-blind, placebo-controlled core study and its 24-week open-label extension phase. Patients involved in this study had an MMSE (Mini-Mental State Examination) score of 10–24. Efficacy has been established by the use of two independent scales which were assessed at regular intervals during a 6-month treatment period as shown in Table 5 below: the ADAS-Cog, a measure of cognition, and the global measure ADCS-CGIC (Alzheimer's Disease Cooperative Study-Clinician's Global Impression of Change).
Table 5
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1 Based on ANCOVA with treatment and country as factors and baseline ADAS-Cog as a covariate. A positive change indicates improvement.
2 Mean data shown for convenience, categorical analysis performed using van Elteren test
ITT: Intent-To-Treat; RDO: Retrieved Drop Outs; LOCF: Last Observation Carried Forward
Although a treatment effect was demonstrated in the overall study population, the data suggested that a larger treatment effect relative to placebo was seen in the subgroup of patients with moderate dementia associated with Parkinson's disease. Similarly a larger treatment effect was observed in those patients with visual hallucinations (see Table 6).
Table 6
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1 Based on ANCOVA with treatment and country as factors and baseline ADAS-Cog as a covariate. A positive change indicates improvement.
ITT: Intent-To-Treat; RDO: Retrieved Drop Outs
Absorption
Rivastigmine is rapidly and completely absorbed. Peak plasma concentrations are reached in approximately 1 hour. As a consequence of rivastigmine's interaction with its target enzyme, the increase in bioavailability is about 1.5-fold greater than that expected from the increase in dose. Absolute bioavailability after a 3 mg dose is about 36%±13%. Administration of rivastigmine with food delays absorption (tmax) by 90 min and lowers Cmax and increases AUC by approximately 30%.
Distribution
Protein binding of rivastigmine is approximately 40%. It readily crosses the blood brain barrier and has an apparent volume of distribution in the range of 1.8–2.7 l/kg.
Metabolism
Rivastigmine is rapidly and extensively metabolised (half-life in plasma approximately 1 hour), primarily via cholinesterase-mediated hydrolysis to the decarbamylated metabolite. In vitro, this metabolite shows minimal inhibition of acetylcholinesterase (<10%). Based on evidence from in vitro and animal studies the major cytochrome P450 isoenzymes are minimally involved in rivastigmine metabolism. Total plasma clearance of rivastigmine was approximately 130 l/h after a 0.2 mg intravenous dose and decreased to 70 l/h after a 2.7 mg intravenous dose.
Excretion
Unchanged rivastigmine is not found in the urine; renal excretion of the metabolites is the major route of elimination. Following administration of 14C-rivastigmine, renal elimination was rapid and essentially complete (>90%) within 24 hours. Less than 1% of the administered dose is excreted in the faeces. There is no accumulation of rivastigmine or the decarbamylated metabolite in patients with Alzheimer's disease.
Elderly subjects
While bioavailability of rivastigmine is greater in elderly than in young healthy volunteers, studies in Alzheimer patients aged between 50 and 92 years showed no change in bioavailability with age.
Subjects with hepatic impairment
The Cmax of rivastigmine was approximately 60% higher and the AUC of rivastigmine was more than twice as high in subjects with mild to moderate hepatic impairment than in healthy subjects.
Subjects with renal impairment
Cmax and AUC of rivastigmine were more than twice as high in subjects with moderate renal impairment compared with healthy subjects; however there were no changes in Cmax and AUC of rivastigmine in subjects with severe renal impairment.
Repeated-dose toxicity studies in rats, mice and dogs revealed only effects associated with an exaggerated pharmacological action. No target organ toxicity was observed. No safety margins to human exposure were achieved in the animal studies due to the sensitivity of the animal models used.
Rivastigmine was not mutagenic in a standard battery of in vitro and in vivo tests, except in a chromosomal aberration test in human peripheral lymphocytes at a dose 104 times the maximum clinical exposure. The in vivo micronucleus test was negative.
No evidence of carcinogenicity was found in studies in mice and rats at the maximum tolerated dose, although the exposure to rivastigmine and its metabolites was lower than the human exposure. When normalised to body surface area, the exposure to rivastigmine and its metabolites was approximately equivalent to the maximum recommended human dose of 12 mg/day; however, when compared to the maximum human dose, a multiple of approximately 6-fold was achieved in animals.
In animals, rivastigmine crosses the placenta and is excreted into milk. Oral studies in pregnant rats and rabbits gave no indication of teratogenic potential on the part of rivastigmine.
Gelatin
Magnesium stearate
Hypromellose
Microcrystalline cellulose
Silica, colloidal anhydrous
Yellow iron oxide (E172)
Red iron oxide (E172)
Titanium dioxide (E171)
Not applicable.
5 years
Do not store above 30°C.
