Consumer medicine information

Motilium Tablets

Domperidone

BRAND INFORMATION

Brand name

Motilium

Active ingredient

Domperidone

Schedule

SUMMARY CMI

MOTILIUM^®

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 MOTILIUM?

MOTILIUM contains the active ingredient domperidone. MOTILIUM is used to treat the following condition in adults

nausea and vomiting
discomfort caused by a sow moving stomach known as gastroparesis. Symptoms include not being able to finish a meal, a feeling of being “too full”, or bloated after a meal, a loss of appetite, feeling sick and maybe comiting or belching without relief.

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

2. What should I know before I use MOTILIUM?

Do not use if you have ever had an allergic reaction to MOTILIUM 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 MOTILIUM? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with MOTILIUM 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 MOTILIUM?

The usual dose in adults is one tablet three times a day.
For nausea and vomiting this medicine is usually used for a maximum of 1 week.

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

5. What should I know while using MOTILIUM?

Things you should do	Remind any doctor, dentist or pharmacist you visit that you are using MOTILIUM
Things you should not do	Do not use MOTILIUM If you have a tumour of the pituitary gland called prolactinoma, have or have had liver disease, an increase in stomach or bowel contractions, have problems with your heart including an abnormal heart beat or are taking one of the medicines listed in section 2 in the full CMI.
Driving or using machines	Be careful before you drive or use any machines or tools until you know how MOTILIUM affects you.
Drinking alcohol	Tell your Doctor if you drink alcohol.
Looking after your medicine	Keep MOTILIUM tablets in the pack until it is time to take them Keep MOTILIUM tablets in a cool dry place where the temperature is below 30°C.

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

6. Are there any side effects?

A risk of unusual heart beat or sudden heart failure has been associated with MOTILIUM use. The risk is higher in patients older than 60 years or taking more than three tablets daily. Tell your Doctor if you have heart disease, or if you experience an allergic reaction to this medicine.

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

MOTILIUM^®

Active ingredient: Domperidone

Consumer Medicine Information (CMI)

This leaflet provides important information about using MOTILIUM. 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 MOTILIUM.

Where to find information in this leaflet:

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

1. Why am I using MOTILIUM?

MOTILIUM contains the active ingredient domperidone.

MOTILIUM is an antiemetic and a prokinetic medicine. It works by clocking the action of a chemical messenger in the brain which causes the feeling of nausea and vomiting, as well as increasing the moment or contractions of the stomach and intestines, allowing food to move more easily though the stomach.

MOTILIUM is used to treat

nausea and vomiting
discomfort caused by a slow moving stomach know as gastroparesis.

2. What should I know before I use MOTILIUM?

Warnings

Do not use MOTILIUM if:

you are allergic to domperidone, or any of the ingredients listed at the end of this leaflet. Always check the ingredients to make sure you can use this medicine
you have a tumour of the pituitary gland called prolactinoma
you have or have had liver disease
an increase in stomach or bowel contractions, for example, if you have had bleeding, a blockage or puncture in your gastrointestinal tract
you have problems with your heart, including abnormal heart beat
you are taking another medicine containing the active ingredient ketoconazole, voriconazole, itraconazole, posaconazole which is used to treat fungal infections
you are taking another medicine containing the active ingredient ritonavir or saquinavir which is used to treat HIV
you are taking another medicine containing the active ingredient telaprevir which is used to treat hepatitis C
you are taking an antibiotic containing the active ingredient erythromycin, clarithromycin or telithromycin.

Check with your doctor if you:

have a pre-existing heart condition
have or have ever had a kidney disease
have or have ever had breast cancer
are not able to digest lactose which is a sugar found in milk and milk products.

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.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

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.

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

Medicines that slowing down the breaking down (metabolism) of other medicines in the body and can also affect your heart rhythm such as:

itraconazole, ketoconazole, posaconazole, or voriconazole, which are used to treat fungal infections
erythromycin, clarithromycin, or telithromycin which are antibiotics
amiodarone which is a heart medicine
ritonavir or saquinavir which are medicines for HIV/AIDS
teleprevir which is a medicine for hepatitis C.

In particular, tell your doctor or pharmacist if you are taking any of the following:

medicines for treating fungal infections, such as ketoconazole, fluconazole, itraconazole and voriconazole
anticholinergic drugs (medicines to treat allergy, asthma, incontinence, gastrointestinal cramps, muscular spasms, depression or sleep disorders, for example, dextromethorphan or diphenhydramine)
dopaminergic agonists (used to treat Parkinson's Disease or digestive disorders
an antibiotic, such as clarithromycin, telithromycin and erythromycin
medicines used to treat HIV infections, such as amprenavir, atazanavir, fosamprenavir, indinavir, nelfinavir, ritonavir and saquinavir
medicines used to treat high blood pressure or chest pain, such as diltiazem and verapamil
amiodarone used to treat fast heart rate
aprepitant used to treat nausea and vomiting
an antidepressant called nefazodone
medicines that neutralise or reduce the amount of stomach acid, such as antacids. Do not take medicines that neutralise stomach acid or medicines that reduce the production of stomach acid within 2 hours of taking MOTILIUM. This is because sufficient stomach acid is required to ensure that MOTILIUM is properly absorbed by the body.

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

4. How do I use MOTILIUM?

How much to take / use

The usual dose in adults is one tablet three times a day.
For nausea and vomiting this medicine is usually used for a maximum of 1 week.

The other conditions the initial duration of treatment is up to a maximum of 4 weeks.

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

When to take / use MOTILIUM

MOTILIUM is best taken 15 to 30 minutes before meals, and if necessary at bedtime.

If you do not understand the instructions provided with this medicine, ask your doctor or pharmacist for help.

If you forget to use MOTILIUM

Try to take each dose at the scheduled time.
The missed dose should be omitted and the actual dosing schedule resumed. If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.
Do not take a double dose to make up for the dose you missed.

If you have missed more than one dose, or are not sure what to do, check with your doctor or pharmacist.

If you use too much MOTILIUM

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

You should immediately:

phone the Poisons Information Centre
Australia: 13 11 26
New Zealand: 0800 POISON (or 0800 764766)
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.

5. What should I know while using MOTILIUM?

Things you should do

A risk of unusual heart beat or sudden heart failure has been associated with MOTILIUM use. The risk is higher in patients older than 60 years or taking more than three tablets daily. MOTILIUM should be used with caution and should be taken at the lowest effective dose, particularly in older patients. Talk to your doctor if you have a pre-existing heart condition.

Treatment with MOTILIUM should be stopped if signs or symptoms occur that may be associated with unusual heart beat, please talk to your doctor for advice.

Driving or using machines

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

Drinking alcohol

Tell your doctor if you drink alcohol.

Looking after your medicine

Keep MOTILIUM tablets in the pack until it is time to take them.
Keep MOTILIUM tablets in a cool dry place where the temperature is below 30°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 window sills.

Keep it where young children cannot reach it.

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.

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

Tell your doctor if you experience any of the following side effects	What to do
headache, trouble sleeping, nervousness, depression dizziness, tiredness or irritability sleepiness or drowsiness, fits or seizures, agitation dry mouth or thirst regurgitation, diarrhoea, constipation, nausea, changes in appetite or heartburn rash or itchy skin itchy eyes and crusty eyelids with discharge mouth ulcers or cold sores.	Speak to your doctor if you experience any of these side effects

Mild side effects

What to do

These are mild side effects of MOTILIUM. Tell your doctor if they continue.

uncontrollable movements of the face or arms and legs, excessive trembling, excessive muscle stiffness or muscle spasm
irregular or no menstrual period
unusual secretion of breast milk or decrease in sex drive in men or women
breast tenderness or breast enlargement in men and women.

These effects will reverse on stopping treatment.

These are mild side effects of MOTILIUM. Tell your doctor if they continue.

Serious side effects	What to do
fast or irregular heart beats swelling of hands, ankles or feet passing urine more frequent or pain when passing urine.	Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.
you have an allergic reaction to MOTILIUM (allergy can be recognised, for instance, by skin rash, itching, shortness of breath and/or swelling of the face, lips, mouth, tongue or throat which may cause difficulty in swallowing or breathing)	STOP using MOTILIUM and tell your doctor immediately if you have an allergic reaction.

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 MOTILIUM contains

Active ingredient (main ingredient)	10 mg of domperidone as the active ingredient.
Other ingredients (inactive ingredients)	lactose, maize starch, microcrystalline cellulose, pregelatinised potato starch, povidone, magnesium stearate, hydrogenated cottonseed oil, sodium lauryl sulfate and hypromellose.

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

What MOTILIUM looks like

MOTILIUM tablets are white, film coated, round tablets. Each tablet is marked "M/10" on one side and "JANSSEN" on the reverse. They are available in blister in carton of 25 or 100 tablets. (AUST R 39510).

Who distributes MOTILIUM

Johnson & Johnson Pacific
AUSTRALIA · NEW ZEALAND
45 Jones Street, Ultimo NSW 2007
® Registered Trademark

Consumer Care Centre
Australia: 1800 029 979
New Zealand: 0800 446 147
Overseas Customers: +61 2 8260 8366

This leaflet was prepared in November 2023.

Published by MIMS January 2024

BRAND INFORMATION

Brand name

Motilium

Active ingredient

Domperidone

Schedule

1 Name of Medicine

Domperidone.

2 Qualitative and Quantitative Composition

Each tablet contains 10 mg domperidone.

Excipient(s) with known effect.

Contains sugars as lactose. Each tablet contains 54.2 mg of lactose monohydrate (see Section 4.4 Special Warnings and Precautions for Use).
For a full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Film-coated tablets.
Motilium 10 mg tablets are white to faintly cream-coloured, circular, biconvex film coated tablets with the inscription "JANSSEN" on one side and "M 10" on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Motilium is indicated for the short-term treatment in adults of:
Symptoms associated with idiopathic or diabetic gastroparesis (once control of diabetes has been established by diet and/or insulin, an attempt should be made to discontinue Motilium).
Intractable nausea and vomiting from any cause.

4.2 Dose and Method of Administration

Long-term use and use with medicines that prolong the QT interval or medicines that inhibit CYP3A should be avoided. The lowest dose needed to alleviate symptoms should be taken for the shortest period of time (see Section 4.4 Special Warnings and Precautions for Use, Cardiac effects).
Motilium should be taken 15-30 minutes before meals and, if necessary, before retiring. Patients should try to take each dose at the scheduled time. If a scheduled dose is missed, the missed dose should be omitted and the usual dosing schedule resumed. The dose should not be doubled to make up for a missed dose.

Adults (weighing ≥ 35 kg).

10 mg three times daily. Domperidone should be initiated at the lowest effective dose for the individual situation, which may be adjusted upward with caution to achieve the desired effect. The expected benefit of an increased dose should outweigh the potential risks. Usually, the maximum treatment duration should not exceed one week for the treatment of acute nausea and vomiting. For other indications, the initial duration of treatment is limited to 4 weeks. Patients should undergo a benefit/risk re-analysis if treatment beyond 4 weeks is contemplated.
The maximum daily dose is 30 mg.
Safety and efficacy of Motilium (domperidone) use beyond six months has not been established.
Motilium tablets are unsuitable for use in adults weighing less than 35 kg. Motilium should not be used in children.

In patients with severe renal insufficiency.

(Creatinine serum > 0.6 mmol/L). The elimination half life of Motilium was increased from 7.4 to 20.8 hours but plasma drug levels were lower than in healthy volunteers. Since very little unchanged drug is excreted via the kidneys, it is unlikely that the dose needs to be adjusted for single acute administration in patients with renal insufficiency. However, on repeated administration, the dosing frequency will need to be reduced to once or twice daily depending on the severity of the impairment, and the dose may need to be reduced. Patients with severe renal impairment on prolonged therapy should be reviewed regularly (see Section 5.2 Pharmacokinetic Properties).

Hepatic impairment.

Motilium is contraindicated for patients with moderate or severe hepatic impairment (see Section 4.3 Contraindications).

Food.

It is recommended that Motilium be taken 15-30 minutes before meals. If taken after meals absorption of the drug is somewhat delayed. Patients should try to take each dose at the scheduled time. If a scheduled dose is missed, the missed dose should be omitted and the usual dosing schedule resumed. The dose should not be doubled to make up for a missed dose.

4.3 Contraindications

Motilium is contraindicated in the following situations:
In patients who have known existing prolongation of cardiac conduction intervals, particularly QTc, patients with significant electrolyte disturbances underlying cardiac diseases such as congestive heart failure.
Co-administration with medicines that prolong the QTc interval (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Co-administration with potent CYP3A4 inhibitors (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Known hypersensitivity to domperidone or any of the excipients.
Prolactin-releasing pituitary tumour (prolactinoma).
Whenever stimulation of gastric motility might be dangerous, e.g. in the presence of gastro-intestinal haemorrhage, mechanical obstruction or perforation.
In patients with moderate or severe hepatic impairment (see Section 5.2 Pharmacokinetic Properties).

4.4 Special Warnings and Precautions for Use

The film coated tablets contain lactose and may be unsuitable for patients with lactose intolerance, galactosemia or glucose/ galactose malabsorption.
Antacids or antisecretory drugs should not be taken simultaneously with Motilium since they reduce its oral bioavailability of domperidone (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). When used concomitantly, Motilium should be taken before meals and antacids or antisecretory agents after meals.

Cardiac effects.

Motilium is associated with an increased risk of sudden cardiac death of approximately 4 per 1000 years compared with no use of medication. This risk is increased in patients aged over 60 years or who have cardiac disease or diabetes. The risk is also increased with Motilium doses > 30 mg daily and when taken in combination with medicines that prolong the QT interval and medicines that inhibit CYP3A4.
Concurrent use of Motilium with medicines that prolong the QTc interval is contraindicated. Concurrent use of Motilium with medicines that are potent inhibitors of CYP3A4 is contraindicated (see Section 4.3 Contraindications; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Concurrent use of Motilium with medicines that are moderate inhibitors of CYP3A4 should be avoided. Long term use of Motilium should be avoided. The lowest dose needed to alleviate symptoms should be taken for the shortest period of time.
Motilium should be used with caution in older patients or those with current or a history of cardiac disease.
In a case control study by van Noord et al (2010), the odds of sudden cardiac death with current domperidone use (10 cases) were two-fold higher than the odds of sudden cardiac death in matched controls from the general population (adjusted odds ratio, 1.99 [95% CI, 0.80 - 4.96]). The adjusted odds ratio for sudden cardiac death in current users of a dose higher than 30 mg daily, relative to matched controls from the general population, was 11.4 (95% CI, 1.99 - 65.2) based on 4 identified cases. In a larger case control study by Johannes et al (2010), the adjusted odds ratio for the composite of sudden cardiac death and serious ventricular arrhythmias was 1.44 (95% CI, 1.12 - 1.86) for current domperidone users relative to current proton pump inhibitor users.
A population based, case control study nested in a cohort of 681,104 patients with at least one recorded prescription for domperidone, any proton pump inhibitor medication, or metoclopramide found 90 cases of out of hospital Sudden Cardiac Death (SCD) with current domperidone use.
The incidence rate of SCD per 1000 person years with current usage of domperidone was 4.47 (95% CI, 43.59 - 5.49). This was higher than that for during person time with no use of any of the study medications (0.87; 95% CI, 0.82 - 0.92).
After adjusting for demographic characteristics, medical conditions, medications, and other potentially confounding factors, the point estimate for current use of domperidone compared with non-use of study medications was OR, 1.71 (95% CI, 0.92 - 3.18).
In all of the medication group strata, the incidence increased with age, was higher in men than women, and was higher in those with diabetes than without.
With exposure to domperidone, the highest OR for SCD was with current exposure to only domperidone for 8-14 days (adjusted OR, 7.77; 95% CI, 1.70 - 35.53). The adjusted OR was 1.69 (95% CI, 0.38 - 7.57) for exposure of ≤ 7 days and 1.12 (95% CI, 0.50 - 2.53) for durations of ≥ 15 days. The risk of SCD compared with no exposure was highest for those prescribed > 30 mg/day (adjusted OR, 3.20; 95% CI, 0.59 - 17.34).
When domperidone was taken concomitantly with any QTc prolongating agent associated with torsade de pointes the risk of SCD increased from an adjusted OR of 1.64 (95% CI, 0.73 - 3.72) to 4.95 (95% CI, 0.84 - 29.07).
Electrolyte disturbances (hypokalaemia, hyperkalaemia, hypomagnesaemia) and bradycardia are known to be conditions increasing the proarrhythmic risk.
Treatment with Motilium should be stopped if signs or symptoms occur that may be associated with cardiac arrhythmia.

Prolactin levels.

There are limited safety data in long-term use (i.e. beyond six months) of Motilium. However, it has been shown to produce an increase in plasma prolactin. The raised level persists with chronic administration but falls to normal on discontinuing the drug (see Section 4.8 Adverse Effects (Undesirable Effects)). During oral administration of 30 mg daily for two weeks the plasma prolactin level measured 90 minutes after drug intake remained fairly constant at 25 nanogram/mL in males (normal value was 5 nanogram/mL) whilst in females the level of 117 nanogram/mL after the first dose decreased to 56 nanogram/mL after 14 doses (pretreatment normal value was 9 nanogram/mL).
Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of Motilium is contemplated in a patient with a past history of breast cancer.
Endocrine disturbances such as galactorrhoea, amenorrhoea, gynaecomastia and impotence have been reported with drugs which stimulate prolactin release. The clinical significance of elevated serum prolactin levels is unknown for most patients. An increase in mammary neoplasms has been found in rodents after chronic administration of Motilium and other prolactin stimulating drugs. Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of these drugs and mammary tumorigenesis.
Motilium does not affect plasma growth hormone or aldosterone.
Despite the lack of penetration of the blood brain barrier, the possibility that extrapyramidal symptoms may occur in very rare instances after long-term use of domperidone should be considered.

Renal impairment.

Since the elimination half-life of domperidone is prolonged in severe renal impairment, on repeated administration the dosing frequency of Motilium should be reduced to once or twice daily, depending on the severity of the impairment, and the dose may need to be reduced. Such patients on prolonged therapy should be reviewed regularly (see Section 5.2 Pharmacokinetic Properties; Section 4.2 Dose and Method of Administration).

Use in the elderly.

See Section 4.4 Special Warnings and Precautions for Use, Cardiac effects.

Paediatric use.

Motilium should not be used in children.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Medicines that prolong the QTc interval.

Co-administration with medicines that prolong the QTc interval is contraindicated due to an increased risk of sudden cardiac death shown in post-market studies (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).
Examples of QTc-prolonging medicines include:
anti arrhythmics class IA (e.g. disopyramide);
anti arrhythmics class III (e.g. amiodarone*, dronedarone, sotalol);
some antipsychotics (e.g. haloperidol);
some antidepressants (e.g. citalopram, escitalopram);
some antibiotics (e.g. erythromycin*, clarithromycin*, levofloxacin, moxifloxacin);
some antifungal agents (e.g. pentamidine);
some antimalarial agents (e.g. lumefantrine);
some azole antifungals, (e.g. itraconazole*, ketoconazole*, voriconazole*, fluconazole*);
some calcium antagonists, (e.g. diltiazem*, verapamil*);
some gastrointestinal agents (e.g. prucalopride, granisetron, ondansetron);
certain HIV protease inhibitors (e.g. atazanavir*, fosamprenavir*, indinavir*, ritonavir*, saquinavir*);
some antineoplastic agents (e.g. toremifene, vandetanib);
others (e.g. aprepitant* and methadone).
*Also potent CYP3A4 inhibitors (see Section 4.3 Contraindications).

Potent CYP3A4 inhibitors.

The main metabolic pathway of domperidone is through the cytochrome P450 isoenzyme CYP3A4. In vitro and human data show that the concomitant use of drugs that significantly inhibit this enzyme may result in increased plasma levels of domperidone.
Concurrent use of Motilium with medicines that are potent inhibitors of CYP3A4 is contraindicated due to an increased risk of sudden cardiac death shown in postmarket studies (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).
Examples of potent CYP3A4 inhibitors include:
azole antifungals, such as fluconazole^, itraconazole^, ketoconazole^ and voriconazole^;
macrolide antibiotics, such as clarithromycin^ and erythromycin^;
HIV protease inhibitors, such as amprenavir^, atazanavir^, fosamprenavir^, indinavir^, nelfinavir^, ritonavir^ and saquinavir^;
calcium antagonists, such as diltiazem^ and verapamil^;
amiodarone^;
aprepitant^;
telithromycin^;
nefazodone.
^Also prolong the QTc interval (see Section 4.3 Contraindications).
Separate pharmacokinetic/ pharmacodynamic interaction studies with oral ketoconazole or oral erythromycin in healthy subjects confirmed domperidone C_max increases < 3 fold under maximal CYP3A4 inhibition by these drugs.
In these studies, domperidone monotherapy at 10 mg four times daily resulted in increases in mean QTc of 1.6 msec (ketoconazole study) and 2.5 msec (erythromycin study), while ketoconazole monotherapy (200 mg twice daily) and erythromycin monotherapy (500 mg three times daily) led to increases in mean QTc of 3.8 and 4.9 msec, respectively, over the observation period. With the combination of domperidone 10 mg four times daily and ketoconazole 200 mg twice daily, a mean QTc prolongation of 9.8 msec was seen over the observation period, with changes at individual time points ranging from 1.2 to 17.5 msec. With the combination of domperidone 10 mg four times daily and erythromycin 500 mg three times daily, mean QTc over the observation period was prolonged by 9.9 msec, with changes at individual time points ranging from 1.6 to 14.3 msec. Both the C_max and AUC of domperidone at steady state were increased approximately three-fold in each of these interaction studies (see Section 4.3 Contraindications).
The contribution of increased plasma concentrations of domperidone to the observed effect on QTc is not known.

Moderate CYP3A4 inhibitors.

Concurrent use of Motilium with medicines that are moderate inhibitors of CYP3A4 should be avoided due to an increased risk of sudden cardiac death shown in postmarket studies (see Section 4.4 Special Warnings and Precautions for Use).

Miscellaneous interactions.

Antacids or antisecretory drugs should not be taken simultaneously with Motilium since they reduce its oral bioavailability (i.e. they should be taken after meals and not before meals) (see Section 4.4 Special Warnings and Precautions for Use). Dosing with these agents should be separated from dosing with Motilium by at least 2 hours.
Concomitant administration of anticholinergic drugs may antagonise the anti-dyspeptic effects of Motilium. If administered prior to atropine, Motilium reduces the relaxant effect of atropine upon the lower oesophageal sphincter, but has no reversing effect if atropine is administered first.
Since Motilium has gastrokinetic effects it could influence the absorption of concomitantly orally administered drugs, particularly those of sustained release or enteric coated formulations. However, in patients already stabilised on digoxin, paracetamol or haloperidol, concomitant administration of Motilium did not influence the blood levels of these drugs.
Motilium has been used with:
dopaminergic agonists (bromocriptine, L-dopa) for suppression of unwanted peripheral effects such as digestive disorders, nausea and vomiting, without affecting their central activity.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No relevant data are available.
(Category B2)
Small amounts of Motilium have been found in rat foetal tissues. Reproduction studies were performed in rats with daily doses of Motilium up to 160 mg/kg orally and 40 mg/kg intravenously and in rabbits with daily doses up to 40 mg/kg orally and 1.25 mg/kg intravenously. There was no evidence of drug related dysmorphogenesis. There are however no adequate and well controlled studies in pregnant women. The potential risk for humans is unknown. Because animal studies are not always predictive of human response and there are limited post-marketing data on the use of domperidone in pregnant women, this drug should be used during pregnancy only if clearly needed.
The amount of domperidone that could be ingested by an infant through breast milk is extremely low. The maximal relative infant dose (%) is estimated to be about 0.1% of the maternal weight adjusted dosage. It is not known whether this is harmful to the newborn. Therefore breast-feeding is not recommended for women who are taking Motilium.

4.7 Effects on Ability to Drive and Use Machines

Dizziness and somnolence have been observed following use of domperidone (see Section 4.8 Adverse Effects (Undesirable Effects)). Therefore, patients should be advised not to drive or use machinery or engage in other activities requiring mental alertness and coordination until they have established how Motilium affects them.

4.8 Adverse Effects (Undesirable Effects)

Clinical trial data.

The safety of Motilium was evaluated in 1221 patients with gastroparesis, or symptoms of it in 45 clinical trials included in the safety database. All patients were ≥ 15 years old and received at least one dose of oral Motilium (domperidone base). Slightly fewer than one-half (553/1221) of patients were diabetic. The median total daily dose was 80 mg (range 10 to 160 mg), with 230 patients receiving a dose greater than 80 mg. Median duration of exposure was 56 days (range 1 to 2248 days).
Adverse Reactions (ARs) - reported by ≥ 1% of patients treated with domperidone in these 45 clinical trials are shown in Table 1.

ARs that occurred in < 1% of Domperidone treated patients in the 45 clinical trials (n=1221) are listed in Table 2.

Postmarketing data.

The adverse reactions are ranked by frequency, using the following convention. Very common: > 1/10; common: > 1/100, < 1/10; uncommon: > 1/1000, < 1/100; rare: > 1/10,000, < 1/1000; very rare: < 1/10,000 including isolated reports.

Immune system disorder.

Very rare: anaphylactic reactions including anaphylactic shock; angioneurotic oedema; allergic reaction.

Endocrine disorder.

Uncommon: increased prolactin levels.

Psychiatric system disorders.

Uncommon: nervousness. Very rare: agitation.

Nervous system disorders.

Common: dry mouth; headache. Uncommon: insomnia; dizziness; thirst; lethargy; irritability. Rare: extrapyramidal side effects. Very rare: convulsion; somnolence.

Gastrointestinal disorders.

Uncommon: diarrhoea; regurgitation; appetite disorder; nausea; heartburn; constipation.

Skin and subcutaneous tissue disorders.

Uncommon: urticaria; pruritus; rash.

Reproductive system and breast disorders.

Rare: galactorrhoea; gynaecomastia; amenorrhoea.

Urinary system disorders.

Uncommon: pollakiuria; dysuria.

Cardiovascular disorders.

Uncommon: oedema; palpitations. Very rare: sudden cardiac death*; serious ventricular arrhythmias* (see Section 4.4 Special Warnings and Precautions for Use).

Musculoskeletal disorders.

Uncommon: muscle spasms; asthenia.

Other.

Uncommon: conjunctivitis; stomatitis; drug intolerance.

Investigations.

Uncommon: liver function test abnormal; cholesterol.
*Based on epidemiology data.
During long-term studies with Motilium, there have been reports of adverse effects possibly related to increases in serum prolactin (see Section 4.4 Special Warnings and Precautions for Use). These effects include: Gynaecomastia, breast tenderness, swelling of the breasts, irregular menses, amenorrhoea, a decrease or loss of libido, breast secretion and lactation. These effects occurred in patients who received up to 120 mg per day in four divided doses.
Extrapyramidal disorder occurs very rarely, and when seen occurs primarily in young children (see Section 4.4 Special Warnings and Precautions for Use).
Other central nervous system related effects of convulsion and agitation also are reported primarily in infants and children.

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

Symptoms and signs.

Overdose has been reported primarily in infants and children. Symptoms of overdosage may include agitation, altered consciousness, convulsion, disorientation, somnolence and extrapyramidal reactions.

Treatment.

There is no specific antidote to domperidone. Anticholinergic antiparkinson drugs may be useful in controlling extrapyramidal reactions.
The patient should be observed closely and supportive measures employed.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Motilium is a dopamine antagonist with antiemetic properties similar to those of metoclopramide and certain neuroleptic drugs. Unlike these drugs, however, domperidone does not readily cross the blood brain barrier. It seldom causes extra-pyramidal side effects, but does cause a rise in prolactin levels. Its antiemetic effect may be due to a combination of peripheral (gastrokinetic) effects and antagonism of central dopamine receptors in the chemo-receptor trigger zone which lies in the area postrema and is regarded as being outside the blood brain barrier. Animal studies have shown that domperidone has no effect on plasma concentrations of homovanillic acid, a metabolite of dopamine. It also antagonises the behavioural effects of dopamine much more effectively when administered intracerebrally than when given systemically. These findings, together with the low concentrations found in the brain, indicate a predominantly peripheral effect of domperidone on dopamine receptors.
Studies in humans have shown intravenous and oral domperidone to: increase the duration of antral and duodenal contractions; increase the gastric emptying of liquids and semi solids in healthy subjects and in patients in whom it was delayed; increase lower oesophageal sphincter pressure in healthy subjects. Motilium has no effect on gastric secretion.

Effect on QT/QTc interval and cardiac electrophysiology.

In accordance with ICH-E14 guidelines, a thorough QT study was performed in healthy subjects. This study included a placebo, active comparator and positive control and was conducted using recommended therapeutic doses (10 or 20 mg administered 4 times a day). This study found a maximal difference of QTc between domperidone and placebo in LS-means in the change from baseline was 3.4 msec for 20 mg domperidone administered 4 times a day on Day 4, and the 2 sided 90% CI (1.0 - 5.9 msec) did not exceed 10 msec. The QT prolongation observed in this study when domperidone was administered according to the recommended dosing is not clinically relevant.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Absorption.

Domperidone is rapidly absorbed following intramuscular and oral administration with peak plasma concentrations occurring at approximately 10 and 30 minutes respectively.
Systemic bioavailability of intramuscular domperidone is about 83% whereas that of oral domperidone is 13 to 17%. The low oral bioavailability is probably due to 'first-pass' gut wall and hepatic metabolism. Oral bioavailability is decreased by prior administration of cimetidine or sodium bicarbonate. The time of peak absorption is slightly delayed and the AUC somewhat increased when the oral drug is taken after a meal.

Distribution.

Oral domperidone does not appear to accumulate or induce its own metabolism; a peak plasma level after 90 minutes of 21 nanogram/mL after two weeks oral administration of 30 mg per day was almost the same as that of 18 nanogram/mL after the first dose. Domperidone is 91-93% bound to plasma proteins.
Distribution studies with radiolabelled drug in animals have shown wide tissue distribution with low brain concentration. Small amounts of drug cross the placenta in rats and the drug is excreted in the breast milk of this species.

Metabolism.

Domperidone undergoes rapid and extensive hepatic metabolism by hydroxylation and N-dealkylation. In vitro metabolism experiments with diagnostic inhibitors revealed that CYP3A4 is a major form of cytochrome P-450 involved in the N-dealkylation of domperidone, whereas CYP3A4, CYP1A2 and CYP2E1 are involved in domperidone aromatic hydroxylation (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Excretion.

Urinary and faecal excretion amounts to 31 and 66%, respectively, of the oral dose. The proportion of the drug excreted unchanged is small (approximately 1% of urinary excretion and 10% of faecal excretion).
The plasma half-life after a single oral dose is 7-9 hours in healthy subjects but is prolonged in patients with severe renal insufficiency.

Special populations.

Hepatic impairment.

Motilium is contraindicated in patients with moderate or severe hepatic impairment (see Section 4.3 Contraindications). In subjects with mild hepatic impairment (Pugh score 5 to 6, Child-Pugh rating A), limited data indicate that the pharmacokinetics of domperidone are not significantly altered. In subjects with moderate hepatic impairment (Pugh score 7 to 9, Child-Pugh rating B), the AUC, C_max and terminal elimination half-life of domperidone were substantially increased; the unbound fraction of domperidone was increased by 25%. Subjects with severe hepatic impairment were not studied (see Section 4.3 Contraindications).

Renal impairment.

In subjects with severe renal insufficiency (serum creatinine > 6 mg/100 mL, i.e. > 0.6 mmol/L) the half-life of domperidone is increased from 7.4 to 20.8 hours, but plasma drug levels are lower than in subjects with normal renal function. Very little unchanged drug (approximately 1%) is excreted via the kidneys (see Section 4.4 Special Warnings and Precautions for Use; Section 4.2 Dose and Method of Administration).

Paediatric patients.

No pharmacokinetics data are available in this population.

5.3 Preclinical Safety Data

Genotoxicity.

No relevant data are available.

Carcinogenicity.

See Prolactin levels.

6 Pharmaceutical Particulars

6.1 List of Excipients

Lactose, maize starch, microcrystalline cellulose, pregelatinised potato starch, povidone, magnesium stearate, hydrogenated cottonseed oil, sodium lauryl sulfate, and hypromellose.

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

Store below 30°C.

6.5 Nature and Contents of Container

Motilium domperidone 10 mg film coated tablets are supplied in PVC/Aluminium blister packs of 25 or 100 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.

Domperidone has the following chemical structure.

C₂₂H₂₄ClN₅O₂. MW: 425.9.
The chemical name for domperidone is 5-Chloro-1-[1-[3-(2-oxo-2,3-dihydro- 1H-benzimidazol-1-yl)propyl]piperidin-4-yl] -1,3-dihydro-2H-benzimidazol-2-one.
Domperidone is a white to slightly beige coloured powder; it is freely soluble in 1.0 M lactic acid, soluble in 1.0 M citric acid, slightly soluble in ethanol and practically insoluble in water.

CAS number.

57808-66-9.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

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Domperidone

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Motilium 10 mg Tablets