Active ingredients: Prucalopride
Resolor 1 mg film-coated tablets
Resolor 2 mg film-coated tablets
Indications Why is Resolor used? What is it for?
Resolor contains the active ingredient prucalopride.
Resolor belongs to a group of medicines that improve intestinal motility (gastrointestinal prokinetics). It acts on the muscle wall of the intestine, helping to restore its normal functioning. Resolor is used to treat chronic constipation in adults in whom laxatives do not work properly.
Do not use in children and adolescents under 18 years.
Contraindications When Resolor should not be used
Do not take Resolor
- if you are allergic to prucalopride or any of the other ingredients of this medicine (listed in section 6),
- if you are undergoing kidney dialysis,
- if you have a perforation or obstruction of the intestinal wall, severe inflammation of the intestinal tract, such as Crohn's disease, ulcerative colitis or toxic megacolon / megaretto.
Precautions for use What you need to know before taking Resolor
Talk to your doctor before taking Resolor.
Take special care with Resolor and tell your doctor:
- if you have severe kidney disease,
- if you have severe liver disease,
- if you are currently under medical supervision for a serious health problem, such as a heart or lung disease, a mental or nervous system disorder, cancer, AIDS or a hormonal disorder.
Interactions Which drugs or foods can modify the effect of Resolor
Tell your doctor if you are taking, have recently taken or might take any other medicines.
Resolor with food and drink
Resolor can be taken with or without food and drink at any time of the day.
Warnings It is important to know that:
Pregnancy and breastfeeding
Resolor is not recommended during pregnancy.
- Tell your doctor if you are pregnant or planning to become pregnant.
- Use a reliable method of contraception during treatment with Resolor to avoid becoming pregnant.
- If you become pregnant while taking Resolor, please inform your doctor.
During breastfeeding, prucalopride may pass into breast milk. Breastfeeding is not recommended during treatment with Resolor. Consult your doctor about this.
Ask your doctor for advice before taking any medicine.
Driving and using machines
Resolor is unlikely to affect your ability to drive or use machines. However, in some cases Resolor can cause dizziness and tiredness, particularly on the first day of treatment and this can have an effect on driving and using machines.
Resolor contains lactose
If you have been told by your doctor that you have "intolerance to some sugars, contact your doctor before taking this medicinal product.
Dose, Method and Time of Administration How to use Resolor: Posology
Always take this medicine exactly as described in this leaflet or as your doctor has told you.
If in doubt, consult your doctor or pharmacist. Continue to take Resolor every day for the time set by your doctor. Your doctor may want to re-evaluate your condition and the benefit of prolonged treatment after the first 4 weeks and at regular intervals thereafter.
The usual dose of Resolor for most patients is one 2 mg tablet once a day.
If you are over 65 or have severe liver disease, the starting dose is one 1 mg tablet once a day; if necessary, your doctor may increase the dose to 2 mg once a day.
Your doctor may also recommend the lower dose of one 1 mg tablet once a day if you have severe kidney disease.
Taking more than the recommended dose will not increase the effectiveness of the medicine.
Resolor is indicated for adults only and should not be taken by children or adolescents up to 18 years of age.
Overdose What to do if you have taken too much Resolor
If you take more Resolor than you should
It is important to stick to the dose prescribed by your doctor. If you have taken more Resolor than prescribed, you may experience diarrhea, headache and / or nausea. In case of diarrhea, make sure you drink enough water.
If you forget to take Resolor
Do not take a double dose to make up for a forgotten tablet. Take your next dose at the usual time.
If you stop using Resolor
If you stop Resolor, the symptoms of constipation may return.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist
Side Effects What are the side effects of Resolor
Like all medicines, this medicine can cause side effects, although not everybody gets them. Undesirable effects occur mainly at the start of treatment and usually disappear within a few days of continued treatment.
The following side effects have occurred very commonly (may affect more than 1 in 10 people): headache, feelings of nausea, diarrhea and abdominal pain.
The following side effects have occurred commonly (may affect up to 1 in 10 people): decreased appetite, dizziness, vomiting, digestive disturbances (dyspepsia), flatulence, abnormal intestinal borborygmas, tiredness.
The following uncommon side effects (may affect up to 1 in 100 people) have also been reported: tremors, palpitations, rectal bleeding, increased frequency of urination (pollakiuria), fever and feeling sick. If palpitations occur, tell your doctor.
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the blister and carton after EXP. The expiry date refers to the last day of that month.
Store in the original blister pack to protect from moisture.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
What Resolor contains
The active ingredient is prucalopride.
One Resolor 1 mg film-coated tablet contains 1 mg of prucalopride (as succinate).
One Resolor 2 mg film-coated tablet contains 2 mg of prucalopride (as succinate).
The other ingredients are:
Lactose monohydrate (see section 2), microcrystalline cellulose, colloidal silica dioxide, magnesium stearate, hypromellose, triacetin, titanium dioxide (E171), macrogol. The 2 mg tablet also contains red iron oxide (E172), yellow iron oxide (E172), indigo carmine aluminum lake (E132).
Description of how Resolor looks and contents of the pack
Resolor 1 mg film-coated tablets are white to off-white, round tablets marked "PRU 1" on one side.
Resolor 2 mg film-coated tablets are pink, round tablets with "PRU 2" debossed on one side.
Resolor is available in aluminum / aluminum perforated unit dose blister (calendar) containing 7 tablets. Each pack contains 7x1, 14x1, 28x1 or 84x1 film-coated tablets.
Not all pack sizes may be marketed.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
RESOLOR 1 MG TABLETS COATED WITH FILM
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 1 mg of prucalopride (as succinate).
Excipients with known effect: Each film-coated tablet contains 142.5 mg of lactose (as monohydrate).
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Film-coated tablet (tablet).
White to off-white, round, biconvex tablets, debossed with "PRU 1" on one side.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Resolor is indicated for the symptomatic treatment of chronic constipation in adults for whom laxatives fail to provide adequate relief.
04.2 Posology and method of administration
Dosage
Adults: 2 mg once daily with or without food, at any time of the day.
Due to the specific mode of action of prucalopride (stimulation of propulsive motility), a daily dose greater than 2 mg is not expected to lead to an increase in efficacy.
If once daily prucalopride is not effective after 4 weeks of treatment, the patient will need to be reexamined and the benefit of continuing treatment should be assessed.
The efficacy of prucalopride has been demonstrated in double-blind placebo-controlled studies of up to three months duration. Efficacy beyond three months has not been demonstrated in placebo-controlled studies (see section 5.1). In case of prolonged treatment, the benefit should be reassessed at regular intervals.
Special populations
Elderly (> 65 years): Start with 1 mg once daily (see section 5.2); if necessary the dose can be increased up to 2 mg once daily.
Patients with renal insufficiency: The dose for patients with severe renal impairment (GFR 2) 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 suffering from hepatic insufficiency: Patients with severe hepatic impairment (Child-Pugh class C) start with a dose of 1 mg once daily, which can be increased to 2 mg if needed to improve efficacy and if the 1 mg dose is well tolerated (see sections 4.4 and 5.2) No dose adjustment is required for patients with mild to moderate hepatic impairment.
Pediatric population: Resolor should not be used in children and adolescents under 18 years (see section 5.1).
Method of administration
Oral use.
04.3 Contraindications
• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
• Kidney failure requiring dialysis.
• Intestinal perforation or obstruction due to structural or functional disorders of the bowel wall, obstructive ileus, severe inflammatory conditions of the intestinal tract such as Crohn's disease and ulcerative colitis, as well as toxic megacolon / megarect.
04.4 Special warnings and appropriate precautions for use
The major route of elimination of prucalopride is renal excretion (see section 5.2). A 1 mg dose is recommended in subjects with severe renal impairment (see section 4.2).
Resolor should be prescribed with caution to patients with severe hepatic impairment (Child-Pugh class C), because data on use in such patients are limited (see section 4.2).
The safety and efficacy of Resolor for use in patients with concomitant severe and clinically unstable disease (for example, cardiovascular or pulmonary disease, neurological or psychiatric disorders, cancer or AIDS and other endocrine disorders) have not been established in controlled clinical trials. Resolor should be prescribed with caution to patients with these conditions, particularly when used in patients with a history of arrhythmias or ischemic cardiovascular disease.
In case of severe diarrhea, the efficacy of oral contraceptives may be reduced; therefore, the use of an additional method of contraception is recommended to prevent possible ineffectiveness of oral contraception (see information on prescribing oral contraceptives).
The tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
04.5 Interactions with other medicinal products and other forms of interaction
Prucalopride has a low pharmacokinetic interaction potential. It is largely excreted unchanged in the urine (approximately 60% of the dose) and metabolism in vitro it is very slow.
Prucalopride did not inhibit specific CYP450 activities in the studies in vitro in human liver microsomes, at therapeutically relevant concentrations.
Although prucalopride may be a weak substrate for P-glycoprotein (P-gp), it is not a P-gp inhibitor at clinically relevant concentrations.
Effects of prucalopride on the pharmacokinetics of other medicinal products
There was a 30% increase in plasma concentrations of erythromycin during concomitant treatment with prucalopride. The mechanism behind this interaction is unclear.
Prucalopride had no clinically relevant effect on the pharmacokinetics of warfarin, digoxin, alcohol, and paroxetine or oral contraceptives.
Effects of other medicinal products on the pharmacokinetics of prucalopride
Ketoconazole (200 mg twice daily), a potent inhibitor of CYP3A4 and P-gp, increased systemic exposure to prucalopride by approximately 40%. This effect is too small to be clinically relevant. Interactions of similar significance. may be expected with other potent P-gp inhibitors such as verapamil, cyclosporine A and quinidine.
Therapeutic doses of probenecid, cimetidine, erythromycin and paroxetine did not affect the pharmacokinetics of prucalopride.
04.6 Pregnancy and lactation
Women of childbearing potential
Women of childbearing potential should use effective contraceptive methods during treatment with prucalopride.
Pregnancy
Experience with prucalopride in pregnancy is limited. Cases of spontaneous abortion have been observed in clinical studies, although in the presence of other risk factors, the relationship to prucalopride is unknown. Animal studies do not indicate direct or harmful effects. indirect effects on pregnancy, embryonic / fetal development, parturition or postnatal development (see section 5.3) Resolor is not recommended in pregnancy.
Feeding time
Prucalopride is excreted in breast milk. However, at therapeutic doses of Resolor no effects on breastfed newborns / infants are anticipated. In the absence of human data, the use of Resolor is not recommended during lactation.
Fertility
Animal studies indicate that there is no effect on male or female fertility.
04.7 Effects on ability to drive and use machines
Resolor may slightly impair the ability to drive and use machines as dizziness and fatigue were observed in clinical studies, particularly during the first day of treatment (see section 4.8).
04.8 Undesirable effects
Summary of the safety profile
An integrated analysis of 17 double-blind placebo-controlled studies was performed in which Resolor was administered orally to approximately 3,300 patients with chronic constipation. Of these patients, over 1,500 took Resolor at the recommended dose of 2 mg per day, while approximately 1,360 were treated with 4 mg prucalopride per day. The most frequently reported adverse reactions associated with Resolor 2 mg therapy are headache (17.8%) and gastrointestinal symptoms (abdominal pain (13.7%) , nausea (13.7%) and diarrhea (12.0%)). Adverse reactions occur mainly at the start of therapy and usually disappear within a few days of continued treatment. Other adverse reactions have occasionally been reported. Most adverse events were "mild to moderate" in intensity.
Tabulated list of adverse reactions
The following adverse reactions were reported in controlled clinical trials at the recommended dose of 2 mg with frequencies corresponding to: very common (≥ 1/10), common (≥ 1/100,
Description of some adverse reactions
After the first day of treatment, the most common adverse reactions were reported with similar frequency (difference in incidence of no more than 1% between prucalopride and placebo) during therapy with Resolor and during treatment with placebo, with the exception of nausea and diarrhea which continued to occur more frequently during Resolor therapy, although less pronounced (differences in incidence between Resolor and placebo of 1.3% (nausea) and 3.4% (diarrhea), respectively).
Palpitations were reported in 0.7% of patients treated with placebo, 0.9% of patients treated with 1 mg prucalopride, 0.9% of patients treated with 2 mg prucalopride and 1.9% of patients treated with 4 mg prucalopride Most patients continued to take prucalopride Patients should discuss with the treating physician the new onset of palpitations, as well as the appearance of any new symptoms.
Reporting of suspected adverse reactions
The reporting of suspected adverse reactions that occur after the authorization of the medicinal product is important, as it allows continuous monitoring of the benefit / risk ratio of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Italian Medicines Agency. . Website: http://www.agenziafarmaco.gov.it/it/responsabili.
04.9 Overdose
In a study in healthy volunteers, prucalopride treatment was well tolerated when administered in an escalating regimen up to 20 mg once daily (10 times the recommended therapeutic dose). An overdose may result in symptoms that "amplify the known pharmacodynamic effects of prucalopride and include headache, nausea and diarrhea. No specific treatment is available for Resolor overdose. Should an overdose occur, the patient should be treated symptomatically and should be treated". Supportive measures be taken as needed. Excessive fluid loss caused by diarrhea or vomiting may require correction of electrolyte imbalances.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: other laxatives, ATC code: A06AX05.
Mechanism of action
Prucalopride is a dihydrobenzofuranecarboxamide with gastrointestinal prokinetic activity.Prucalopride is a selective, high-affinity serotonin (5-HT4) receptor agonist, which probably explains its prokinetic effects. In vitro an "affinity for other receptors was detected only at concentrations that exceed its affinity for the 5-HT4 receptor by at least 150 times. In rats, prucalopride in vivo, at doses above 5 mg / kg (30-70 times the clinical exposure and beyond), it induces hyperprolactinemia caused by an antagonist action against the D2 receptor.
In dogs, prucalopride alters colon motility patterns through stimulation of the serotonin 5-HT4 receptor: it stimulates proximal colon motility, improves gastroduodenal motility and accelerates delayed gastric emptying. Prucalopride also induces giant migrating contractions. These are equivalent to the mass movements of the colon in humans and provide the main driving force for defecation. In dogs, the effects observed in the gastrointestinal tract are sensitive to blockade with selective 5-HT4 receptor antagonists, thereby demonstrating that the effects observed are exerted through the selective action on 5-HT4 receptors.
These pharmacodynamic effects of prucalopride were confirmed in humans by manometry used in subjects with chronic constipation in a randomized, open-label, crossover study with blinded evaluation of the effects of prucalopride 2 mg and an osmotic laxative on colon motility based on of the number of colon contractions that propagate at great amplitude (HAPC, high-amplitude propagating contractions, also known as giant migrant contractions). Compared to treatments for osmotic constipation, the prokinetic stimulation produced by prucalopride increased the motility of the colon to the extent expressed by the number of HAPCs in the 12 hours after administration of the experimental product. The benefit or clinical relevance of this mechanism of action relative to other laxatives has not been studied.
Clinical efficacy and safety
Adult population
The efficacy of Resolor was demonstrated in three multicentre, randomized, double-blind, 12-week, placebo-controlled studies in subjects with chronic constipation (n = 1,279 treated with Resolor, 1,124 females, 155 males). The doses of Resolor assessed in each of these three studies were 2 mg and 4 mg once daily. The primary efficacy endpoint was the percentage (%) of subjects achieving normalization of bowel movements defined as a mean of three or more spontaneous and complete movements of the intestine (Spontaneous complete bowel movements, SCBM) per week over the 12-week treatment period.
The percentage of female patients for whom laxatives failed to provide adequate relief, treated with the recommended 2 mg dose of Resolor (n = 458), who achieved a mean of ≥ 3 SCBMs per week was 31. 0% (week 4) and 24.7% (week 12), versus 8.6% (week 4) and 9.2% (week 12) in the placebo group. A clinically significant improvement in ≥1 SCBM per week, the most important secondary efficacy endpoint, was achieved in 51.0% (week 4) and 44.2% (week 12) of subjects treated with 2 mg of Resolor, versus 21.7% (week 4) and 22.6% (week 12) of placebo.
The effect of Resolor on spontaneous bowel movements (Spontaneous Bowel Movements, SBM) was also statistically superior to placebo in the proportion of patients who had an increase of ≥1 SBM / week over the 12-week treatment period. At week 12, 68.3% of patients treated with Resolor 2 mg had a mean increase of ≥1 SBM / week, compared with 37.0% of patients treated with placebo (p
In all three studies, treatment with Resolor also resulted in significant improvements in assessments of a range of specific and validated pathological symptoms (PAC-SYM, patient constipation symptom assessment), which include abdominal symptoms (bloating, discomfort, pain and cramps), defecators (incomplete bowel movements, false alarms, exertion, excessive stool hardness, insufficient stool volume) and rectal (painful bowel movements, burning, bleeding / tearing), assessed at week 4 and week 12. At Week 4, the percentage of patients with ≥1 improvement from baseline on the PAC-SYM subscales of abdominal, defecatory and rectal symptoms was 41.3%, 41.6% and 31.3%, respectively, in patients treated with Resolor 2 mg, compared with 26.9%, 24.4% and 22.9% in placebo-treated patients. Similar results were observed at Week 12: 43.4%, 42.9%, and 31.7% respectively in patients treated with Resolor 2 mg, compared with 26.9%, 27.2% and 23.4% in placebo-treated patients (p
In both evaluations, at week 4 and week 12, a significant benefit was also observed with respect to a number of parameters concerning the quality of life, such as the level of satisfaction with the treatment, bowel habits and worries, discomfort and physical and psychosocial discomfort. At week 4, the percentage of patients with ≥1 improvement from baseline on the Subjective Constipation Assessment-Quality of Life (PAC-QOL) subscale was 47.7% in patients treated with Resolor 2 mg, compared with 20, 2% in patients treated with placebo. Similar results were observed at Week 12: 46.9% in patients treated with Resolor 2 mg, respectively, compared with 19.0% in patients treated with placebo (p
In addition, the efficacy, safety and tolerability of Resolor in male patients with chronic constipation were evaluated in a 12-week, multicenter, randomized, double-blind, placebo-controlled study (N = 370). The primary endpoint of the study was met: a statistically significant higher proportion of subjects in the Resolor group (37.9%) had a mean weekly SCMB ≥ 3, compared to subjects in the placebo group (17.7 %) (p
Long-term study
The efficacy and safety of Resolor in patients (aged ≥18 years) with chronic constipation were evaluated in a 24-week, multicenter, randomized, double-blind, placebo-controlled study (N = 361). of patients with a mean weekly frequency of spontaneous and complete bowel movements (SCBM) ≥3 (responders) during the 24-week double-blind treatment phase was not statistically different (p = 0.367) between treatment groups with Resolor (25.1%) and placebo (20.7%). The difference between treatment groups from mean weekly SCBM frequency ≥3 was not statistically significant for Weeks 1 to 12, a result in contrast to the other 5 multicenter, randomized, double-blind, placebo-controlled studies. 12 weeks duration which demonstrated efficacy of prucalopride in adult patients for the same evaluation period. Therefore the study is considered inconclusive with respect to efficacy. However, the totality of the data, including the other double-blind, placebo-controlled, 12-week studies, supports the efficacy of Resolor. The safety profile of Resolor observed in this 24-week study is consistent with that. emerged from previous 12-week studies.
Resolor showed no rebound phenomena and was not addictive.
In-depth study on QT
A thorough QT study was performed to evaluate the effects of Resolor on the QT interval at therapeutic (2 mg) and supra-therapeutic (10 mg) doses and the results were compared with the effects of placebo and a positive control. This study did not demonstrated significant differences between Resolor used at both doses and placebo based on mean QT measurements and an "abnormal value analysis." This confirmed the results of two placebo-controlled QT studies. In double-blind clinical trials, the incidence of QT-related adverse events and ventricular arrhythmias was low and comparable to that of the placebo group.
Pediatric population
The efficacy and safety of Resolor in pediatric patients (ages 6 months - 18 years) with functional constipation were evaluated in an 8-week, double-blind, placebo-controlled study (N = 213), followed by a 16-week open-label comparator-controlled study (polyethylene glycol 4000) lasting up to 24 weeks (N = 197). Children weighing ≤50 kg were given an increased starting dose of 0.04 mg / kg / day gradually between 0.02 and 0.06 mg / kg / day (for a maximum of 2 mg / day) of Resolor oral solution or corresponding placebo. Children weighing> 50 kg received 2 mg / day of Resolor tablets or corresponding placebo.
Response to treatment was defined as a mean of ≥3 spontaneous bowel movements (SBM) per week and a mean number of faecal incontinence episodes ≤1 every 2 weeks. Study results showed no differences. in terms of efficacy between Resolor and placebo: response rates were 17% and 17.8%, respectively (P = 0.9002). Resolor was generally well tolerated. The incidence of subjects with at least 1 adverse event onset during treatment (TEAE) was similar between the Resolor group (69.8%) and the placebo group (60.7%). Overall, the safety profile of Resolor in children was the same as in adults.
05.2 "Pharmacokinetic properties
Absorption
Prucalopride is rapidly absorbed; after a single oral dose of 2 mg, Cmax was reached in 2-3 hours. Absolute oral bioavailability is> 90%. Concomitant food intake does not affect the oral bioavailability of prucalopride.
Distribution
Prucalopride is widely distributed and has a steady state volume of distribution (Vdss) of 567 liters. The protein binding of prucalopride is about 30%.
Biotransformation
Metabolism is not the major route of elimination for prucalopride. In vitro, human liver metabolism is very slow and only a minimal amount of metabolites are found. In an oral dose study in humans with radiolabelled prucalopride, small amounts of seven metabolites were found in urine and faeces. The quantitatively most represented metabolite in excretion, R107504, accounted for 3.2% and 3.1%, respectively. of the dose in urine and faeces. Other metabolites identified and quantified in urine and faeces were R084536 (formed by N-dealkylation), corresponding to 3% of the dose and the products of hydroxylation (3% of the dose) and N-oxidation ( 2% of dose) The unchanged active substance constituted approximately 92-94% of the total radioactivity in plasma. R107504, R084536 and R104065 (formed by O-demethylation) were identified as minor plasma metabolites.
Elimination
A large fraction of the active substance is eliminated unchanged (60-65% of the administered dose in the urine and about 5% in the faeces). Renal excretion of unchanged prucalopride involves both passive filtration and active secretion. Plasma clearance of prucalopride averages 317 ml / minutes. Its terminal half-life is approximately one day. Steady state is reached within three to four days. With once daily treatment with 2 mg prucalopride, steady-state plasma concentrations fluctuate between minimum and maximum values of 2.5 and 7 ng / ml, respectively. The accumulation ratio after a single daily dose ranged from 1 , 9 and 2.3. The pharmacokinetics of prucalopride are dose proportional both within the therapeutic range and beyond (tested up to 20 mg). Prucalopride administered once daily exhibits 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 and that age, body weight, gender or race had no influence.
Senior citizens
After a single daily dose of 1 mg, the maximum plasma concentrations and AUC of prucalopride in elderly subjects were 26-28% higher than in young adults. This effect may be attributed to a decrease in renal function in the elderly.
Kidney failure
Compared to subjects with normal renal function, plasma concentrations of prucalopride after a single dose of 2 mg were on average 25% and 51% higher in subjects with mild renal insufficiency, respectively (ClCR 50-79 ml / minutes). and moderate (ClCR25-49 ml / minutes). In subjects with severe renal impairment (ClCR ≤ 24 ml / minutes), plasma concentrations were 2.3 times the levels found in healthy subjects (see sections 4.2 and 4.4).
Hepatic insufficiency
Non-renal elimination contributes approximately 35% to total elimination. In a small pharmacokinetic study, the Cmax and AUC of prucalopride were on average 10-20% higher in patients with moderate to severe hepatic impairment than in healthy subjects (see sections 4.2 and 4.4).
05.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, reproductive and developmental toxicity. A large number of drug safety studies, carried out with particular attention to cardiovascular parameters, have shown no relevant changes in hemodynamic and ECG-derived (QTc) parameters, except for a modest increase in heart rate and blood pressure observed in anesthetized pigs after intravenous administration, and an increase in blood pressure in conscious dogs after intravenous bolus administration, which, however, was not observed in either anesthetized dogs or after oral administration in dogs in which similar plasma levels are achieved. A neonatal / juvenile subcutaneous toxicity study conducted on 7-55 day old rats showed a NOAEL of 100 mg / kg / day. The exposure rates determined based on the AUC0-24h at NOAEL compared to those detected in pediatric subjects (treated with approximately 0.04 mg / kg / day) were included in the range from 21 to 71, thus ensuring adequate safety margins for the clinical dose.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Core of the cornpress
Lactose monohydrate
Microcrystalline cellulose
Colloidal silica dioxide
Magnesium stearate
Tablet coating
Hypromellose
Lactose monohydrate
Triacetin
Titanium dioxide (E171)
Macrogol
06.2 Incompatibility
Not relevant.
06.3 Period of validity
4 years.
06.4 Special precautions for storage
Store in the original blister to protect from moisture.
06.5 Nature of the immediate packaging and contents of the package
Aluminum / aluminum perforated (calendar) unit dose blisters containing 7 tablets. Each pack contains 7 x 1, 14 x 1, 28 x 1 or 84 x 1 film-coated tablets.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
No special instructions.
07.0 MARKETING AUTHORIZATION HOLDER
Shire Pharmaceuticals Ireland Limited
5 Riverwalk
Citywest Business Campus
Dublin 24
Ireland
08.0 MARKETING AUTHORIZATION NUMBER
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)
041016015
041016027
041016041
041016066
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 15 October 2009
Date of most recent renewal: 06 June 2014
10.0 DATE OF REVISION OF THE TEXT
05/2015
