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Urokinase medac 10,000 I.U.
Powder for solution for injection or infusion
Each vial contains 10,000 I.U. of human urokinase extracted from human urine.
For a full list of excipients, see section 6.1.
Powder for solution for injection or infusion
Intravascular lysis of blood clots in the following conditions:
• extensive acute proximal deep vein thrombosis
• acute massive pulmonary embolism
• acute occlusive peripheral arterial disease with limb threatening ischemia
• thrombosed arteriovenous haemodialysis shunts
• thrombosed central venous catheters
Urokinase medac should only be used by physicians experienced in the management of thrombotic diseases in hospitals where adequate diagnostic and monitoring techniques are available.
Depending on the indication, the route of administration of Urokinase medac is by systemic intravenous infusion, by local intra-arterial catheter-directed infusion during arteriography, or by local instillation.
It must not be given by subcutaneous or intramuscular injection.
For instructions regarding reconstitution and further dilution, see section 6.6.
Adults
The dosage may be adjusted individually depending on the clinical condition. The following dose regimens should be used as a guideline.
Deep vein thrombosis
Urokinase medac should be administered by intravenous infusion into a peripheral vein using an initial dose of 4,400 I.U./kg bodyweight infused over 10 – 20 min, followed by a maintenance dose of 100,000 I.U. per hour for 2 – 3 days.
Pulmonary embolism
Urokinase medac should be administered by intravenous infusion into a peripheral vein using an initial dose of 4,400 I.U./kg bodyweight infused over 10 – 20 min, followed by a maintenance dose of 4,400 I.U./kg bodyweight per hour for 12 hours.
Occlusive peripheral arterial disease
Urokinase medac should be administered by local intra-arterial catheter-directed graded infusion using an initial dose of 4,000 I.U./min (i.e. 240,000 I.U. per hour) for 2 – 4 hours or until restoration of antegrade flow, followed by a dose of 1,000 – 2,000 I.U./min until complete lysis or a maximum of 48 hours.
Thrombosed arteriovenous haemodialysis shunts
Urokinase medac should be administered by local forced periodic infusion (pulse spray) into both branches of the shunt at a concentration of 5,000 to 25,000 I.U./ml up to a total dose of 250,000 I.U. If necessary, the application can be repeated every 30 – 45 minutes up to a maximum of 2 hours.
Thrombosed central venous catheters
Urokinase medac should be dissolved in physiological saline at a concentration of 5,000 I.U./ml. A volume sufficient to completely fill the lumen of the occluded catheter should be instilled and either locked for a duration of 20 to 60 minutes or pushed with aliquots of saline before the lysate is aspirated. The procedure may be repeated if necessary.
Special populations
• Elderly patients: Available data are limited in patients over 65 years and it is not known whether they respond differently from younger subjects. Urokinase medac should be used with caution in elderly patients (see section 4.4).
• Patients with renal or hepatic impairment: A dose reduction may be required in patients with impaired renal and/or hepatic function. In these cases, the fibrinogen level should not fall below 100 mg/dl.
Paediatric patients
There is very limited experience with urokinase in children with thromboembolic occlusive vascular disease and urokinase should not be used in this indication.
Urokinase medac may be used in children of all ages for the treatment of thrombosed central venous catheters using the same lock procedure as in adults.
Therapeutic monitoring
Before starting thrombolytic therapy, haemostasis tests should be performed including haematocrit, platelet count, thrombin time (TT) and activated partial thromboplastin time (aPTT).
If heparin has been given, it should be discontinued and the aPTT should be less than twice the normal control value before urokinase therapy is initiated.
For systemic administration, a 3 to 5 fold prolongation of the TT measured 4 hours after initiation of therapy is generally considered sufficient. However, results of coagulation tests and fibrinolytic activity do not reliably predict either efficacy or risk of bleeding.
Follow-up treatment
In order to prevent recurrent thrombosis subsequent administration of anticoagulants should be instituted provided the aPTT is less than twice the normal control value.
• Hypersensitivity to the active substance or to any of the excipients
• Active clinically relevant bleeding
• Aneurysm and arteriovenous malformation
• Intracranial neoplasm or other neoplasm with risk of haemorrhage
• Decreased blood coagulation (haemorrhagic diathesis, concomitant therapy with anticoagulants, spontaneous fibrinolysis) and severe thrombocytopenia
• Severe uncontrolled arterial hypertension (systolic > 200 mmHg, diastolic > 100 mmHg; grade III or IV hypertensive retinopathy)
• Acute pancreatitis, pericarditis, bacterial endocarditis, sepsis
• Recent cerebrovascular accident (e.g. within 2 months)
• Recent trauma including cardiopulmonary resuscitation, thoracic surgery or neurosurgery (e.g. within 2 months)
• Recent major surgery until primary wound healing, recent organ biopsy, lumbar puncture, translumbal aortography (e.g. within 10 days)
In the following conditions, the risk of bleeding may be increased and should be weighed against the anticipated benefits:
• Recent severe gastrointestinal bleeding
• Recent surgery other than thoracic or neurosurgery, recent obstetrical delivery, puncture of non-compressible vessels
• Moderate coagulation defects including those due to severe hepatic or renal diseases
• Cavernous pulmonary diseases
• Genitourinary tract diseases with existing or potential sources of bleeding (e.g. implanted bladder catheter)
• High likelihood of a left heart thrombus (e.g. mitral stenosis with atrial fibrillation) with possible risk of cerebral embolism
• Known septic thrombotic disease
• Severe cerebrovascular disease
• Elderly patients (especially those over 75 years)
Concomitant administration of urokinase with other thrombolytic agents, anticoagulants, or agents inhibiting platelet function may further increase the risk of serious bleeding (see section 4.5).
When bleeding occurs in patients receiving urokinase, it may be difficult to control. Although urokinase is intended to produce sufficient amounts of plasmin to lyse intravascular deposits of fibrin, other fibrin deposits including those which provide haemostasis (at sites of needle puncture, catheter insertion, cut, etc.) are also subject to lysis, and bleeding from such sites may result. Oozing of blood from sites of percutaneous trauma occurs frequently.
The possibility of bruising or haematoma formation, especially after intramuscular injections, is high during urokinase therapy. Intramuscular injections and unnecessary handling of the patient should be avoided. Venipunctures and invasive venous procedures should be performed as infrequently as possible and with care to minimize bleeding. If bleeding from an invasive site is not serious, urokinase therapy may be continued while closely observing the patient; local measures such as application of pressure should be initiated immediately.
Arterial invasive procedures must be avoided before and during urokinase treatment to minimise bleeding. If an arterial puncture is absolutely essential, it should be performed by a physician experienced in the procedure, using a radial or brachial rather than a femoral artery. Direct pressure should be applied at the puncture site for at least 30 minutes, a pressure dressing applied, and the site checked frequently for evidence of bleeding.
If severe bleeding occurs following systemic treatment with urokinase, infusion should be stopped immediately and measures to manage the bleeding implemented. Plasma volume expanders other than dextrans may be used to replace blood volume deficits; if blood loss has been extensive, administration of packed red blood cells is preferred to whole blood. If very rapid reversal of the fibrinolytic state is required, administration of an antifibrinolytic agent such as epsilon-aminocaproic acid may be considered (see section 4.9).
Urokinase medac is a highly purified enzyme produced from human urine. It also contains human serum albumin. Products manufactured from human source materials have the potential to transmit infectious agents. Procedures to control such risks strongly reduce but cannot completely eliminate the risk of transmitting infectious agents.
Anticoagulants
Oral anticoagulants or heparin may increase the risk of haemorrhage and should not be used concomitantly with urokinase.
Active substances affecting platelet function
Due to increased risk of haemorrhage, concomitant use of urokinase and active substances that affect platelet function (e.g., acetylsalicylic acid, other non-steroidal anti-inflammatory agents, dipyridamole, dextrans) should be avoided.
Contrast agents
Contrast agents may delay fibrinolysis.
There are no adequate data from the use of urokinase in pregnant women. Animal studies are insufficient with respect to effects on pregnancy, embryonal/fetal development, parturition or postnatal development. The potential risk for humans is unknown. However, low-molecular urokinase fragments and active plasmin cross the placenta.
Urokinase should not be used during pregnancy or in the immediate post-partum period unless clearly necessary.
It is unknown whether urokinase is excreted into human breast milk. Breast-feeding should be avoided during treatment with urokinase.
Not relevant.
Haemorrhage
The most frequent and severe adverse effect of urokinase therapy is haemorrhage. The haemostatic status of the patient may be more profoundly altered with urokinase therapy than with heparin or coumarin-derivative anticoagulant therapy.
Severe spontaneous bleeding, including fatalities resulting from cerebral haemorrhage, has occurred during urokinase therapy. Less severe spontaneous bleeding has occurred approximately twice as frequently as that occurring during heparin therapy. Patients with pre-existing haemostatic defects have the greatest risk of spontaneous bleeding.
Moderate decreases in haematocrit not accompanied by clinically detectable bleeding have been reported in approximately 20 % of patients receiving urokinase.
Hypersensitivity reactions
In contrast to streptokinase, urokinase is reportedly non-antigenic. However, mild allergic reactions including bronchospasm and rash have been reported rarely. In addition, very rare cases of fatal anaphylaxis have been reported.
Infusion reactions
Fever and chills, including shaking chills (rigors), have been reported occasionally in patients receiving urokinase. Symptomatic treatment is usually sufficient to alleviate discomfort caused by urokinase-induced fever; however, acetylsalicylic acid should not be used.
Other infusion reactions reported with urokinase therapy include dyspnoea, cyanosis, hypoxemia, acidosis, back pain, and nausea and/or vomiting; these reactions generally occurred within one hour of beginning urokinase infusion.
The following frequency convention was used as a basis for the evaluation of undesirable effects:
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Immune system disorders
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Vascular disorders
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General disorders and administration site conditions
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Investigations
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Haemorrhage that occurs during treatment with urokinase may be controlled with local pressure and treatment continued. If severe bleeding occurs, treatment with urokinase must be stopped and inhibitors such as aprotinin, epsilon-aminocaproic acid, p-aminoethylbenzoic acid or tranexamic acid can be given. In serious cases, human fibrinogen, factor XII, packed red cells or whole blood should be given as appropriate. For correction of volume deficiency, dextrans should be avoided.
ATC code: B01A D04, antithrombotic agent.
Urokinase medac is a highly purified form of naturally occurring human urokinase extracted from urine. Urokinase exists in two distinct molecular entities, a high molecular weight (approximately 54,000 daltons) and a low molecular weight (approximately 33,000 daltons). Urokinase medac contains more than 85 % of the HMW form.
Urokinase is a thrombolytic agent which converts plasminogen into plasmin (fibrinolysin) a proteolytic enzyme that degrades fibrin as well as fibrinogen and other plasma proteins. The activity of urokinase leads to a dose-dependent decrease in plasminogen and fibrinogen levels and to increased presence of fibrin and fibrogen degradation products, which have an anticoagulant effect and potentiate the effect of heparin. These effects persist for 12 – 24 hours after the end of urokinase infusion.
Urokinase is eliminated rapidly from the circulation by the liver with a half-life of 10 to 20 minutes. The inactive degradation products are excreted via the bile and primarily via the kidneys.
Elimination is delayed in patients with liver disease and impaired kidney function.
There is no preclinical safety data of additional value to the prescribing physician.
Disodium phosphate dodecahydrate, sodium dihydrogen phosphate dihydrate, human albumin.
No information is available regarding loss of activity in PVC containers or plastic bags/syringes.
26 months
Use reconstituted material immediately.
After reconstitution and dilution, chemical and physical stability has been demonstrated for 72 hours at room temperature. From a microbiological point of view, the product should be used immediately after reconstitution and dilution. 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 °C to 8 °C.
Do not store above 25 ºC.
Keep the vial in the outer container to protect from light.
All presentations are contained in borosilicate clear type 1 glass vials closed with chlorobutyl rubber stoppers and sealed with an aluminium flip-off cap.
The powder for solution for infusion should be dissolved in water for injection and further diluted with 0.9 % sodium chloride solution or glucose 5 % or glucose 10 % solution.
The powder is to be reconstituted as follows:
For a 10,000 I.U. vial use 2 ml of water for injection.
After reconstitution the solution must be clear and colourless.
medac
Gesellschaft für klinische
Spezialpräparate mbH
Fehlandtstr. 3
20354 Hamburg
Germay
Phone: +49 (0)4103 8006-0
Fax: +49 (0)4103 8006-100
PL 11587/0065
17/03/2010
22/09/2010
Mirtazep may be available in the countries listed below.
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Rec.INN
0076610-84-9
C22-H29-N9-O9-S2
627
Antibacterial: Cephalosporin
(6R,7S)-7-[(2R,3S)-2-(4-Ethyl-2,3-dioxo-1-piperazinecarboxamido)-3-hydroxybutyramido]-7-methoxy-3-[(1-methyl-1H-tetrazol-5-yl)-thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (USAN)
5-Thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 7-[[2-[[(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl]amino]-3-hydroxy-1-oxobutyl]amino]-7-methoxy-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo, [6R-[6α,7α,7(2R*,3S*)]]- (USAN)
7ß-[D-α-(4-ethyl-2,3-dioxo-1-piperazine-carboxamido)-ß-(S)-hydroxybutanamido]-7α-methoxy-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-delta³-cephem-4-carboxylic acid
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Glossary
| IS | Inofficial Synonym |
| JAN | Japanese Accepted Name |
| OS | Official Synonym |
| PH | Pharmacopoeia Name |
| Rec.INN | Recommended International Nonproprietary Name (World Health Organization) |
| USAN | United States Adopted Name |
Epirenat may be available in the countries listed below.
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In some countries, this medicine may only be approved for veterinary use.
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In the US, Invirase (saquinavir systemic) is a member of the drug class protease inhibitors and is used to treat HIV Infection and Nonoccupational Exposure.
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Glossary
| SPC | Summary of Product Characteristics (UK) |
Louse Powder may be available in the countries listed below.
In some countries, this medicine may only be approved for veterinary use.
Permethrin is reported as an ingredient of Louse Powder in the following countries:
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In some countries, this medicine may only be approved for veterinary use.
Rec.INN
D08AE02,G01AX03
0101418-00-2
Wound healing agent
Antiseptic
Benzenesulfonic acid, 2-hydroxy-3-methyl-, polymer with formaldehyde
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Glossary
| Rec.INN | Recommended International Nonproprietary Name (World Health Organization) |
Free may be available in the countries listed below.
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Glossary
| DCF | Dénomination Commune Française |
Resolor 1 mg film-coated tablets.
Each film-coated tablet contains 1 mg prucalopride (as prucalopride succinate).
Excipients: Each film-coated tablet contains 150 mg lactose monohydrate.
For a full list of excipients, see section 6.1.
Film-coated tablet (tablet).
White to off-white, round, biconvex tablets marked “PRU 1” on one side.
Resolor is indicated for symptomatic treatment of chronic constipation in women in whom laxatives fail to provide adequate relief.
Posology
Women: 2 mg once daily.
Men: The safety and efficacy of Resolor for use in men has not been established in controlled clinical trials therefore Resolor is not recommended for use in men until further data becomes available.
Elderly (>65 years): Start with one 1 mg once daily (see section 5.2); if needed the dose can be increased to 2 mg once daily.
Children and adolescents: Resolor is not recommended in children and adolescents younger than 18 years until further data become available. Currently available data are described in section 5.2.
Patients with renal impairment: The dose for patients with severe renal impairment (GFR < 30 ml/min/1.73 m2) is 1 mg once daily (see sections 4.3 and 5.2). No dose adjustment is required for patients with mild to moderate renal impairment.
Patients with hepatic impairment: The dose for patients with severe hepatic impairment (Child-Pugh class C) is 1 mg once daily (see sections 4.4 and 5.2). No dose adjustment is required for patients with mild to moderate hepatic impairment.
Due to the specific mode of action of prucalopride (stimulation of propulsive motility) exceeding the daily dose of 2 mg is not expected to increase efficacy.
If the intake of once daily prucalopride is not effective after 4 weeks of treatment, the patient should be re-examined and the benefit of continuing treatment reconsidered.
The efficacy of prucalopride has been established in double blind placebo controlled studies for up to 3 months. In case of prolonged treatment the benefit should be reassessed at regular intervals.
Method of administration
Resolor film-coated tablets are for oral use and can be taken with or without food, at any time of the day.
- Hypersensitivity to the active substance or to any of the excipients.
- Renal impairment requiring dialysis.
- Intestinal perforation or obstruction due to structural or functional disorder of the gut wall, obstructive ileus, severe inflammatory conditions of the intestinal tract, such as Crohn's disease, and ulcerative colitis and toxic megacolon/megarectum.
Renal excretion is the main route of elimination of prucalopride (see section 5.2). A dose of 1 mg is recommended in subjects with severe renal impairment (see section 4.2).
Patients with severe and clinically unstable concomitant disease (e.g. liver, cardiovascular or lung disease, neurological or psychiatric disorders, cancer or AIDS and other endocrine disorders) have not been studied. Caution should be exercised when prescribing Resolor to patients with these conditions. In particular Resolor should be used with caution in patients with a history of arrhythmias or ischaemic cardiovascular disease.
In case of severe diarrhoea, the efficacy of oral contraceptives may be reduced and the use of an additional contraceptive method is recommended to prevent possible failure of oral contraception (see the prescribing information of the oral contraceptive).
It is unlikely that hepatic impairment will affect prucalopride metabolism and exposure in man to a clinically relevant extent. No data are available in patients with mild, moderate or severe hepatic impairment, and therefore a lower dose is recommended for patients with severe hepatic impairment (see section 4.2).
Men: The safety and efficacy of Resolor for use in men has not been established in controlled clinical trials therefore Resolor is not recommended for use in men until further data becomes available.
The tablets contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption must not take this medicinal product.
In vitro data indicate that prucalopride has a low interaction potential, and therapeutic concentrations of prucalopride are not expected to affect the CYP-mediated metabolism of co-medicated medicinal products. Although prucalopride may be a weak substrate for P-glycoprotein (P-gp), it is not an inhibitor of P-gp at clinically relevant concentrations.
Ketoconazole (200 mg b.i.d.), a potent inhibitor of CYP3A4 and of P-gp, increased the area under the curve (AUC) of prucalopride by approximately 40%. This effect is too small to be clinically relevant and is likely attributable to inhibition of P-gp mediated renal transport. Interactions of similar magnitude as observed with ketoconazole may also occur with other potent inhibitors of P-gp such as verapamil, cyclosporine A and quinidine. Prucalopride is likely also secreted via another renal transporter(s). Inhibition of all transporters involved in the active secretion of prucalopride (including P-gp) may theoretically increase the exposure by up to 75%.
Studies in healthy subjects showed that there were no clinically relevant effects of prucalopride on the pharmacokinetics of warfarin, digoxin, alcohol and paroxetine. A 30% increase in the plasma concentrations of erythromycin was found during prucalopride co-treatment. The mechanism for this interaction is not fully known, but the available data support that this is the consequence of the high intrinsic variability in erythromycin kinetics, rather than a direct effect of prucalopride.
Therapeutic doses of probenecid, cimetidine, erythromycin and paroxetine did not affect the pharmacokinetics of prucalopride.
Resolor should be used with caution in patients receiving concomitant drugs known to cause QTc prolongation.
Because of the mechanism of action, the use of atropine-like substances may reduce the 5-HT4 receptor mediated effects of prucalopride.
Interactions with food have not been observed.
Pregnancy
Experience with prucalopride during pregnancy is limited. Cases of spontaneous abortion have been observed during clinical studies, although, in the presence of other risk factors, the relationship to prucalopride is unknown. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). Resolor is not recommended during pregnancy. Women of childbearing potential should use effective contraception during treatment with prucalopride.
Lactation
Prucalopride is excreted in breast milk. However, at therapeutic doses of Resolor no effects on the breastfed newborns/infants are anticipated. In the absence of human data, it is not recommended to use Resolor during breast-feeding.
Fertility
Animal studies indicate that there is no effect on male or female fertility.
No studies on the effects of prucalopride on the ability to drive and use machines have been performed. Resolor has been associated with dizziness and fatigue particularly during the first day of treatment which may have an effect on driving and using machines (see section 4.8).
Resolor has been given orally to approximately 2,700 patients with chronic constipation in controlled clinical studies. Of these patients, almost 1,000 patients received Resolor at the recommended dose of 2 mg per day, while about 1,300 patients were treated with 4 mg prucalopride daily. Total exposure in the clinical development plan exceeded 2,600 patient years. The most frequently reported adverse reactions associated with Resolor therapy are headache and gastrointestinal symptoms (abdominal pain, nausea or diarrhoea) occurring in approximately 20% of patients each. The adverse reactions occur predominantly at the start of therapy and usually disappear within a few days with continued treatment. Other adverse reactions have been reported occasionally. The majority of adverse events were mild to moderate in intensity.
The following adverse reactions were reported in controlled clinical studies at the recommended dose of 2 mg with frequencies corresponding to Very common (
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After the first day of treatment, the most common adverse reactions were reported in similar frequencies (incidence less than 1% different between prucalopride and placebo) during Resolor therapy as during placebo, with the exception of nausea and diarrhoea that still occurred more frequently during Resolor therapy, but less pronounced (difference in incidence between prucalopride and placebo between 1 and 3%).
Palpitations were reported in 0.7% of the placebo patients, 1.0% of the 1 mg prucalopride patients, 0.7% of the 2 mg prucalopride patients and 1.9% of the 4 mg prucalopride patients. The majority of patients continued using prucalopride. As with any new symptom, patients should discuss the new onset of palpitations with their physician.
In a study in healthy volunteers treatment with prucalopride was well tolerated when given in an up-titrating scheme up to 20 mg once daily (10 times the recommended therapeutic dose). An overdose may result in symptoms resulting from an exaggeration of the medicinal product's known pharmacodynamic effects and include headache, nausea and diarrhoea. Specific treatment is not available for Resolor overdose. Should an overdose occur, the patient should be treated symptomatically and supportive measures instituted, as required. Extensive fluid loss by diarrhoea or vomiting may require correction of electrolyte disturbances.
Pharmacotherapeutic group: Drugs acting on serotonin receptors, ATC code: A03AE04.
Mechanism of action
Prucalopride is a dihydrobenzofurancarboxamide with enterokinetic activities. Prucalopride is a selective, high affinity serotonin (5-HT4) receptor agonist, which is likely to explain its enterokinetic effects. In vitro, only at concentrations exceeding its 5-HT4 receptor affinity by at least 150-fold, affinity for other receptors was detected. In rats prucalopride in vivo at doses above 5 mg/kg (at and above 30-70 times the clinical exposure) induced hyperprolactinaemia caused by an antagonistic action at the D2 receptor.
In dogs, prucalopride alters colonic motility patterns via serotonin 5-HT4 receptor stimulation: it stimulates proximal colonic motility, enhances gastroduodenal motility and accelerates delayed gastric emptying. Furthermore, giant migrating contractions are induced by prucalopride. These are equivalent to the colonic mass movements in humans, and provide the main propulsive force to defecation. In dogs, the effects observed in the gastrointestinal tract are sensitive to blockade with selective 5-HT4 receptor antagonists illustrating that the observed effects are exerted via selective action on 5-HT4 receptors.
Clinical experience
The efficacy of prucalopride was established in three multicentre, randomised, double-blind, 12-week placebo-controlled studies in subjects with chronic constipation (n=1,279 on prucalopride, 1,124 females, 155 males). The prucalopride doses studied in each of these three studies included 2 mg and 4 mg once daily. The primary efficacy endpoint was the proportion (%) of subjects that reached normalisation of bowel movements defined as an average of three or more spontaneous, complete bowel movements (SCBM) per week over the 12-week treatment period. Both doses were statistically superior (p<0.001) to placebo at the primary endpoint in each of the three studies, with no incremental benefit of the 4 mg over the 2 mg dose. The proportion of patients treated with the recommended dose of 2 mg prucalopride that reached an average of
In all three studies, treatment with prucalopride also resulted in significant improvements in a validated and disease specific set of symptom measures (PAC SYM), including abdominal, stool and rectal symptoms, determined at week 4 and week 12. A significant benefit on a number of Quality of Life measures, such as degree of satisfaction with treatment and with bowel habits, physical and psychosocial discomfort and worries and concerns, was also observed at both the 4 and 12 week assessment time points.
Prucalopride has been shown not to cause rebound phenomena, nor to induce dependency.
A thorough QT study was performed to evaluate the effects of prucalopride on the QT interval at therapeutic (2 mg) and supratherapeutic doses (10 mg) and compared with the effects of placebo and a positive control. This study did not show significant differences between prucalopride and placebo at either dose, based on mean QT measurements and outlier analysis. This confirmed the results of two placebo controlled QT studies. In double blind clinical studies, the incidence of QT-related adverse events and ventricular arrhythmias was low and comparable to placebo.
Data from open label studies up to 2.6 years offer some evidence for longer-term safety and efficacy; however, no placebo controlled efficacy data for treatments longer than 12 weeks duration are available.
Absorption
Prucalopride is rapidly absorbed; after a single oral dose of 2 mg Cmax was attained in 2-3 hours. The absolute oral bioavailability is >90%. Concomitant intake of food does not influence the oral bioavailability of prucalopride.
Distribution
Prucalopride is extensively distributed, and has a steady-state volume of distribution (Vdss) of 567 litre. The plasma protein binding of prucalopride is about 30%.
Metabolism
Metabolism is not the major route of elimination of prucalopride. In vitro, human liver metabolism is very slow and only minor amounts of metabolites are found. In an oral dose study with radiolabelled prucalopride in man small amounts of eight metabolites were recovered in urine and faeces. The major metabolite (R107504, formed by O-demethylation and oxidation of the resulting alcohol function to a carboxylic acid) accounted for less than 4% of the dose. Unchanged active substance made up about 85% of the total radioactivity in plasma and only R107504 was a minor plasma metabolite.
Elimination
A large fraction of the active substance is excreted unchanged (about 60% of the administered dose in urine and at least 6% in faeces). Renal excretion of unchanged prucalopride involves both passive filtration and active secretion. The plasma clearance of prucalopride averages 317 ml/min. Its terminal half-life is about one day. Steady-state is reached within three to four days. On once daily treatment with 2 mg prucalopride steady-state plasma concentrations fluctuate between trough and peak values of 2.5 and 7 ng/ml, respectively. The accumulation ratio after once daily dosing ranged from 1.9 to 2.3. The pharmacokinetics of prucalopride is dose-proportional within and beyond the therapeutic range (tested up to 20 mg). Prucalopride o.d. displays time-independent kinetics during prolonged treatment.
Special populations
Population pharmacokinetics
A population pharmacokinetic analysis showed that the apparent total clearance of prucalopride was correlated with creatinine clearance, but that age, body weight, sex or race had no influence.
Elderly
After once daily dosing of 1 mg, peak plasma concentrations and AUC of prucalopride in elderly subjects were 26% to 28% higher than in young adults. This effect can be attributed to a diminished renal function in elderly.
Renal impairment
Compared to subjects with normal renal function, plasma concentrations of prucalopride after a single 2 mg dose were on average 25% and 51% higher in subjects with mild (ClCR 50-79 ml/min) and moderate (ClCR 25-49 ml/min) renal impairment, respectively. In subjects with severe renal impairment (ClCR
Hepatic impairment
Non-renal elimination contributes to about 35% of total elimination, and hepatic impairment is unlikely to affect the pharmacokinetics of prucalopride to a clinically relevant extent (see section 4.2 and 4.4).
Paediatric population
After a single oral dose of 0.03 mg/kg in paediatric patients aged between 4 and 12 years , Cmax of prucalopride was comparable to the Cmax in adults after a single 2 mg dose, while unbound AUC was 30-40% lower than after 2 mg in adults. Unbound exposure was similar over the whole age-range (4-12 years).The average terminal half life in the paediatric subjects was about 19 hours (range 11.6 to 26.8 hours) (see section 4.2).
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction and development. An extended series of safety pharmacology studies with special emphasis on cardiovascular parameters showed no relevant changes in haemodynamic and ECG derived parameters (QTc) with the exception of a modest increase in heart rate and blood pressure observed in anaesthesized pigs after intravenous administration, and an increase in blood pressure in conscious dogs after bolus intravenous administration, which was not observed either in anaesthetized dogs or after oral administration in dogs reaching similar plasma levels.
Tablet core
Lactose monohydrate
Microcrystalline cellulose
Colloidal silicon dioxide
Magnesium stearate
Coating
Hypromellose
Lactose monohydrate
Triacetin
Titanium dioxide (E171)
Macrogol 3000
Not applicable.
4 years.
Store in the original blister in order to protect from moisture.
Aluminium/aluminium perforated unit dose blisters (calendar marked) containing 7 tablets. Each pack contains 7 x 1, 14 x 1, 28 x 1 or 84 x 1 film-coated tablet.
Not all pack sizes may be marketed.
No special requirements.
Shire-Movetis NV
Veedijk 58
B-2300 Turnhout
Belgium
Tel.: 008006683 8470
EU/1/09/581/001 (28 tablets)
EU/1/09/581/003 (7 tablets)
EU/1/09/581/005 (14 tablets)
EU/1/09/581/007 (84 tablets)
15/10/09
October 2011
Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/.
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