Consumer medicine information

Rospride

Prucalopride

BRAND INFORMATION

Brand name

Rospride

Active ingredient

Prucalopride

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Rospride.

SUMMARY CMI

ROSPRIDE

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using ROSPRIDE?

ROSPRIDE contains the active ingredient Prucalopride succinate. ROSPRIDE 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.

For more information, see Section 1. Why am I using ROSPRIDE? in the full CMI.

2. What should I know before I use ROSPRIDE?

Do not use if you have ever had an allergic reaction to ROSPRIDE or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use ROSPRIDE? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with ROSPRIDE and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use ROSPRIDE?

  • 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.
  • This medicine should be taken with or without food and drinks, at any time once a day.

More instructions can be found in Section 4. How do I use ROSPRIDE? in the full CMI.

5. What should I know while using ROSPRIDE?

Things you should do

  • Remind any doctor, dentist or pharmacist you visit that you are using ROSPRIDE.
  • Tell your doctor immediately if you become pregnant/ if you experience changes in mood or behaviour, or if your depression gets worse while you are taking this medicine.

Things you should not do

  • Do not stop using this medicine suddenly unless your doctor tells you to.
  • Do not use more than your doctor tells you to.

Driving or using machines

  • ROSPRIDE may cause drowsiness. If affected do not drive or operate machinery or do anything else that could be dangerous.

Looking after your medicine

  • Prucalopride tablets should be kept out of reach of children.
  • Store below 25°C. Store in the original blister in order to protect from moisture.

For more information, see Section 5. What should I know while using ROSPRIDE? in the full CMI.

6. Are there any side effects?

Prucalopride tablets may cause headache, nausea, weakness, dizziness or spinning sensation (vertigo), fatigue, abnormal bowel sounds, flatulence, general feeling of discomfort or uneasiness (malaise), back pain, 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.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

ROSPRIDE

Active ingredient(s): Prucalopride succinate

Consumer Medicine Information (CMI)

This leaflet provides important information about using ROSPRIDE. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using ROSPRIDE.

Where to find information in this leaflet:

1. Why am I using ROSPRIDE?
2. What should I know before I use ROSPRIDE?
3. What if I am taking other medicines?
4. How do I use ROSPRIDE?
5. What should I know while using ROSPRIDE?
6. Are there any side effects?
7. Product details

1. Why am I using ROSPRIDE?

ROSPRIDE contains the active ingredient Prucalopride succinate. ROSPRIDE acts on the muscle wall of the gut, helping to restore the normal functioning of the bowel.

ROSPRIDE 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.

ROSPRIDE 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.

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.

2. What should I know before I use ROSPRIDE?

Warnings

Do not use ROSPRIDE if:

  • you are allergic to prucalopride succinate, or any of the ingredients listed at the end of this leaflet.
  • Always check the ingredients to make sure you can use this medicine.
  • ROSPRIDE 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.
  • 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

Check with your doctor if you:

  • If you are not sure whether you should take this medicine
  • have any other 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
  • take any medicines for any other condition.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant. It is recommended not to take ROSPRIDE if you are pregnant or if you intend to become pregnant, unless your doctor advises you to do so.

Talk to your doctor if you are breastfeeding or intend 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.

Do not use this medicine:

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

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your 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

Some medicines may interfere with ROSPRIDE and affect how 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.

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

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect ROSPRIDE.

4. How do I use ROSPRIDE?

How much to take / use

  • 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.
  • Follow the instructions provided and use ROSPRIDE until your doctor tells you to stop.

When to take / use ROSPRIDE

  • ROSPRIDE 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.

How to take ROSPRIDE

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

If you forget to use ROSPRIDE

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 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 ROSPRIDE your constipation symptoms may come back again.

If you use too much ROSPRIDE

If you think that you have used too much ROSPRIDE, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26 in Australia), or (0800 POISON or 0800 764 766 in New Zealand)
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

It is important to keep to the dose as prescribed by your doctor. If you have taken more ROSPRIDE 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.

5. What should I know while using ROSPRIDE?

Things you should do

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

Call your doctor straight away if you:

  • become pregnant while you are taking this medicine
  • experience changes in mood or behaviour, or if your depression gets worse while you are taking this medicine

Always follow your doctor's instructions carefully. Remind any doctor, dentist or pharmacist you visit that you are using ROSPRIDE if you are about to be started on any new medicines.

Things you should not do

  • Do not stop using this medicine suddenly or lower the dose without checking with your doctor.
  • 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.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how ROSPRIDE affects you.

ROSPRIDE 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.

Looking after your medicine

  • 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.
  • Store below 25°C.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on windowsills.

Keep it where young children cannot reach it.

A locked cupboard at least one-and-a-half meters above the ground is a good place to store medicines.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

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

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effects

What to do

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

Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effects

What to do

  • decreased appetite
  • fever
  • diarrhoea
  • vomiting
  • disturbed digestion (dyspepsia)
  • increase in frequency of passing urine (pollakiuria)
  • abdominal pain
Tell your doctor as soon as possible if you have any of the following as you may need medical attention

Very Serious side effects

Very Serious side effects

What to do

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

Call your doctor straight away, go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

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

What ROSPRIDE contains

Active ingredient

(main ingredient)

Prucalopride succinate

Other ingredients

(inactive ingredients)

Lactose monohydrate
Microcrystalline cellulose
Magnesium stearate
Colloidal anhydrous silica
Hypromellose
Titanium dioxide
Macrogol 400
Polysorbate 80

Iron oxide red (2 mg tablet only)

Do not take this medicine if you are allergic to any of these ingredients.

What ROSPRIDE looks like

ROSPRIDE Film-coated tablets are available in two strengths:

1 mg – white to off-white, round, tablets with “C” debossed on one side and “11” on the other side.

2 mg – pink, round, tablets with “C” debossed on one side and “12” on the other side.

Pack sizes:

ROSPRIDE comes in blister packs of 28 film-coated tablets.

Australian Registration Number

ROSPRIDE 1 mg tablets - AUST R 358078

ROSPRIDE 2 mg tablets - AUST R 358079

Who distributes ROSPRIDE

Medsurge Healthcare Pty Limited
Unit 2, 6-7 Gilda Court
MULGRAVE VICTORIA 3170
Tel: 1300 788 261
www.medsurge.com.au

This leaflet was prepared in July 2022.

Published by MIMS September 2022

BRAND INFORMATION

Brand name

Rospride

Active ingredient

Prucalopride

Schedule

S4

 

Notes

Distributed by Medsurge Healthcare

1 Name of Medicine

Prucalopride.

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, tablets with "C" debossed on one side and "11" on the other side.

2 mg.

Pink, round, tablets with "C" debossed on one side and "12" on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Prucalopride is indicated for the treatment of chronic functional constipation in adults in whom laxatives fail to provide adequate relief.
Before prucalopride 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 prucalopride is not effective within four weeks, the benefit of continuing treatment should be reconsidered.

4.2 Dose and Method of Administration

Dosage.

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

Adults.

2 mg once daily.

Method of administration.

Prucalopride 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 prucalopride (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.

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

Treatment duration.

If the intake of the prescribed once daily dose of prucalopride 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 prucalopride 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 prucalopride 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 prucalopride 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 prucalopride 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 prucalopride has been demonstrated only in patients with chronic functional constipation. Efficacy and safety of prucalopride 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 prucalopride 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 prucalopride 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 prucalopride to patients with these conditions. In particular, prucalopride 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 prucalopride 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 prucalopride 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.

Prucalopride 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 prucalopride.
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 prucalopride on the pharmacokinetics of warfarin, digoxin, alcohol, paroxetine and oral contraceptives. 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.
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.
Prucalopride 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 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. Prucalopride is not recommended during pregnancy, and women of childbearing potential should use effective contraception during treatment with prucalopride.
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 prucalopride, no effects on the breastfed newborns/infants are anticipated. In the absence of human data in women who breastfed while taking prucalopride, it is not recommended to use prucalopride 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 prucalopride on the ability to drive and use machines have been performed. Prucalopride 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)

Prucalopride has been given orally to approximately 2,700 patients with chronic constipation in controlled clinical studies. Of these patients, almost 1,000 patients received prucalopride 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 prucalopride 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 prucalopride 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 prucalopride 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 prucalopride 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 prucalopride treatment among the elderly (> 65 years) groups were gastrointestinal disorders and headache. No clinically meaningful increase of adverse events was observed in prucalopride 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 prucalopride and placebo) during prucalopride therapy as during placebo, with the exception of nausea and diarrhoea that still occurred more frequently during prucalopride 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.
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.

Suicidal behaviour/ideation.

In the double-blind clinical trials, one patient reported a suicide attempt 7 days after the end of treatment with prucalopride 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 prucalopride 2 mg or 4 mg; both discontinued prucalopride 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 prucalopride in adult patients with chronic idiopathic constipation. The standardized incidence rate (IR) per 1000 subject-years for MACE for prucalopride was compared with the IR for placebo. The total exposure in the double-blind studies was 565.2 subject-years in the prucalopride group, 384 subject-years in the placebo group and 2769 subject-years in the double-blind and open-label clinical studies. The IR for MACE was 3.5 (2 subjects out of 3366) in the double-blind prucalopride group, 5.2 (2 subjects out of 2019) in the placebo group, and 3.3 (9 subjects out of 4472) for prucalopride in the combined double-blind and open-label clinical studies. The data do not indicate an increased risk of MACE attributable to prucalopride when compared to placebo.

Observational cardiovascular cohort study.

The overall (CV) safety of prucalopride was assessed in an observational population-based cohort study using European healthcare databases. New users of prucalopride (N=5715) were matched to new users of polyethylene glycol 3350 (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 prucalopride 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 prucalopride 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 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 prucalopride 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 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) 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 prucalopride 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 prucalopride 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 prucalopride 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 prucalopride 2 mg daily, one additional patient had ≥ 3 SCBM per week (i.e. NNT=8), indicating that for patients on prucalopride 2 mg, 2 out of 8 patients responded. For an average of 7 patients who received prucalopride 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 prucalopride 2 mg daily or 4 patients receiving prucalopride 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, prucalopride significantly improved the time to first bowel movement when compared with placebo. In addition, for all three studies, treatment with prucalopride 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 prucalopride 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 prucalopride 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 prucalopride 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 prucalopride 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 radio-labelled 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). Prucalopride 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 & 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

Prucalopride tablets contain the following inactive ingredients:

Tablet core.

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

Coating.

Hypromellose, titanium dioxide, macrogol 400, polysorbate 80, iron oxide red (2 mg tablet only).

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

Prucalopride tablets should be kept out of reach of children. Store below 25°C. Store in the original blister in order to protect from moisture.

6.5 Nature and Contents of Container

Both strengths of prucalopride film-coated tablets are available in Alu - OPA/Alu/PVC or Alu - PVC/PE.EVOH.PE/PCTFE perforated unit dose blisters containing 28 film-coated tablets.

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

Prucalopride succinate is a white to almost white powder.

Chemical structure.

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)

S4 - Prescription Only Medicine.

Summary Table of Changes