Consumer medicine information

Resotrans

Prucalopride

BRAND INFORMATION

Brand name

Resotrans

Active ingredient

Prucalopride

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Resotrans.

What is in this leaflet

This leaflet answers some common questions about RESOTRANS. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking RESOTRANS against the benefits this medicine is expected to have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet while being treated. You may need to read it again.

What RESOTRANS is used for

RESOTRANS tablets are used for the treatment of long-standing constipation in adults in whom conventional medicines used to treat constipation (laxatives) fail to provide adequate relief.

RESOTRANS is not used to treat constipation due to other medical conditions including disorders which involve the over-production or under-production of hormones from the endocrine gland, disorders that involve an alteration in normal metabolism, disorders of the nervous system and constipation due to use of medicines including opioid medicines such as codeine, oxycodone and morphine.

RESOTRANS contains the active ingredient prucalopride succinate. It acts on the muscle wall of the gut, helping to restore the normal functioning of the bowel.

Your doctor may have prescribed this medicine for another reason. Ask your doctor if you have any questions about why it has been prescribed for you.

There is no evidence that this medicine is addictive.

This medicine is available only with a doctor's prescription.

Before you take RESOTRANS

When you must not take it

Do not take RESOTRANS if you have an allergy to:

  • prucalopride, the active ingredient in the medicine
  • any of the ingredients listed at the end of this leaflet.

RESOTRANS contains lactose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.

Symptoms of an allergic reaction may include rash, itching or hives on the skin, shortness of breath, wheezing or difficulty breathing, swelling of the face, lips, tongue or other parts of the body.

Do not take RESOTRANS if:

  • you are on kidney dialysis (a procedure used to remove waste products from the blood of a person with kidney failure)
  • if you suffer from perforation or obstruction of the gut wall, or severe inflammation of the intestines
  • if you had recent bowel surgery.

If you are not sure whether you should take this medicine, talk to your doctor.

Before you start to take RESOTRANS:

Tell your doctor if you have or have had any medical conditions, especially the following:

  • severe kidney disease
  • severe liver disease
  • any other serious medical problem such as lung or heart disease, neurological or psychiatric disorders or other endocrine disorders, cancer or AIDS for which you are currently under supervision by your doctor
  • a history of changes in heart rate (fast, slow or irregular) or heart disease caused by reduced blood flow in the blood vessels of the heart muscle

You must tell your doctor if you:

  • are pregnant or planning to become pregnant. It is recommended not to take RESOTRANS if you are pregnant or if you intend to become pregnant, unless your doctor advises you to do so.
  • are breastfeeding or wish to breastfeed. When breast-feeding, prucalopride can pass into breast milk, and although there is no evidence that this is harmful, it is better not to use this medicine while breastfeeding unless your doctor advises you to do so.

If you have not told your doctor about any of the above, tell them before you start taking RESOTRANS.

Do not take this medicine if the packaging is torn or shows signs of tampering.

Do not take this medicine beyond the expiry date (month and year) printed on the pack.

The medicine must not be given to children or adolescents (under 18 years of age).

Taking other medicines:

Tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines that you can buy without a prescription from a pharmacy, supermarket or health food shop.

In particular, tell your doctor if you are taking the following medicines:

  • ketoconazole (an antifungal agent)
  • verapamil
  • cyclosporine A
  • quinidine
  • erythromycin (an antibiotic used to treat infections)
  • medicines known to cause irregular heart beat or other heart problems
  • atropine-like substances
  • oral contraceptives

These medicines may be affected by RESOTRANS or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

You doctor or pharmacist will have more information on medicines to be careful with or avoid while taking this medicine.

RESOTRANS does not interact with the following medicines: warfarin, digoxin and paroxetine.

How to take RESOTRANS

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

How much to take

The usual dose for most patients is one 2 mg tablet once a day. If you are older than 65 years, the starting dose is one 1 mg tablet once a day, which your doctor may increase to 2 mg once a day if needed. Your doctor may also recommend a lower dose of one 1 mg tablet daily if you have severe kidney or liver disease.

How to take it

This medicine can be taken with or without food and drinks, at any time of the day.

When to take it

This medicine should be taken once a day. You must take this medicine every day for as long as your doctor prescribes it.

Your doctor may want to reassess your condition and the benefit of continued treatment after the first 4 weeks and thereafter at regular intervals.

If you forget to take it

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to. Otherwise, take it as soon as you remember, and then go back to taking it as you would normally.

Do not take a double dose to make up for the dose that you missed. This may increase the chance of you getting an unwanted side effect.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you stop taking it

If you stop taking RESOTRANS, your constipation symptoms may come back again.

If you have taken too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre for advice or go to Accident and Emergency at your nearest hospital, if you think that you or anyone else may have taken too much RESOTRANS. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

Poisons Information Centre telephone numbers:

  • Australia: 13 11 26
  • New Zealand: 0800 POISON or 0800 764 766.

Keep these telephone numbers handy.

It is important to keep to the dose as prescribed by your doctor. If you have taken more RESOTRANS than you should, it is possible that you will get diarrhoea, headache and/or nausea. In case of diarrhoea, make sure that you drink enough water.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

While you are taking RESOTRANS

If you experience severe diarrhoea after taking RESOTRANS, certain medicines such as the oral contraceptive pill may not work properly and the use of an extra method of contraception is recommended.

Things you must do

  • Always follow your doctor's instructions carefully
  • Tell your doctor immediately if you become pregnant while you are taking this medicine
  • Tell your doctor immediately if you experience changes in mood or behaviour, or if your depression gets worse while you are taking this medicine
  • Tell your doctor or pharmacist that you are taking this medicine if you are about to be started on any new medicines.

Things you must not do

  • Do not give your medicine to anyone else, even if they have the same condition as you.
  • Do not use this medicine to treat any other complaints unless your doctor tells you to.
  • Do not stop taking your medicine or lower the dose without checking with your doctor.

Things to be careful of

Be careful driving or operating machinery until you know how RESOTRANS affects you. RESOTRANS has been associated with dizziness and fatigue particularly during the first day of treatment which may have an effect on driving and using machines.

If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

Side Effects

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some side effects.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor if you experience any of the following and they worry you:

  • Headache or migraine
  • nausea
  • weakness
  • dizziness or spinning sensation (vertigo)
  • fatigue
  • abnormal bowel sounds
  • flatulence
  • general feeling of discomfort or uneasiness (malaise)
  • back pain

Tell your doctor as soon as possible if you have any of the following as you may need medical attention:

  • decreased appetite
  • fever
  • diarrhoea
  • vomiting
  • disturbed digestion (dyspepsia)
  • increase in frequency of passing urine (pollakiuria)
  • abdominal pain

Tell your doctor immediately if you notice any of the following:

  • suicidal thoughts or attempts
  • tremors
  • pounding heart
  • rectal bleeding.

Other side effects not listed above may also occur in some people. Tell your doctor if you notice any other effects.

After using RESOTRANS

Storage

Keep your tablets in their blister pack until it is time to take them.

If you take the tablet out of the blister pack, they may not keep well.

Keep RESOTRANS in a cool dry place where the temperature stays below 30°C. Do not store this medicine or any other medicines in a bathroom or near a sink. Do not leave it in the car or on window sills.

Heat and dampness can destroy some medicines.

Keep this medicine where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking RESOTRANS or the tablets have passed their expiry date, ask your pharmacist what to do with any tablets that are left over.

Product Description

What it looks like

RESOTRANS 1 mg tablets are white to off-white, round, biconvex tablets marked PRU 1 on one side.

RESOTRANS 2 mg tablets are pink, round, biconvex shaped tablets marked PRU 2 on one side.

Ingredients

The active ingredient in RESOTRANS tablets is prucalopride succinate. The 1 mg tablet contains 1 mg of prucalopride and the 2 mg tablet contains 2 mg of prucalopride in pack sizes of 7 and 28 film-coated tablets.

The other ingredients in the 1 mg tablet are lactose monohydrate, microcrystalline cellulose, magnesium stearate, colloidal anhydrous silica and Opadry II complete film coating system 33G28707 WHITE (ARTG PI No 107234).

The other ingredients in the 2 mg tablet are lactose monohydrate, microcrystalline cellulose, magnesium stearate, colloidal anhydrous silica and Opadry II complete film coating system 33G34847 PINK (ARTG PI No 107235).

Sponsor

Amdipharm Mercury (Australia) Pty Ltd
Level 9, 76 Berry Street
North Sydney NSW 2060

Ph: 1800 627 680

Amdipharm Mercury (Australia) Pty Ltd is an ADVANZ PHARMA company

This leaflet was prepared in December 2022.

TGA registration number:

1mg tablet - AUST R 176747

2mg tablet - AUST R 176746

Published by MIMS February 2023

BRAND INFORMATION

Brand name

Resotrans

Active ingredient

Prucalopride

Schedule

S4

 

1 Name of Medicine

Prucalopride (as succinate).

2 Qualitative and Quantitative Composition

Each film-coated tablet contains 1 mg or 2 mg of prucalopride as the succinate salt.

Excipient of known effect.

Sugars as lactose.
For a full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Film-coated tablet.
1 mg - white to off-white, round, biconvex tablets marked "PRU 1" on one side.
2 mg - pink, round, biconvex tablets marked "PRU 2" on one side.

4 Clinical Particulars

4.1 Therapeutic Indications

Resotrans is indicated for the treatment of chronic functional constipation in adults in whom laxatives fail to provide adequate relief.
Before Resotrans is considered patients must have tried at least two different types of laxatives from different classes (at the highest tolerated recommended doses) for at least six months, but have not had adequate relief from constipation.
If treatment with Resotrans is not effective within four weeks, the benefit of continuing treatment should be reconsidered.

4.2 Dose and Method of Administration

Dosage.

Resotrans film coated tablets are for oral use and can be taken with or without food.

Adults.

2 mg once daily.

Method of administration.

Resotrans film-coated tablets are for oral use and can be taken with or without food.

Dosage adjustment.

Hepatic impairment.

The dose for patients with severe hepatic impairment (Child-Pugh class C) is 1 mg once daily (see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties). No dose adjustment is required for patients with mild to moderate hepatic impairment.
Due to the specific mode of action of Resotrans (stimulation of propulsive motility), exceeding the daily dose of 2 mg is not expected to increase efficacy.

Renal impairment.

The dose for patients with severe renal impairment not requiring dialysis (GFR < 30 mL/min/1.73 m2) is 1 mg once daily (see Section 4.3 Contraindications; Section 5.2 Pharmacokinetic Properties). No dose adjustment is required for patients with mild to moderate renal impairment.

Elderly (> 65 years).

Start with one 1 mg tablet once daily (see Section 5.2 Pharmacokinetic Properties); if needed the dose can be increased to 2 mg once daily.

Paediatric.

Resotrans is not recommended in children and adolescents younger than 18 years.

Treatment duration.

If the intake of the prescribed once daily dose of Resotrans is not effective after four weeks of treatment, the patient should be re-examined and the benefit of continuing treatment should be reconsidered.
Efficacy and safety of Resotrans has been established in double-blind placebo controlled studies for up to 12 weeks. Patients should be reassessed after 12 weeks prior to continuation of treatment with prucalopride.

Use with laxatives.

Efficacy and safety of Resotrans when used in combination with laxatives has not been assessed, although laxatives were used as rescue medications in the pivotal clinical trials.

4.3 Contraindications

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 and active severe inflammatory conditions of the intestinal tract, such as Crohn's disease, and ulcerative colitis and toxic megacolon/megarectum.
Recent bowel surgery.

4.4 Special Warnings and Precautions for Use

Prior to receiving Resotrans patients require a thorough history and examination to exclude secondary causes of constipation and to establish failure to respond adequately to at least 2 different types of laxatives from different classes for at least 6 months.
The safety and efficacy of Resotrans in combination with laxatives has not been assessed, although laxatives were used as rescue medications in the pivotal clinical trials.

Secondary constipation.

Efficacy and safety of Resotrans has been demonstrated only in patients with chronic functional constipation. Efficacy and safety of Resotrans in patients with secondary causes of constipation including endocrine disorders, metabolic disorders and neurologic disorders have not been assessed and use in these patients is not recommended. Efficacy and safety of Resotrans in patients with medication related constipation, including constipation due to opioid use as a secondary cause of constipation, has not been demonstrated and use of Resotrans is not recommended.

Concomitant disease.

There is limited information in 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). Therefore, caution should be exercised when prescribing Resotrans to patients with these conditions. In particular, Resotrans should be used with caution in patients with a history of arrhythmias or ischaemic cardiovascular disease.

Oral contraceptives.

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).

Lactose.

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.

Psychiatric disorders.

Suicides, suicide attempts, and suicidal ideation have been reported in clinical trials and post-market experience. A causal association between treatment with Resotrans and suicidal ideation and behaviour has not been established. Patients should be monitored for persistent worsening of depression or the emergence of suicidal thoughts and behaviours. Counsel the patients and their caregivers and family members to be aware of any unusual changes in mood or behaviour, and to discontinue Resotrans and alert the healthcare provider immediately.

Use in hepatic impairment.

A lower dose is recommended for patients with severe hepatic impairment (see Section 4.2 Dose and Method of Administration).

Use in renal impairment.

Renal excretion is the main route of elimination of prucalopride (see Section 5.2 Pharmacokinetic Properties). A dose of 1 mg is recommended in subjects with severe renal impairment (see Section 4.2 Dose and Method of Administration).

Use in the elderly.

Start with one 1 mg tablet once daily (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties). If needed, the dose can be increased to 2 mg once daily.

Paediatric use.

Resotrans is not recommended in children and adolescents younger than 18 years.

Effects on laboratory tests.

No effects are known.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Potentiation of effect.

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%.

Reduction of effect.

Because of the mechanism of action, the use of atropine-like substances may reduce the 5-HT4 receptor mediated effects of Resotrans.
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. Prucalopride is a weak substrate for P-glycoprotein (P-gp). Prucalopride is a weak in vitro inhibitor of P-gp and BCRP transporters, and it is not a significant inhibitor of OATP1B1, OATP1B3, OAT1, OAT3, BSEP and MRP2 transporters.
Studies in healthy subjects showed that there were no clinically relevant effects of Resotrans on the pharmacokinetics of warfarin, digoxin, alcohol, paroxetine and oral contraceptives. A 30% increase in the plasma concentrations of erythromycin was found during Resotrans 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 Resotrans.
There are no data on the effect of prucalopride on SSRIs other than paroxetine or of the effect of SSRIs on prucalopride.
Therapeutic doses of probenecid, cimetidine, erythromycin and paroxetine did not affect the pharmacokinetics of prucalopride.
Resotrans should be used with caution in patients receiving concomitant drugs known to cause QTc prolongation.
Interactions with food have not been observed.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There is no information on the effects of prucalopride on human fertility. There were no adverse effects on the fertility of rats treated orally or subcutaneously with prucalopride at doses up to 20 mg/kg/day, with estimated exposure about 100 times clinical exposure at the MRHD, based on AUC.
(Category B1)
Experience with Resotrans 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 Resotrans is unknown. Resotrans is not recommended during pregnancy, and women of childbearing potential should use effective contraception during treatment with Resotrans.
There was no evidence of teratogenicity in rats or rabbits treated with prucalopride during the period of organogenesis at oral doses up to 80 mg/kg/day (respective exposures about 400 times and 40 times the clinical exposure at the MRHD, based on AUC).
 Prucalopride is excreted in breast milk. However, at therapeutic doses of Resotrans, no effects on the breastfed newborns/infants are anticipated. In the absence of human data in women who breastfed while taking Resotrans, it is not recommended to use Resotrans during breastfeeding.
Oral administration of prucalopride to rats from early gestation to weaning at doses up to 80 mg/kg/day was associated with slightly reduced pup survival due to maternotoxicity, with estimated exposure at least 100 times clinical exposure at the MRHD, based on AUC.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects of Resotrans on the ability to drive and use machines have been performed. Resotrans 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 Adverse Effects (Undesirable Effects)).

4.8 Adverse Effects (Undesirable Effects)

Resotrans has been given orally to approximately 2,700 patients with chronic constipation in controlled clinical studies. Of these patients, almost 1,000 patients received Resotrans at the recommended dose of 2 mg per day, while about 1,300 patients were treated with 4 mg Resotrans daily. Total exposure in the clinical development plan exceeded 2,600 patient years. The most frequently reported adverse reactions associated with Resotrans 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.
Adverse events reported by more than 2.0% of the patients in the 'all prucalopride' treatment group in the phase II and III double-blind placebo controlled trials in patients with chronic constipation are shown in Table 1.
A total of 564 elderly patients (≥ 65 years) with chronic constipation were treated with Resotrans in double-blind studies, with a total exposure of 63 person years. Most patients in the phase II/III double-blind placebo controlled studies were younger than 65 years. The incidence of adverse events in the < 65 years old group was 71.2% (1534 out of 2153 patients) in the Resotrans group, and 61.6% (712 out of 1155) in the placebo group. In the group of patients older than 65 years, the incidence of adverse events in the Resotrans group was 58.7% (331 out of 564) and in the placebo group 52.8% (113 out of 214). Similar to the younger age group, the most common adverse events with Resotrans treatment among the elderly (> 65 years) groups were gastrointestinal disorders and headache. No clinically meaningful increase of adverse events was observed in Resotrans treated groups as compared to placebo group.
The following adverse reactions were reported in controlled clinical studies at the recommended dose of 2 mg with frequencies corresponding to very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (> 1/1,000 to < 1/100), rare (> 1/10,000 to < 1/1,000) and very rare (≤ 1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are calculated based on the placebo controlled clinical study data.

Metabolism and nutrition disorders.

Common: decreased appetite.

Nervous system disorders.

Very common: headache. Common: dizziness. Uncommon: tremors, migraine.

Cardiac disorders.

Uncommon: palpitations.

Ear and labyrinth disorders.

Uncommon: vertigo.

Gastrointestinal disorders.

Very common: nausea, diarrhoea, abdominal pain. Common: vomiting, dyspepsia, flatulence, abnormal bowel sounds.
Uncommon: rectal haemorrhage.

Renal and urinary disorders.

Common: polyuria.

General disorders and administration site conditions.

Common: fatigue. Uncommon: fever, malaise.
After the first day of treatment, the most common adverse reactions were reported in similar frequencies (incidence less than 1% difference between Resotrans and placebo) during Resotrans therapy as during placebo, with the exception of nausea and diarrhoea that still occurred more frequently during Resotrans therapy, but less pronounced (difference in incidence between Resotrans and placebo between 1 and 3%).
Palpitations were reported in 0.7% of the placebo patients, 1.0% of the 1 mg Resotrans patients, 0.7% of the 2 mg Resotrans patients and 1.9% of the 4 mg Resotrans patients. The majority of patients continued using Resotrans. As with any new symptom, patients should discuss the new onset of palpitations with their physician.
Resotrans has been shown not to cause rebound phenomena, nor to induce dependency.
A thorough QT study was performed to evaluate the effects of Resotrans 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 Resotrans 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.

Suicidal behaviour/ ideation.

In the double-blind clinical trials, one patient reported a suicide attempt 7 days after the end of treatment with Resotrans 2 mg once daily; none were reported in patients on placebo. In the open-label trials, two patients reported a suicide attempt and another patient reported suicidal ideation. Completed suicide was reported in two patients, previously treated with Resotrans 2 mg or 4 mg; both discontinued Resotrans for at least one month prior to the event.

Cardiovascular safety analysis.

An evaluation was performed by an independent adjudication committee of all potential major adverse cardiovascular events (MACE) across 28 completed double-blind and open-label clinical studies for Resotrans in adult patients with chronic idiopathic constipation. The standardized incidence rate (IR) per 1,000 subject-years for MACE for Resotrans was compared with the IR for placebo. The total exposure in the double-blind studies was 565.2 subject-years in the Resotrans group, 384 subject-years in the placebo group and 2,769 subject-years in the double-blind and open-label clinical studies. The IR for MACE was 3.5 (2 subjects out of 3,366) in the double-blind Resotrans group, 5.2 (2 subjects out of 2,019) in the placebo group, and 3.3 (9 subjects out of 4,472) for Resotrans in the combined double-blind and open-label clinical studies. The data do not indicate an increased risk of MACE attributable to Resotrans when compared to placebo.

Observational cardiovascular cohort study.

The overall (CV) safety of Resotrans was assessed in an observational population-based cohort study using European healthcare databases. New users of Resotrans (N = 5,715) were matched to new users of polyethylene glycol 3,350 (PEG) (N = 29,372) to determine the standardized incidence rate (IR) and the adjusted incidence rate ratio (IRR) per 1,000 person-years for MACE. In this cohort study, the pooled, standardized IR for MACE was 6.57 (95% CI: 3.90, 10.39) for Resotrans compared to an IR of 10.24 (95% CI: 6.97, 14.13) for PEG and the IRR for MACE was 0.64 (95% CI: 0.36, 1.14). These data do not indicate an increased risk of MACE in patients using Resotrans as compared with patients using PEG for chronic idiopathic constipation.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

In a study in healthy volunteers, treatment with Resotrans was well tolerated when given in an uptitrating 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 Resotrans 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.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Pharmacotherapeutic group: Drugs acting on serotonin receptors, ATC code: A03AE04.
In subjects with chronic constipation, there was a reduction in small bowel transit time, an increase in gastric emptying and more rapid colonic filling. There was an increase in the frequency of bowel motions but no significant effect on colonic transit time.

Clinical trials.

The efficacy of Resotrans was established in three multicentre, randomised, double-blind, 12 week placebo controlled studies in subjects with chronic constipation (n = 1,279 on Resotrans, 1,124 females, 155 males) namely PRU-INT-6, PRU-USA-11 and PRU-USA-13. The studies consisted of 2 phases: a 2 week drug free run-in phase followed by a randomised, 12 week, double-blind, placebo controlled treatment phase. The Resotrans doses studied in each of these three studies included 2 mg and 4 mg once daily. The respective mean ages of patients in the three studies were 43.9, 48.3, and 47.9 (range 17-95) years. Patients with secondary causes of constipation including opioid use, endocrine disorders, metabolic disorders and neurologic disorders were excluded from the studies. Table 2 provides a summary of the constipation history (prior to study enrolment) demonstrating that the patients enrolled were chronically constipated. Over 70% of patients had ≤ 1 SBM at baseline and more than 80% indicated that prior therapy was inadequate.
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. The main secondary efficacy parameter was the proportion of patients with an average increase of ≥ 1 SCBM per week from run-in. A summary of primary efficacy data for individual pivotal studies is provided in Table 3. 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.
Results from the analyses of proportion of patients achieving an average of ≥ 3 SCBM per week during weeks 1-4 were similar to that for the primary efficacy endpoint. Both doses were significantly superior (p < 0.001) to placebo in each of the three studies.
In the pooled 3 pivotal study data analyses, the proportion of patients treated with the recommended dose of 2 mg Resotrans that reached an average of ≥ 3 SCBM per week was 27.8% (week 4) and 23.6% (week 12), versus 10.5% (week 4) and 11.3% (week 12) on placebo. A clinically meaningful improvement of ≥ 1 SCBM per week, the most important secondary efficacy endpoint, was achieved in 48.1% (week 4) and 43.1% (week 12) of patients treated with 2 mg Resotrans versus 23.4% (week 4) and 24.6% (week 12) of placebo patients. Based on the 12 weeks pooled data, for placebo, 1 out of 8 patients responded (i.e. had ≥ 3 SCBM/week). For an average number of 8 patients receiving Resotrans 2 mg daily, one additional patient had ≥ 3 SCBM per week (i.e. NNT = 8), indicating that for patients on Resotrans 2 mg, 2 out of 8 patients responded. For an average of 7 patients who received Resotrans 4 mg daily, one additional patient had ≥ 3 SCBM/week compared with the placebo control (i.e. NNT = 7). For a clinically meaningful improvement of ≥ 1 SCBM/week, for placebo, 1 out of 4 patients had ≥ 1 SCBM/week. For an average of 5 patients receiving Resotrans 2 mg daily or 4 patients receiving Resotrans 4 mg daily, one additional patient had ≥ 1 SCBM/week, compared with the placebo control (i.e. NNTT = 5 for the 2 mg daily, and NNTT = 4 for the 4 mg daily).
In all three studies, Resotrans significantly improved the time to first bowel movement when compared with placebo. In addition, for all three studies, treatment with Resotrans 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.

Other clinical studies.

Study INT-12 was a double-blind, placebo controlled study that evaluated the efficacy, safety and quality of life of Resotrans in 303 elderly patients (≥ 65 years) with chronic constipation. The doses studied were 1 mg, 2 mg and 4 mg. The primary efficacy endpoint was the proportion of patients with an average of ≥ 3 SCBM per week evaluated over the 4 week treatment period. The key secondary efficacy endpoint was the proportion of patients with an average increase of ≥ 1 SCBM per week. Results showed that there was a higher proportion of patients in all 3 Resotrans groups with ≥ 3 SCBM per week compared to placebo, although this observation was not statistically significant. The proportion of patients with an average increase of ≥ 1 SCBM per week was significantly higher for all 3 Resotrans treatment groups when compared to placebo. The results showed that no advantage was gained by increasing the dose beyond 1 mg.
Over 600 elderly subjects were investigated in double-blind placebo controlled phase II and III studies comparing the 0.5 mg, 1 mg, 2 mg and 4 mg doses of Resotrans with placebo. Results demonstrated that the 1 mg daily dose is the lowest effective dose in achieving the primary endpoint of ≥ 3 SCBM per week and the secondary endpoint of increase ≥ 1 SCBM per week.
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.

5.2 Pharmacokinetic Properties

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 L. 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 of prucalopride 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.

Excretion.

A large fraction of the active substance is excreted unchanged (about 60% of the administered dose in urine and at least 6% in faeces) via both passive filtration and active renal transporters (P-gp and BCRP). 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 nanogram/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, and that there was no additional effect of age, body weight, sex or race.

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 the 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 ≤ 24 mL/min), plasma concentrations were 2.3 times the levels in healthy subjects (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use).

Hepatic impairment.

Non-renal elimination contributes to about 35% of total elimination. After a single oral dose of 2 mg, Cmax and AUC of prucalopride were on average 10-20% higher in patients with moderate and severe hepatic impairment than in subjects with normal hepatic function.

Paediatric.

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 area under the curve (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 Dose and Method of Administration). Resotrans is not recommended in children or adolescents (see Section 4.4 Special Warnings and Precautions for Use, Paediatric use).

5.3 Preclinical Safety Data

Genotoxicity.

The standard bacterial reverse mutation test had a weak positive result in one of the five strains at high concentrations (≥ 0.5 mg/plate). All subsequent in vivo tests on gene mutation, chromosomal damage, unscheduled DNA repair and DNA adduct induction showed negative results, which demonstrated that prucalopride did not have genotoxic potential.

Carcinogenicity.

Carcinogenicity studies were conducted with oral prucalopride doses up to 80 mg/kg/day in mice, and 40 (female) and 80 (male) mg/kg/day in rats, for two years. In mice, the incidence of mammary gland adenocarcinomas was increased at 80 mg/kg/day (200 times clinical exposure at the MRHD, based on AUC); the no-effect dose was 20 mg/kg/day (27 times clinical exposure at the MRHD, based on AUC). In rats, the high doses were associated with increased incidences of benign adrenal phaeochromocytomas, pituitary adenomas, pancreatic adenomas, hepatocellular adenomas (mid and high doses) and thyroid follicular tumours (45 times clinical exposure at MRHD, based on AUC); the no adverse effect dose was 5 mg/kg/day (7 times clinical exposure at the MRHD, based on AUC). Mechanistic studies showed that hyperprolactinaemia resulted from D2 antagonism at high prucalopride concentrations likely caused the mammary, pituitary, pancreatic and adrenal tumours in both mice and rats. Prucalopride and its rat specific metabolism at high doses had hepatic enzyme induction potential that led to the liver and thyroid tumours in rats. Since no increase of plasma prolactin levels was observed in clinical studies and human prucalopride metabolism was very different from that of the rat, these tumour findings were considered to have minimum clinical relevance.

6 Pharmaceutical Particulars

6.1 List of Excipients

Resotrans tablets contain the following inactive ingredients:

Tablet core.

Lactose monohydrate, microcrystalline cellulose, magnesium stearate, colloidal anhydrous silica.

Coating.

1 mg: Opadry II complete film coating system 33G28707 White (ARTG PI No 107234)
2 mg: Opadry II complete film coating system 33G34847 Pink (ARTG PI No 107235).

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Resotrans tablets should be kept out of reach of children. Store below 30°C. Protect from moisture.

6.5 Nature and Contents of Container

Both strengths of Resotrans film-coated tablets are available in PA/Al/PVC/Al blisters containing 7 tablets. Each pack contains 7 or 28 film-coated tablets.
Not all pack sizes are marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.

Prucalopride succinate is a white to almost white powder.
The chemical name for prucalopride is 4-amino-5-chloro-2,3-dihydro-N-[1-(3-methoxypropyl)-4-piperidinyl]-7-benzofurancarboxamide butanedioate (1:1). Prucalopride has the following chemical structure:
C18H26ClN3O3.C4H6O4. Molecular weight: 485.96.

CAS number.

179474-85-2.

Solubility.

In organic media, prucalopride succinate is soluble in N,N-dimethylformamide, sulfinylbismethane and N,N-dimethylacetamide and sparingly soluble in methanol. In aqueous media, prucalopride succinate is freely soluble in acidic aqueous media. However, this solubility decreases with increasing pH.

Dissociation constant.

The pKa for the piperidine moiety of prucalopride succinate is 8.5, determined at 20°C by potentiometric titration of an aqueous solution of prucalopride succinate. The pKa for the amino moiety of prucalopride succinate is less than 3, determined at 20°C by spectrometric measurements of solutions of prucalopride succinate in water at different pH values.

Partition coefficient.

The partition coefficients are determined at 20°C between n-octanol and aqueous buffered solutions. The partition coefficient P is defined as the ratio of the equilibrium concentrations of a single molecular species in a two phase system of n-octanol and an aqueous buffered solution. The results for partition coefficient P are shown in Table 4.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes