Consumer medicine information

APO-Domperidone

Domperidone

BRAND INFORMATION

Brand name

APO-Domperidone

Active ingredient

Domperidone

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using APO-Domperidone.

What is in this leaflet

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

All medicines have risks and benefits. Your doctor has weighed the risks of you taking domperidone against the benefits they expect it will have for you.

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

Keep this leaflet with your medicine. You may want to read it again.

What this medicine used for

Domperidone is used to treat nausea, vomiting, and discomfort caused by a slow-moving stomach (known as gastroparesis). Symptoms include not being able to finish a meal, a feeling of being bloated after a meal, a loss of appetite, feeling sick, vomiting, or belching without relief.

How it works

Domperidone belongs to a group of medicines called antiemetics and prokinetics. It works by blocking the action of a chemical messenger in the brain which causes the feeling of nausea and vomiting. It also works to increase the movement or contractions of the stomach and intestines, allowing food to move more easily through the stomach.

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

This medicine is not addictive.

It is available only with a doctor's prescription.

Domperidone should not be used in children under the age of 18 years.

Before you take this medicine

When you must not take it

Do not take this medicine if you have an allergy to:

  • domperidone
  • any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue, throat or other parts of the body
  • rash, itching or hives on the skin:

Do not take this medicine if you have or have had any of the following medical conditions:

  • a tumour of the pituitary gland called prolactinoma
  • you have or have had liver disease
  • an increase in stomach or bowel contractions e.g. if you have had bleeding, a blockage or puncture in your gastrointestinal tract
  • heart problems, including an abnormal heartbeat

Do not take this medicine if you take any of the following medications:

  • ketoconazole, fluconazole, voriconazole, itraconazole or posaconazole which are used to treat fungal infections.
  • ritonavir or saquinavir used to treat HIV
  • telaprevir used to treat hepatitis C
  • erythromycin, clarithromycin or telithromycin antibiotics
  • amiodarone, diltiazem or verapamil

There may be other medicines not listed above that should not be taken with domperidone.

Your doctor and pharmacist have more information on medicines to avoid while taking this medicine.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

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

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

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

  • pre-existing heart condition
  • liver or kidney disease
  • breast cancer
  • lactose intolerance

Tell your doctor if you are pregnant, plan to become pregnant or are breastfeeding or wishing to breastfeed

Do not take this medicine until you and your doctor have discussed the risks and benefits involved.

Tell your doctor if you are planning to have surgery, dental treatment or an anaesthetic.

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

Taking other medicines

Tell your doctor and pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may interact with domperidone. Do not take domperidone if you are taking medicines that slow down the breaking down (metabolism) of other medicines in the body and can also affect your heart rhythm, these include:

  • ketoconazole, fluconazole, itraconazole and voriconazole, used for treating fungal infections
  • anticholinergic drugs, used to prevent travel sickness, gastrointestinal cramps, muscular spams, or sleep disorders e.g. dextromethorphan or diphenhydramine
  • dopaminergic agonists, used to treat Parkinson's Disease or digestive disorders
  • clarithromycin, erythromycin and moxifloxacin, antibiotics used to treat certain bacterial infections
  • amprenavir, atazanavir, fosamprenavir, indinavir, nelfinavir, ritonavir and saquinavir, used to treat HIV infections
  • telaprevir which is a medicine for hepatitis C.
  • certain medicines used to treat heart conditions e.g. diltiazem, verapamil, sotalol or amiodarone
  • aprepitant, used to treat nausea and vomiting
  • methadone, used to treat chronic pain or opioid dependence
  • nefazodone, used for mood disorders
  • antacids, ranitidine, cimetidine or omeprazole, used to neutralise or reduce the amount of stomach acid.
    Do not take medicines that neutralize stomach acid or medicines that reduce the production of stomach acid within 2 hours of taking domperidone. This is because sufficient stomach acid is required to ensure that domperidone is properly absorbed by the body.

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

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

Other medicines not listed above may also interact with domperidone.

How to take this medicine

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

If you do not understand the instructions on the box, ask your doctor or pharmacist for help.

How much to take

Your doctor will tell you how much of this medicine you should take. This will depend on your condition and whether you are taking any other medicines.

The usual dose is one tablet taken three times a day.

How to take it

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

When to take it

Take your medicine at about the same time each day. Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

How long to take it for

Continue taking your medicine for as long as your doctor tells you.

For nausea and vomiting, this medicine is usually used for a maximum of 1 week.

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

Make sure you have enough to last over weekends and holidays.

If you forget to take it

If it is almost time to take your next dose, skip the dose you missed and take your next dose at the usual time.

Otherwise, take it as soon as you remember and then go back to taking your medicine as you would normally.

Do not take a double dose to make up for missed doses. This may increase the chance of you experiencing side effects.

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

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at your nearest hospital, if you think that you or anyone else may have taken too much of this medicine. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

If you take too much domperidone you may experience agitation, seizure, drowsiness, confusion and uncontrolled movements, such as irregular eye movements, or abnormal posture like a twisted neck.

While you are taking this medicine

Talk to your doctor if you have a pre-existing heart condition. The risk of unusual heartbeat or sudden heart failure has been associated with domperidone use. The risk is higher in patients older than 60 years or taking more than three tablets daily. Domperidone should be used with caution and should be taken at the lowest effective dose, particularly in older patients. Treatment with domperidone should be stopped if signs or symptoms occur that may be associated with unusual heartbeat. Please talk to your doctor for advice.

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking this medicine.

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

If you become pregnant while taking this medicine, tell your doctor immediately.

Tell your doctor if you are going to have surgery, an anaesthetic or are going into hospital.

Keep all your doctor's appointments so that your progress can be checked. Your doctor may do some tests from time to time to make sure the medicine is working and to prevent unwanted side effects.

Things you must not do

Do not give this medicine to anyone else, even if they have the same condition as you.

Do not take your medicine to treat any other complaint unless your doctor tells you to.

Do not stop taking your medicine, or change the dosage, without first checking with your doctor.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking domperidone.

This medicine helps most people, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some side effects.

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

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

Tell your doctor or pharmacist if you notice any of the following:

  • 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
  • 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 enlargement in men and women.

Some of these effects will reverse on stopping treatment.

If you experience any of the following, stop taking your medicine and contact your doctor immediately or go to the Accident and Emergency department at your nearest hospital.

  • fast or irregular heart beats
  • swelling of hands, ankles or feet
  • passing urine more frequently or pain when passing urine
  • shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue, throat or other parts of the body; rash, skin rash, itching; swelling of the face, lips, mouth, tongue or throat which may cause difficulty in swallowing or breathing (signs of an allergic reaction)

Tell your doctor or pharmacist if you notice any other side effects.

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

Storage and disposal

Storage

Keep your medicine in its pack until it is time to take it. If you take your medicine out of its pack it may not keep well.

Keep your medicine in a cool dry place where the temperature stays below 30°C.

Do not store your medicine, or any other medicine, in the bathroom or near a sink. Do not leave it on a windowsill or in the car. Heat and dampness can destroy some medicines.

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

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine left over.

Product description

What it looks like

White round, biconvex uncoated tablets with inscription 'Dm 10' on one side.

Available in blisters of 25, 30 and 100 tablets. AUST R 242333.

*Not all pack sizes may be marketed.

Ingredients

Each tablet contains 10 mg of domperidone as the active ingredient.

It also contains the following:

  • lactose monohydrate
  • maize starch
  • microcrystalline cellulose
  • povidone
  • sodium lauryl sulfate
  • colloidal anhydrous silica
  • magnesium stearate

APO-Domperidone tablets contains sugars as lactose and is Gluten free.

Sponsor

Apotex Pty Ltd
16 Giffnock Avenue
Macquarie Park, NSW 2113

This leaflet was prepared in November 2021.

Published by MIMS December 2021

BRAND INFORMATION

Brand name

APO-Domperidone

Active ingredient

Domperidone

Schedule

S4

 

1 Name of Medicine

Domperidone maleate.

2 Qualitative and Quantitative Composition

Each tablet contains domperidone maleate, as the active ingredient.
Each tablet contains 10 mg domperidone (as maleate), as the active ingredient.

Excipients with known effect.

Lactose monohydrate (see Section 4.4 Special Warnings and Precautions for Use).
For the full list of excipients see Section 6.1 List of Excipients.

3 Pharmaceutical Form

White round, biconvex uncoated tablet with the inscription 'Dm 10' on one side.

4 Clinical Particulars

4.1 Therapeutic Indications

Domperidone 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 domperidone).
Intractable nausea and vomiting from any cause.

4.2 Dose and Method of Administration

APO-Domperidone tablets are intended for oral administration.

Dosage.

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).
Domperidone 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 domperidone use beyond six months has not been established.
Domperidone tablets are unsuitable for us in adults weighing less than 35 kg. Domperidone should not be used in children.

Renal impairment.

In patients with severe renal insufficiency (creatinine serum > 0.6 mmol/L).

The elimination half-life of domperidone 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).

Food.

It is recommended that domperidone 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.

Hepatic impairment.

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

4.3 Contraindications

Domperidone is contraindicated in the following situations:
Known hypersensitivity to domperidone or any of the excipients.
Prolactin-releasing pituitary tumour (prolactinoma).
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).
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).
In patients who have known existing prolongation of cardiac conduction intervals, particularly QTc, patients with significant electrolyte disturbances or 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).

4.4 Special Warnings and Precautions for Use

The 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 domperidone since they reduce its oral bioavailability of domperidone (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). When used concomitantly, domperidone should be taken before meals and antacids or antisecretory agents after meals.

Cardiac effects.

Domperidone is associated with an increased risk of sudden cardiac death of approximately 4 per 1000 per 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 domperidone doses > 30 mg daily and when taken in combination with medicines that prolong the QT interval and medicines that inhibit CYP3A4.
Concurrent use of domperidone with medicines that prolong the QTc interval is contraindicated.
Concurrent use of domperidone 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 domperidone with medicines that are moderate inhibitors of CYP3A4 should be avoided. Long term use of domperidone should be avoided. The lowest dose needed to alleviate symptoms should be taken for the shortest period of time.
Domperidone 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 1,000 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 domperidone 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 domperidone. 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 domperidone 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 domperidone 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.
Domperidone 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.

Use in renal impairment.

Since the elimination half-life of domperidone is prolonged in severe renal impairment, on repeated administration the dosing frequency of domperidone 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.

Domperidone 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 domperidone 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 Cmax 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 Cmax 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 domperidone with medicines that are moderate inhibitors of CYP3A4 should be avoided due to an increased risk of sudden cardiac death shown in post-market studies (see Section 4.4 Special Warnings and Precautions for Use).

Miscellaneous interactions.

Antacids or antisecretory drugs should not be taken simultaneously with domperidone 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 domperidone by at least 2 hours.
Concomitant administration of anticholinergic drugs may antagonise the anti-dyspeptic effects of domperidone. If administered prior to atropine, domperidone reduces the relaxant effect of atropine upon the lower oesophageal sphincter, but has no reversing effect if atropine is administered first.
Since domperidone 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 domperidone did not influence the blood levels of these drugs.
Domperidone 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 data available.
(Category B2)
Small amounts of domperidone have been found in rat foetal tissues. Reproduction studies were performed in rats with daily doses of domperidone 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 domperidone.

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 domperidone affects them.

4.8 Adverse Effects (Undesirable Effects)

Clinical trial data.

The safety of domperidone 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 domperidone (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 below 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: > 1/1,000, < 1/100; rare: > 1/10,000, < 1/1000; very rare: < 1/10,000 including isolated reports. See Table 3.
During long-term studies with domperidone 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 http://www.tga.gov.au/reporting-problems and contact Apotex Medical Information Enquiries/Adverse Drug Reaction Reporting on 1800 195 055.

4.9 Overdose

Symptoms.

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. Anticholinergics, 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 Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Domperidone 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. Domperidone 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.

Domperidone 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, Cmax 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 data available.

Carcinogenicity.

See Section 4.4 Special Warnings and Precautions for Use, Prolactin levels.

6 Pharmaceutical Particulars

6.1 List of Excipients

Lactose monohydrate, maize starch, microcrystalline cellulose, povidone, magnesium stearate, sodium lauryl sulfate, colloidal anhydrous silica.

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

APO-Domperidone tablet.

Blister pack (PVC/Aluminium) of 25, 30 or 100 tablets (AUST R 242333).
APO and Apotex are registered trade marks of Apotex Inc.
Not all pack sizes may be available.

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

Domperidone maleate is a white or almost white powder; it is very slightly soluble in water or ethanol, sparingly soluble in dimethylformamide and slightly soluble in methanol.

Chemical structure.


Chemical Name: 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 hydrogen (Z)-butenedioate.
Molecular Formula: C26H28ClN5O6.
Molecular Weight: 542.0.

CAS number.

83898-65-1.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes