Aspirine du Rhône may be available in the countries listed below.
Acetylsalicylic Acid is reported as an ingredient of Aspirine du Rhône in the following countries:
International Drug Name Search
Loratadine Ranbaxy may be available in the countries listed below.
Loratadine is reported as an ingredient of Loratadine Ranbaxy in the following countries:
International Drug Name Search
Insulin Injection may be available in the countries listed below.
Insulin Injection (BAN) is also known as Insulin Injection, Soluble (Ph. Eur.)
International Drug Name Search
Glossary
| BAN | British Approved Name |
| Ph. Eur. | European Pharmacopoeia |
Arcental Topica may be available in the countries listed below.
Ketoprofen is reported as an ingredient of Arcental Topica in the following countries:
International Drug Name Search
Klaridol may be available in the countries listed below.
Loratadine is reported as an ingredient of Klaridol in the following countries:
International Drug Name Search
Pidocar may be available in the countries listed below.
Clopidogrel is reported as an ingredient of Pidocar in the following countries:
International Drug Name Search
Claritron may be available in the countries listed below.
Clarithromycin is reported as an ingredient of Claritron in the following countries:
International Drug Name Search
Terra-Cortil may be available in the countries listed below.
Oxytetracycline hydrochloride (a derivative of Oxytetracycline) is reported as an ingredient of Terra-Cortil in the following countries:
International Drug Name Search
Glibemet may be available in the countries listed below.
Glibenclamide is reported as an ingredient of Glibemet in the following countries:
Metformin is reported as an ingredient of Glibemet in the following countries:
International Drug Name Search
In the US, Terazol (terconazole topical) is a member of the drug class vaginal anti-infectives and is used to treat Vaginal Yeast Infection.
US matches:
Terconazole is reported as an ingredient of Terazol in the following countries:
International Drug Name Search
Polaronil may be available in the countries listed below.
Dexchlorpheniramine maleate (a derivative of Dexchlorpheniramine) is reported as an ingredient of Polaronil in the following countries:
International Drug Name Search
Cholhepan may be available in the countries listed below.
Gemfibrozil is reported as an ingredient of Cholhepan in the following countries:
International Drug Name Search
Colchicine Houdé may be available in the countries listed below.
Colchicine is reported as an ingredient of Colchicine Houdé in the following countries:
International Drug Name Search
Meloximek may be available in the countries listed below.
Meloxicam is reported as an ingredient of Meloximek in the following countries:
International Drug Name Search
Lopresor Divitabs may be available in the countries listed below.
Metoprolol tartrate (a derivative of Metoprolol) is reported as an ingredient of Lopresor Divitabs in the following countries:
International Drug Name Search
Clibite may be available in the countries listed below.
Gliclazide is reported as an ingredient of Clibite in the following countries:
International Drug Name Search
Mimedran may be available in the countries listed below.
Sultosilic Acid piperazine salt (a derivative of Sultosilic Acid) is reported as an ingredient of Mimedran in the following countries:
International Drug Name Search
Paroxetin may be available in the countries listed below.
Paroxetine is reported as an ingredient of Paroxetin in the following countries:
International Drug Name Search
Amlodipino Alter may be available in the countries listed below.
Amlodipine besilate (a derivative of Amlodipine) is reported as an ingredient of Amlodipino Alter in the following countries:
International Drug Name Search
Flohale may be available in the countries listed below.
Fluticasone propionate (a derivative of Fluticasone) is reported as an ingredient of Flohale in the following countries:
International Drug Name Search
Ekilid may be available in the countries listed below.
Sulpiride is reported as an ingredient of Ekilid in the following countries:
International Drug Name Search
Citalobell may be available in the countries listed below.
Citalopram hydrobromide (a derivative of Citalopram) is reported as an ingredient of Citalobell in the following countries:
International Drug Name Search
Impamid may be available in the countries listed below.
Indapamide is reported as an ingredient of Impamid in the following countries:
International Drug Name Search
Ferro Destrano may be available in the countries listed below.
In some countries, this medicine may only be approved for veterinary use.
Iron Dextran is reported as an ingredient of Ferro Destrano in the following countries:
International Drug Name Search
Carbamazepine CF may be available in the countries listed below.
Carbamazepine is reported as an ingredient of Carbamazepine CF in the following countries:
International Drug Name Search
Lisiken may be available in the countries listed below.
Clindamycin hydrochloride (a derivative of Clindamycin) is reported as an ingredient of Lisiken in the following countries:
International Drug Name Search
Telebrix Meglumine may be available in the countries listed below.
Ioxitalamic Acid meglumine (a derivative of Ioxitalamic Acid) is reported as an ingredient of Telebrix Meglumine in the following countries:
International Drug Name Search
Provair may be available in the countries listed below.
Montelukast sodium salt (a derivative of Montelukast) is reported as an ingredient of Provair in the following countries:
International Drug Name Search
Medazepam Q may be available in the countries listed below.
Medazepam is reported as an ingredient of Medazepam Q in the following countries:
International Drug Name Search
Bazaroin may be available in the countries listed below.
Serrapeptase is reported as an ingredient of Bazaroin in the following countries:
International Drug Name Search
Mucobroxol may be available in the countries listed below.
Ambroxol hydrochloride (a derivative of Ambroxol) is reported as an ingredient of Mucobroxol in the following countries:
International Drug Name Search
Xuzal may be available in the countries listed below.
Levocetirizine dihydrochloride (a derivative of Levocetirizine) is reported as an ingredient of Xuzal in the following countries:
International Drug Name Search
Amlodipin Stiching Registratiebeheer may be available in the countries listed below.
Amlodipine is reported as an ingredient of Amlodipin Stiching Registratiebeheer in the following countries:
International Drug Name Search
Cefuroxima Arrowblue may be available in the countries listed below.
Cefuroxime axetil (a derivative of Cefuroxime) is reported as an ingredient of Cefuroxima Arrowblue in the following countries:
International Drug Name Search
In the US, Tilade (nedocromil systemic) is a member of the drug class mast cell stabilizers and is used to treat Asthma, Maintenance.
US matches:
UK matches:
Nedocromil sodium (a derivative of Nedocromil) is reported as an ingredient of Tilade in the following countries:
International Drug Name Search
Glossary
| SPC | Summary of Product Characteristics (UK) |
Ecron may be available in the countries listed below.
Vecuronium Bromide is reported as an ingredient of Ecron in the following countries:
International Drug Name Search
Tamsulosina GP-Pharm may be available in the countries listed below.
Tamsulosin hydrochloride (a derivative of Tamsulosin) is reported as an ingredient of Tamsulosina GP-Pharm in the following countries:
International Drug Name Search
Roxylid may be available in the countries listed below.
Roxithromycin is reported as an ingredient of Roxylid in the following countries:
International Drug Name Search
Gobbizolam may be available in the countries listed below.
Midazolam is reported as an ingredient of Gobbizolam in the following countries:
International Drug Name Search
Bactirid may be available in the countries listed below.
Cefixime is reported as an ingredient of Bactirid in the following countries:
International Drug Name Search
Couren may be available in the countries listed below.
Captopril is reported as an ingredient of Couren in the following countries:
International Drug Name Search
Bricasma Epectorant may be available in the countries listed below.
Guaifenesin is reported as an ingredient of Bricasma Epectorant in the following countries:
Terbutaline sulfate (a derivative of Terbutaline) is reported as an ingredient of Bricasma Epectorant in the following countries:
International Drug Name Search
Emflex may be available in the countries listed below.
Acemetacin is reported as an ingredient of Emflex in the following countries:
International Drug Name Search
Méthoxyflurane may be available in the countries listed below.
Méthoxyflurane (DCF) is known as Methoxyflurane in the US.
International Drug Name Search
Glossary
| DCF | Dénomination Commune Française |
Cellondan lingual may be available in the countries listed below.
Ondansetron is reported as an ingredient of Cellondan lingual in the following countries:
International Drug Name Search
Lobiavers may be available in the countries listed below.
In some countries, this medicine may only be approved for veterinary use.
Levamisole hydrochloride (a derivative of Levamisole) is reported as an ingredient of Lobiavers in the following countries:
International Drug Name Search
Roname may be available in the countries listed below.
Glimepiride is reported as an ingredient of Roname in the following countries:
International Drug Name Search
Cefotiam Hydrochloride may be available in the countries listed below.
Cefotiam Hydrochloride (BANM, JAN, USAN) is also known as Cefotiam (Rec.INN)
International Drug Name Search
Glossary
| BANM | British Approved Name (Modified) |
| JAN | Japanese Accepted Name |
| Rec.INN | Recommended International Nonproprietary Name (World Health Organization) |
| USAN | United States Adopted Name |
Miconazol saar may be available in the countries listed below.
Miconazole nitrate (a derivative of Miconazole) is reported as an ingredient of Miconazol saar in the following countries:
International Drug Name Search
In the US, Follistim (follicle stimulating hormone systemic) is a member of the drug class gonadotropins and is used to treat Follicle Stimulation, Hypogonadism - Male and Ovulation Induction.
US matches:
Follitropin Alfa is reported as an ingredient of Follistim in the following countries:
Follitropin Beta is reported as an ingredient of Follistim in the following countries:
International Drug Name Search
Mucoserum may be available in the countries listed below.
Ambroxol hydrochloride (a derivative of Ambroxol) is reported as an ingredient of Mucoserum in the following countries:
International Drug Name Search
Benylin Original may be available in the countries listed below.
Ammonium Chloride is reported as an ingredient of Benylin Original in the following countries:
Diphenhydramine hydrochloride (a derivative of Diphenhydramine) is reported as an ingredient of Benylin Original in the following countries:
International Drug Name Search
Iliadin may be available in the countries listed below.
Oxymetazoline is reported as an ingredient of Iliadin in the following countries:
Oxymetazoline hydrochloride (a derivative of Oxymetazoline) is reported as an ingredient of Iliadin in the following countries:
International Drug Name Search
Loropoz may be available in the countries listed below.
Loratadine is reported as an ingredient of Loropoz in the following countries:
International Drug Name Search
Chlorhexidine Acetate may be available in the countries listed below.
Chlorhexidine Acetate (BANM) is known as Chlorhexidine in the US.
International Drug Name Search
Glossary
| BANM | British Approved Name (Modified) |
Paracetamol comp. Stada may be available in the countries listed below.
Codeine phosphate hemihydrate (a derivative of Codeine) is reported as an ingredient of Paracetamol comp. Stada in the following countries:
Paracetamol is reported as an ingredient of Paracetamol comp. Stada in the following countries:
International Drug Name Search
Ethifix may be available in the countries listed below.
Cefixime is reported as an ingredient of Ethifix in the following countries:
International Drug Name Search
Apocanda may be available in the countries listed below.
Clotrimazole is reported as an ingredient of Apocanda in the following countries:
International Drug Name Search
Leviogel may be available in the countries listed below.
Diclofenac sodium salt (a derivative of Diclofenac) is reported as an ingredient of Leviogel in the following countries:
International Drug Name Search
Acido Borico Alvita may be available in the countries listed below.
Boric Acid is reported as an ingredient of Acido Borico Alvita in the following countries:
International Drug Name Search
Rowatanal may be available in the countries listed below.
Bismuth Subgallate is reported as an ingredient of Rowatanal in the following countries:
International Drug Name Search
Motivan may be available in the countries listed below.
Paroxetine hydrochloride (a derivative of Paroxetine) is reported as an ingredient of Motivan in the following countries:
International Drug Name Search
Getamisin may be available in the countries listed below.
Gentamicin sulfate (a derivative of Gentamicin) is reported as an ingredient of Getamisin in the following countries:
International Drug Name Search
Progesterone-Retard Pharlon may be available in the countries listed below.
Hydroxyprogesterone caproate (a derivative of Hydroxyprogesterone) is reported as an ingredient of Progesterone-Retard Pharlon in the following countries:
International Drug Name Search
Izokappa may be available in the countries listed below.
In some countries, this medicine may only be approved for veterinary use.
Menadione sodium sulfonate (a derivative of Menadione) is reported as an ingredient of Izokappa in the following countries:
International Drug Name Search
Torocef may be available in the countries listed below.
Ceftriaxone is reported as an ingredient of Torocef in the following countries:
Ceftriaxone disodium salt (a derivative of Ceftriaxone) is reported as an ingredient of Torocef in the following countries:
International Drug Name Search
Faximin may be available in the countries listed below.
Glucosamine sulfate (a derivative of Glucosamine) is reported as an ingredient of Faximin in the following countries:
International Drug Name Search
Fulpen may be available in the countries listed below.
Bromhexine hydrochloride (a derivative of Bromhexine) is reported as an ingredient of Fulpen in the following countries:
International Drug Name Search
Alpram may be available in the countries listed below.
Alprazolam is reported as an ingredient of Alpram in the following countries:
International Drug Name Search
Esertia Orifarm may be available in the countries listed below.
Escitalopram oxalate (a derivative of Escitalopram) is reported as an ingredient of Esertia Orifarm in the following countries:
International Drug Name Search
Chiphone may be available in the countries listed below.
Benzbromarone is reported as an ingredient of Chiphone in the following countries:
International Drug Name Search
Indometacine PCH may be available in the countries listed below.
Indometacin is reported as an ingredient of Indometacine PCH in the following countries:
International Drug Name Search
Garexin may be available in the countries listed below.
Gentamicin sulfate (a derivative of Gentamicin) is reported as an ingredient of Garexin in the following countries:
International Drug Name Search
Rec.INN
J01MA10
0101363-10-4
C17-H18-F-N3-O3-S
363
Antibacterial: Gyrase inhibitor
9-Fluoro-2,3-dihydro-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzothiazine-6-carboxylic acid
International Drug Name Search
Glossary
| BAN | British Approved Name |
| IS | Inofficial Synonym |
| OS | Official Synonym |
| Rec.INN | Recommended International Nonproprietary Name (World Health Organization) |
Adasept b.p.5 Acne Gel may be available in the countries listed below.
Benzoyl Peroxide is reported as an ingredient of Adasept b.p.5 Acne Gel in the following countries:
International Drug Name Search
Propranolol HCl PCH may be available in the countries listed below.
Propranolol hydrochloride (a derivative of Propranolol) is reported as an ingredient of Propranolol HCl PCH in the following countries:
International Drug Name Search
Xylocain mit Adrenalin may be available in the countries listed below.
Epinephrine bitartrate (a derivative of Epinephrine) is reported as an ingredient of Xylocain mit Adrenalin in the following countries:
Lidocaine hydrochloride (a derivative of Lidocaine) is reported as an ingredient of Xylocain mit Adrenalin in the following countries:
Lidocaine hydrochloride monohydrate (a derivative of Lidocaine) is reported as an ingredient of Xylocain mit Adrenalin in the following countries:
International Drug Name Search
Akineton LP may be available in the countries listed below.
Biperiden is reported as an ingredient of Akineton LP in the following countries:
Biperiden hydrochloride (a derivative of Biperiden) is reported as an ingredient of Akineton LP in the following countries:
International Drug Name Search
Flutamida AC Farma may be available in the countries listed below.
Flutamide is reported as an ingredient of Flutamida AC Farma in the following countries:
International Drug Name Search
Avlezan may be available in the countries listed below.
In some countries, this medicine may only be approved for veterinary use.
Flunixin meglumine (a derivative of Flunixin) is reported as an ingredient of Avlezan in the following countries:
International Drug Name Search
Remexin may be available in the countries listed below.
Ethinylestradiol is reported as an ingredient of Remexin in the following countries:
Norethisterone 17ß-acetate (a derivative of Norethisterone) is reported as an ingredient of Remexin in the following countries:
International Drug Name Search
Rhinigenta may be available in the countries listed below.
In some countries, this medicine may only be approved for veterinary use.
Gentamicin sulfate (a derivative of Gentamicin) is reported as an ingredient of Rhinigenta in the following countries:
International Drug Name Search
Tevalen may be available in the countries listed below.
Alendronic Acid sodium trihydrate (a derivative of Alendronic Acid) is reported as an ingredient of Tevalen in the following countries:
International Drug Name Search
Tepavil may be available in the countries listed below.
Sulpiride is reported as an ingredient of Tepavil in the following countries:
International Drug Name Search
Glycerol Suppositories BP may be available in the countries listed below.
Glycerol is reported as an ingredient of Glycerol Suppositories BP in the following countries:
International Drug Name Search
Tenivalan may be available in the countries listed below.
In some countries, this medicine may only be approved for veterinary use.
Praziquantel is reported as an ingredient of Tenivalan in the following countries:
International Drug Name Search
Amlodipin Heumann maleat may be available in the countries listed below.
Amlodipine maleate (a derivative of Amlodipine) is reported as an ingredient of Amlodipin Heumann maleat in the following countries:
International Drug Name Search
Replagal 1 mg/ml concentrate for solution for infusion.
1 ml of concentrate for solution for infusion contains 1 mg of agalsidase alfa.
Each vial of 1 ml of concentrate contains 1 mg of agalsidase alfa.
Each vial of 3.5 ml of concentrate contains 3.5 mg of agalsidase alfa.
Agalsidase alfa is the human protein α-galactosidase A produced in a human cell line by genetic engineering technology.
For a full list of excipients, see section 6.1.
Concentrate for solution for infusion.
A clear and colourless solution.
Replagal is indicated for long-term enzyme replacement therapy in patients with a confirmed diagnosis of Fabry Disease (α-galactosidase A deficiency).
Replagal treatment should be supervised by a physician experienced in the management of patients with Fabry Disease or other inherited metabolic diseases.
Replagal is administered at a dose of 0.2 mg/kg body weight every other week by intravenous infusion over 40 minutes. For preparation and administration instructions, see section 6.6.
Patients aged over 65 years
Studies in patients over the age of 65 have not been performed and no dosage regimen can presently be recommended in these patients as safety and efficacy have not yet been established.
Patients with hepatic impairment
No studies have been performed in patients with hepatic impairment.
Patients with renal impairment
No dose adjustment is necessary in patients with renal impairment.
The presence of extensive renal damage (eGFR <60mL/min) may limit the renal response to enzyme replacement therapy. Limited data are available in patients on dialysis or post-kidney transplantation, no dose adjustment is recommended.
Paediatric Patients
The experience in children is limited. No dosage regimen in children (0-6 years) can presently be recommended as safety and efficacy have not yet been sufficiently established. Limited clinical data in children (7-18 years) do not permit to recommend an optimal dosage regimen presently (see sections 5.1 and 5.2). Because no unexpected safety issues were encountered in the 6 month study with Replagal administered at 0.2 mg/kg in this population, this dose regimen is suggested for children between 7– 18 years of age.
Hypersensitivity to the active substance or any of the excipients.
Idiosyncratic infusion related reactions
13.7% of adult patients treated with Replagal in clinical trials have experienced idiosyncratic infusion related reactions. Four of 17 (23.5%) paediatric patients >7 years of age enrolled in clinical trials experienced at least one infusion reaction over a period of 4.5 years of treatment (mean duration of approx. 4 years). Three of 8 (37.5%) paediatric patients <7 years of age experienced at least one infusion related reaction over a mean observation time of 4.2 years. The most common symptoms have been rigors, headache, nausea, pyrexia, flushing and fatigue. Serious infusion reactions have been reported uncommonly; symptoms reported include pyrexia, rigors, tachycardia, urticaria, nausea/vomiting, angioneurotic oedema with throat tightness, stridor and swollen tongue. Other infusion-related symptoms may include dizziness and hyperhidrosis. A review of cardiac events showed that infusion reactions may be associated with hemodynamic stress triggering cardiac events in patients with pre-existing cardiac manifestations of Fabry disease. The onset of infusion related reactions has generally occurred within the first 2-4 months after initiation of treatment with Replagal although later onset (after 1 year) has been reported as well. These effects have decreased with time. If mild or moderate acute infusion reactions occur, medical attention must be sought immediately and appropriate actions instituted. The infusion can be temporarily interrupted (5 to 10 minutes) until symptoms subside and the infusion may then be restarted. Mild and transient effects may not require medical treatment or discontinuation of the infusion. In addition, oral or intravenous pre-treatment with antihistamines and/or corticosteroids, from 1 to 24 hours prior to infusion may prevent subsequent reactions in those cases where symptomatic treatment was required.
Allergic-type hypersensitivity reactions
As with any intravenous protein product, allergic-type hypersensitivity reactions are possible. If severe allergic or anaphylactic-type reactions occur, the administration of Replagal should be discontinued immediately and appropriate treatment initiated. The current medical standards for emergency treatment are to be observed.
IgG antibodies to the protein
As with all protein pharmaceutical products, patients may develop IgG antibodies to the protein. A low titre IgG antibody response has been observed in approximately 24% of the male patients treated with Replagal. Based on limited data this percentage has been found to be lower (7%) in the male paediatric population. These IgG antibodies appeared to develop following approximately 3-12 months of treatment. After 12 to 54 months of therapy, 17% of Replagal treated patients were still antibody positive whereas 7% showed evidence for the development of immunologic tolerance, based on the disappearance of IgG antibodies over time. The remaining 76% remained antibody negative throughout. The remaining 76% remained antibody negative throughout. In paediatric patients >7 yrs of age, 1/16 male patients tested positive for IgG anti-agalsidase alfa antibodies during the study. No increase in the incidence of adverse events was apparent for this patient. In paediatric patients <7 yrs of age, 0/7 male patients tested positive for IgG anti-agalsidase alfa antibodies. No IgE antibodies have been detected in any patient receiving Replagal.
Patients with renal impairment
The presence of extensive renal damage may limit the renal response to enzyme replacement therapy, possibly due to underlying irreversible pathological changes. In such cases, the loss of renal function remains within the expected range of the natural progression of disease.
Replagal should not be co-administered with chloroquine, amiodarone, benoquin or gentamicin since these substances have the potential to inhibit intra-cellular α-galactosidase activity.
As α-galactosidase A is itself an enzyme, it would be an unlikely candidate for cytochrome P450 mediated drug-drug interactions. In clinical studies, neuropathic pain medicinal products (such as carbamazepine, phenytoin and gabapentin) were administered concurrently to most patients without any evidence of interaction.
Very limited clinical data on pregnancies exposed to Replagal (n=4) have shown no adverse effects on the mother and newborn child. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy or embryonal/foetal development when exposed during organogenesis (see Section 5.3).
It is not known whether Replagal is excreted in human milk. Caution should be exercised when prescribing to pregnant or breast-feeding women.
Replagal has no or negligible influence on the ability to drive and use machines.
The most commonly reported undesirable effects were infusion associated reactions, which occurred in 13.7% of adult patients treated with Replagal in clinical trials. Most undesirable effects were mild to moderate in severity. Table 1 lists adverse drug reactions (ADRs) reported for the 177 patients treated with Replagal in clinical trials, including 21 patients with history of endstage renal disease, 24 paediatric patients (7 to 17 years of age) and 17 female patients. Information is presented by system organ class and frequency (very common >1/10; common >1/100, <1/10; uncommon >1/1000, <1/100). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. The occurrence of an event in a single patient is defined as uncommon in view of the number of patients treated. A single patient could be affected by several ADRs.
|
| |
|
|
| |
|
|
|
|
|
|
| |
|
|
| |
|
|
| |
|
|
| |
|
|
|
|
| |
|
|
| |
|
|
|
|
| |
|
|
|
|
| |
|
|
|
|
| |
|
|
|
|
| |
|
|
|
|
See also section 4.4.
Adverse drug reactions reported in patients with history of end stage renal disease were similar to those reported in the general patient population.
Infusion related reactions (also see section 4.4 Special warnings and precautions for use) may also include cardiac events such as cardiac arrhythmias (atrial fibrillation, ventricular extrasystoles, tachyarrhythmia), myocardial ischemia, and heart failure in patients with Fabry disease involving the heart structures. Infusion-related symptoms may include dizziness and hyperhidrosis. The most frequent were mild infusion-related reactions that mainly included rigors, pyrexia, flushing, headache, nausea, and dyspnoea.
Adverse drug reactions reported in the paediatric population (children and adolescents) were, in general, similar to those reported in adults. However, infusion related reactions (pyrexia, dyspnoea, chest pain) and pain exacerbation occurred more frequently.
No case of overdose has been reported.
Pharmacotherapeutic group: Other alimentary tract and metabolism products - Enzymes.
ATC code: A16AB03 agalsidase alfa.
Fabry Disease is a glycosphingolipid storage disorder that is caused by deficient activity of the lysosomal enzyme α-galactosidase A, resulting in accumulation of globotriaosylceramide (also referred to as Gb3 or CTH), the glycosphingolipid substrate for this enzyme. Agalsidase alfa catalyses the hydrolysis of Gb3, cleaving a terminal galactose residue from the molecule. Treatment with the enzyme has been shown to reduce accumulation of Gb3 in many cell types including endothelial and parenchymal cells. Agalsidase alfa has been produced in a human cell line to provide for a human glycosylation profile that can influence uptake by mannose-6-phosphate receptors on the surface of target cells.
The safety and efficacy of Replagal was assessed in two randomised, double blind, placebo controlled studies and open label extension studies, in a total of forty patients with a diagnosis of Fabry Disease based on clinical and biochemical evidence. Patients received the recommended dosage of 0.2 mg/kg of Replagal. Twenty-five patients completed the first study and entered an extension study. After 6 months of therapy there was a significant reduction in pain in the Replagal treated patients compared with placebo (p=0.021), as measured by the Brief Pain Inventory (a validated pain measurement scale). This was associated with a significant reduction in chronic neuropathic pain medication use and number of days on pain medication. In subsequent studies, in male paediatric patients above the age of 7, a reduction in pain was observed after 9 and 12 months of Replagal therapy compared to pre-treatment baseline. This pain reduction persisted through 4 years of Replagal therapy in 9 patients (in patients 7 – 18 years of age).
Twelve to 18 months of treatment with Replagal resulted in improvement in quality of life (QoL), as measured by validated instruments. For patients between 0 and 7 years of age, limited data indicate no specific safety issues.
After 6 months of therapy Replagal stabilised renal function compared with a decline in placebo treated patients. Kidney biopsy specimens revealed a significant increase in the fraction of normal glomeruli and a significant decrease in the fraction of glomeruli with mesangial widening in patients reated with Replagal in contrast to the patients treated with placebo. After 12 to 18 months of maintenance therapy, Replagal improved renal function as measured by inulin based glomerular filtration rate by 8.7 ± 3.7 ml/min. (p=0.030). Longer term therapy (48-54 months) resulted in stabilisation of GFR in male patients with normal baseline GFR (2) and with mild to moderate renal dysfunction (GFR 60 to < 90 mL/min/1.73 m2), and in slowing of the rate of decline in renal function and progression to end-stage renal disease in male Fabry patients with more severe renal dysfunction (GFR 30 to < 60 mL/min/1.73 m2).
In male paediatric Fabry patients> 7 years of age, hyperfiltration can be the earliest manifestation of renal involvement in the disease. Reduction in their hypernormal eGFRs was observed within 6 months of initiating Replagal therapy. After one year of treatment with agalsidase alfa 0.2mg/kg every other week, the abnormally high eGFR decreased from 143.4 ± 6.8 to 121.3 ± 5.6 mL/min/1.73 m2 in this subgroup and these eGFRs stabilized in the normal range during 4 years of Replagal 0.2mg/kg therapy, as did the eGFRs of the non-hyperfiltrators.
In a second study, fifteen patients with left ventricular hypertrophy completed a 6 month placebo-controlled study and entered an extension study. Treatment with Replagal resulted in an 11.5 g decrease in left ventricular mass as measured by magnetic resonance imaging (MRI) in the controlled study, while patients receiving placebo exhibited an increase in left ventricular mass of 21.8 g. In addition, in the first study involving 25 patients, Replagal effected a significant reduction in cardiac mass after 12 to 18 months of maintenance therapy (p<0.001). Replagal was also associated with improved myocardial contractility, a decrease in mean QRS duration and a concomitant decrease in septal thickness on echocardiography. Two patients with right bundle branch block in the studies conducted reverted to normal following therapy with Replagal. Subsequent open label studies demonstrated significant reduction from baseline in left ventricular mass by echocardiography in both male and female Fabry patients over 24 to 36 months of Replagal treatment. The reductions in LV mass observed by echocardiography in both male and female Fabry patients over 24 to 36 months of Replagal treatment were associated with meaningful symptom improvement as measured using the NYHA and CCS in Fabry patients with severe heart failure or anginal symptoms at baseline.
In male paediatric patients > 7 years of age, heart rate variability was abnormal at baseline and improved after 6 months of Replagal therapy in 15 boys and the improvement was sustained through 4.0 years of Replagal 0.2mg/kg therapy in an open-label long-term extension study in 9 boys. Individual left ventricular mass indexed to height2.7 was within normal range for children (<39 g/m2.7 in boys) at baseline. A relative reduction in mean LVM of 11% was observed during the 4.5 years of treatment. In 5/6 children < 7 years old, individual left ventricular mass indexed to height 2.7 was borderline elevated or elevated (>95%) for (<39 g/m2.7 in boys) at baseline. LVMI values for all 5 children fell within normal range after starting therapy.
Compared with placebo, treatment with Replagal also reduced accumulation of Gb3. After the first 6 months of therapy mean decreases of approximately 20 - 50 % were observed in plasma, urine sediment and liver, kidney and heart biopsy samples. After 12 to 18 months treatment a reduction of 50 – 80% was observed in plasma and urine sediment. The metabolic effects were also associated with clinically significant weight gain, increased sweating and increased energy. Consistent with the clinical effects of Replagal, treatment with the enzyme reduced accumulation of Gb3 in many cell types, including renal glomerular and tubular epithelial cells, renal capillary endothelial cells (cardiac and dermal capillary endothelial cells were not examined) and cardiac myocytes. In male paediatric Fabry patients plasma Gb3 decreased 40-50% after 6 months of Replagal therapy 0.2mg/kg and this reduction persisted after a total 4 years of treatment in 11 patients..
Antibodies to agalsidase alfa have not been shown to be associated with any clinically significant effects on safety (e.g. infusion reactions) or efficacy.
Infusion of Replagal at home may be considered for patients who are tolerating their infusions well.
This medicinal product has been authorised under “Exceptional Circumstances”. This means that due to the rarity of the disease it has not been possible to obtain complete information on this medicinal product.
The European Medicines Agency (EMEA) will review any new information which may become available every year and this SPC will be updated as necessary.
Single doses ranging from 0.007 - 0.2 mg enzyme per kg body weight were administered to adult male patients as 20 - 40 minute intravenous infusions while female patients received 0.2 mg enzyme per kg body weight as 40 minute infusions. The pharmacokinetic properties were essentially unaffected by the dose of the enzyme. Following a single intravenous dose of 0.2 mg/kg, agalsidase alfa had a biphasic distribution and elimination profile from the circulation. Pharmacokinetic parameters were not significantly different between male and female patients. Elimination half-lives were 108 ± 17 minutes in males compared to 89 ± 28 minutes in females and volume of distribution was approximately 17% body weight in both sexes. Clearance normalised for body weight was 2.66 and 2.10 ml/min/kg for males and females, respectively. Based on the similarity of pharmacokinetic properties of agalsidase alfa in both males and females, tissue distribution in major tissues and organs is also expected to be comparable in male and female patients.
In children (aged 7-18 years), Replagal administered at 0.2 mg/kg was cleared faster from the circulation than in adults. Mean clearance of Replagal in children aged (7-11 years), in adolescents (aged 12-18 years), and adults was 4.2 ml/min/kg, 3.1 ml/min/kg, and 2.3 ml/min/kg, respectively. Pharmacodynamic data suggest that at a dose of 0.2 mg/kg Replagal, the reductions in plasma Gb3 are more or less comparable between adolescents and young children (see section 5.1).
Following six months of Replagal treatment 12 of 28 male patients showed altered pharmacokinetics including an apparent increase in clearance. These changes were associated with the development of low titre antibodies to agalsidase alfa but no clinically significant effects on safety or efficacy were observed in the patients studied.
Based on the analysis of pre- and post-dose liver biopsies in males with Fabry Disease, the tissue half-life has been estimated to be in excess of 24 hours and hepatic uptake of the enzyme estimated to be 10% of administered dose.
Agalsidase alfa is a protein and is therefore: 1) not expected to bind to proteins, 2) expected that metabolic degradation will follow the pathways of other proteins, i.e. peptide hydrolysis, 3) unlikely to be a candidate for drug-drug interactions.
Renal elimination of agalsidase alfa is considered to be a minor clearance pathway since pharmacokinetic parameters are not altered by impaired renal function. As metabolism is expected to occur by peptide hydrolysis, impaired liver function is not expected to affect the pharmacokinetics of agalsidase alfa in a clinically significant manner.
Non-clinical data reveal no special hazard for humans based on studies of repeated dose toxicity. Genotoxic and carcinogenic potential are not expected. Reproduction toxicity studies in female rats and rabbits have shown no effect on pregnancy or the developing foetus. No studies have been conducted with respect to parturition or peri/post-natal development. It is not known whether Replagal crosses the placenta.
Sodium phosphate monobasic, monohydrate
Polysorbate 20
Sodium chloride
Sodium hydroxide
Water for injections
In the absence of compatibility studies this medicinal product must not be mixed with other medicinal products.
2 years
Chemical and physical in use stability has been demonstrated for 24 hours at 25°C.
From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless dilution has taken place in controlled and validated aseptic conditions.
Store in a refrigerator (2°C – 8°C).
1 ml of concentrate for solution for infusion in a 3 ml vial (Type I glass) with a stopper (fluoro-resin coated butyl rubber), a one piece seal (aluminium) and flip-off cap. Pack sizes of 1, 4 or 10 vials.
3.5 ml of concentrate for solution for infusion in a 5 ml vial (Type I glass) with a stopper (fluoro-resin coated butyl rubber), a one piece seal (aluminium) and flip-off cap. Pack sizes of 1, 4 or 10 vials.
Not all pack sizes may be marketed.
• Calculate the dose and number of Replagal vials needed.
• Dilute the total volume of Replagal concentrate required in 100 ml of 9 mg/ml (0.9%) sodium chloride solution for infusion. Care must be taken to ensure the sterility of the prepared solutions since Replagal does not contain any preservative or bacteriostatic agent; aseptic technique must be observed. Once diluted, the solution should be mixed gently but not shaken.
• The solution should be inspected visually for particulate matter and discolouration prior to administration.
• Administer the infusion solution over a period of 40 minutes using an intravenous line with an integral filter. Since no preservative is present, it is recommended that administration is started as soon as possible and within 3 hours of dilution.
• Do not infuse Replagal concomitantly in the same intravenous line with other agents.
• For single use only. Any unused product or waste material should be disposed of in accordance with local requirements.
Shire Human Genetic Therapies AB, Svärdvägen 11 D, 182 33 Danderyd, Sweden
Tel: +46 8 5449 6400
Fax: +46 8 5449 6429
EU/1/01/189/001-006
Date of first authorisation: 03/08/2001
Date of last renewal: 03/08/2006
12/2009
Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/.
Metason may be available in the countries listed below.
Metronidazole is reported as an ingredient of Metason in the following countries:
Mometasone 17-(2-furoate) (a derivative of Mometasone) is reported as an ingredient of Metason in the following countries:
International Drug Name Search
Bioticaps may be available in the countries listed below.
Chloramphenicol succinate sodium (a derivative of Chloramphenicol) is reported as an ingredient of Bioticaps in the following countries:
International Drug Name Search
Phentolamine Mesilate may be available in the countries listed below.
Phentolamine Mesilate (BANM, JAN) is known as Phentolamine in the US.
International Drug Name Search
Glossary
| BANM | British Approved Name (Modified) |
| JAN | Japanese Accepted Name |
Munobal retard may be available in the countries listed below.
Felodipine is reported as an ingredient of Munobal retard in the following countries:
International Drug Name Search
Fada Ambroxol may be available in the countries listed below.
Ambroxol is reported as an ingredient of Fada Ambroxol in the following countries:
International Drug Name Search
