4.1. Therapeutic indications

Epzit 10 mg Orodispersible Tablets are indicated for the relief of the symptoms of nausea and vomiting.

4.2. Posology and method of administration

Epzit should be used at the lowest effective dose for the shortest duration necessary to control nausea and vomiting.

It is recommended to take Epzit 10 mg Orodispersible Tablets 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.

Usually, the maximum treatment duration should not exceed one week.

See section 4.4. for further information.

Adults and adolescents (12 years of age and older and weighing 35 kg or more)

One 10mg tablet up to three times per day with a maximum dose of 30 mg per day.

Hepatic Impairment

Epzit 10 mg Orodispersible Tablets are contraindicated in moderate (Child-Pugh 7 to 9) or severe (Child-Pugh > 9) hepatic impairment (see section 4.3). Dose modification in mild (Child-Pugh 5 to 6) hepatic impairment is however not needed (see section 5.2).

Renal Impairment

Since the elimination half-life of domperidone is prolonged in severe renal impairment (serum creatinine > 6mg/100mL, i.e. 0.6 mmol/L), the dosing frequency of Epzit 10 mg Orodispersible Tablets 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 with severe renal impairment should be reviewed regularly (see section 4.4 and 5.2).

Paediatric population

The efficacy of Epzit in children less than 12 years of age has not been established (see section 5.1).

The efficacy of Epzit in adolescents 12 years of age and older and weighing less than 35 kg has not been established.

Method of administration

For oral use

The tablet should be placed on the tongue and allowed to disintegrate before swallowing with or without water, according to patient preference.

4.3. Contraindications

Domperidone is contraindicated in the following situations:

• Known hypersensitivity to domperidone or any of the excipients.

• Confirmed or suspected pheochromocytoma due to the risk of severe hypertension episodes

• Prolactin-releasing pituitary tumour (prolactinoma).

• When stimulation of the gastric motility could be harmful e.g in patients with gastro- intestinal haemorrhage, mechanical obstruction or perforation.

• In patients with moderate or severe hepatic impairment (see section 5.2)

• 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 (see section 4.4)

• Co-administration with QT-prolonging drugs, at the exception of apomorphine (see sections 4.4 and 4.5)

• Co-administration with potent CYP3A4 inhibitors (regardless of their QT prolonging effects) (see section 4.5)

4.4. Special warnings and precautions for use

Cardiovascular effects:

Domperidone has been associated with prolongation of the QT interval on the electrocardiogram. During post-marketing surveillance, there have been very rare cases of QT prolongation and torsades de pointes in patients taking domperidone. These reports included patients with confounding risk factors, electrolyte abnormalities and concomitant treatment which may have been contributing factors (see section 4.8).

Epidemiological studies showed that domperidone was associated with an increased risk of serious ventricular arrhythmias or sudden cardiac death (see section 4.8). A higher risk was observed in patients older than 60 years, patients taking daily doses greater than 30 mg, and patients concurrently taking QT-prolonging drugs or CYP3A4 inhibitors.

Domperidone should be used at the lowest effective dose in adults and adolescents 12 years of age and older.

Domperidone is contraindicated in patients with known existing prolongation of cardiac conduction intervals, particularly QTc, in patients with significant electrolyte disturbances (hypokalaemia, hyperkalaemia, hypomagnesaemia), or bradycardia, or in patients with underlying cardiac diseases such as congestive heart failure due to increased risk of ventricular arrhythmia (see section 4.3.). Electrolyte disturbances (hypokalaemia, hyperkalaemia, hypomagnesaemia) or bradycardia are known to be conditions increasing the proarrythmic risk.

Treatment with domperidone should be stopped if signs or symptoms occur that may be associated with cardiac arrhythmia, and the patients should consult their physician.

Patients should be advised to promptly report any cardiac symptoms.

Use with apomorphine

Domperidone is contra-indicated with QT prolonging drugs including apomorphine, unless the benefit of the co-administration with apomorphine outweighs the risks, and only if the recommended precautions for co-administration mentioned in the apomorphine SmPC are strictly fulfilled. Please refer to the apomorphine SmPC.

Renal Impairment

The elimination half-life of domperidone is prolonged in severe renal impairment (serum creatinine > 6mg/100mL, i.e. 0.6 mmol/L). The dosing frequency of domperidone should be reduced to once or twice daily depending on the severity of the impairment. The dose may also need to be reduced.

Excipients

Aspartame is hydrolysed in the gastrointestinal tract when orally ingested. One of the major hydrolysis products is phenylalanine. Neither non-clinical nor clinical data are available to assess aspartame use in infants below 12 weeks of age.

Co-administration of levodopa

Although no dosage adjustment of levodopa is deemed necessary, an increase of plasma levodopa concentration (max 30-40%) has been observed when domperidone was taken concomitantly with levodopa. See section 4.5.

4.5. Interaction with other medicinal products and other forms of interaction

The main metabolic pathway of domperidone is through CYP3A4. In vitro and human data suggest that the concomitant use of drugs that significantly inhibit this enzyme may result in increased plasma levels of domperidone.

Increased risk of occurrence of QT-interval prolongation, due to pharmacodynamic and/or pharmacokinetic interactions.

Concomitant use of the following substances is contraindicated

QTc prolonging medicinal products

• anti-arrhythmics class IA (e.g., disopyramide, hydroquinidine, quinidine)

• anti-arrhythmics class III (e.g., amiodarone, dofetilide, dronedarone, ibutilide, sotalol)

• certain anti-psychotics (e.g., haloperidol, pimozide, sertindole)

• certain anti-depressants (e.g., citalopram, escitalopram)

• certain antibiotics (e.g., erythromycin, levofloxacin, moxifloxacin, spiramycin)

• certain antifungal agents (e.g., pentamidine)

• certain antimalarial agents (in particular halofantrine, lumefantrine)

• certain gastro-intestinal medicines (e.g., cisapride, dolasetron, prucalopride)

• certain antihistaminics (e.g., mequitazine, mizolastine)

• certain medicines used in cancer (e.g., toremifene, vandetanib, vincamine)

• certain other medicines (e.g., bepridil, diphemanil, methadone) (see section 4.3).

• apomorphine, unless the benefit of the co-administration outweighs the risks, and only if the recommended precautions for co-administration are strictly fulfilled. Please refer to the apomorphine SmPC.

Potent CYP3A4 inhibitors (regardless of their QT prolonging effects), i.e:

• protease inhibitors

• systemic azole antifungals

• some macrolides (erythromycin, clarithromycin telithromycin) (see section 4.3).

Concomitant use of the following substances is not recommended

Moderate CYP3A4 inhibitors i.e. diltiazem, verapamil and some macrolides. (see section 4.3)

Concomitant use of the following substances requires caution in use

Caution with bradycardia and hypokalaemia-inducing drugs, as well as with the following macrolides involved in QT-interval prolongation: azithromycin and roxithromycin (clarithromycin is contra-indicated as it is a potent CYP3A4 inhibitor).

The above list of substances is representative and not exhaustive.

Separate in vivo pharmacokinetic/pharmacodynamic interaction studies with oral ketoconazole or oral erythromycin in healthy subjects confirmed a marked inhibition of domperidone's CYP3A4 mediated first pass metabolism by these drugs.

With the combination of oral domperidone 10mg four times daily and ketoconazole 200mg 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 10mg four times daily and oral erythromycin 500mg 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. In these studies domperidone monotherapy at 10mg given orally four times daily resulted in increases in mean QTc of 1.6 msec (ketoconazole study) and 2.5 msec (erythromycin study), while ketoconazole monotherapy (200mg twice daily) led to increases in QTc of 3.8 and 4.9 msec, respectively, over the observation period.

Levodopa: Increase of plasma levels of levodopa (max 30-40%). See section 4.4.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are limited post-marketing data on the use of domperidone in pregnant women. Studies in animals have shown reproductive toxicity at maternally toxic doses (see section 5.3). Epzit should only be used during pregnancy when justified by the anticipated therapeutic benefit.

Breast-feeding

Domperidone is excreted in human milk and breast-fed infants receive less than 0.1 % of the maternal weight-adjusted dose. Occurrence of adverse effects, in particular cardiac effects cannot be excluded after exposure via breast milk. A decision should be made whether to discontinue breast-feeding or to discontinue/abstain from domperidone therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman. Caution should be exercised in case of QTc prolongation risk factors in breast-fed infants.

4.7. Effects on ability to drive and use machines

Somnolence have been observed following use of domperidone (see section 4.8). 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. Undesirable effects

Tabulated list of adverse reactions

The safety of domperidone was evaluated in clinical trials and in postmarketing experience. The clinical trials included 1275 patients with dyspepsia, gastro-oesophageal reflux disorder (GORD), Irritable Bowel Syndrome (IBS), nausea and vomiting or other related conditions in 31 double-blind, placebo-controlled studies. All patients were at least 15 years old and received at least one dose of Epzit (domperidone base). The median total daily dose was 30 mg (range 10 to 80 mg), and median duration of exposure was 28 days (range 1 to 28 days). Studies in diabetic gastroparesis or symptoms secondary to chemotherapy or parkinsonism were excluded.

The following terms and frequencies are applied:

very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000). Where frequency can not be estimated from clinical trials data, it is recorded as "Not known".

System Organ Class

Adverse Drug Reaction Frequency

Common

Uncommon

Not known

Immune system disorders

Anaphylactic reaction (including anaphylactic shock)

Psychiatric disorders

Loss of libido

Anxiety

Agitation

Nervousness

Nervous system disorders

Somnolence

Headache

Extrapyramidal disorder

Convulsion

Restless leg syndrome*

Eye disorders

Oculogyric crisis

Cardiac disorders (see section 4.4)

Ventricular arrhythmias

QTc prolongation

Torsade de Pointes

Sudden cardiac death

Gastrointestinal disorders

Dry mouth

Diarrhoea

Skin and subcutaneous tissue disorder

Rash

Pruritus

Urticaria

Angioedema

Renal and urinary disorders

Urinary retention

Reproductive system and breast disorders

Galactorrhoea

Breast pain

Breast tenderness

Gynaecomastia

Amenorrhoea

General disorders and administration site conditions

Asthenia

Investigations

Liver function test abnormal

Blood prolactin increased

*exacerbation of restless legs syndrome in patients with Parkinson's disease

In 45 studies where domperidone was used at higher dosages, for longer duration and for additional indications including diabetic gastroparesis, the frequency of adverse events (apart from dry mouth) was considerably higher. This was particularly evident for pharmacologically predictable events related to increased prolactin. In addition to the reactions listed above, akathisia, breast discharge, breast enlargement, breast swelling, depression, hypersensitivity, lactation disorder, and irregular menstruation were also noted.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via the Yellow Card Scheme website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.”

4.9. Overdose

Symptoms

Symptoms of over dosage may include agitation, altered consciousness, convulsions, disorientation, somnolence and extrapyramidal reactions.

Treatment

There is no specific antidote to domperidone, but in the event of overdose, standard symptomatic treatment should be given immediately. Gastric lavage as well as the administration of activated charcoal, may be useful. ECG monitoring should be undertaken, because of the possibility of QT interval prolongation. Close medical supervision and supportive therapy is recommended.

Anticholinergic, anti-parkinson drugs may be helpful in controlling the extrapyramidal reactions.