Domperidone

Concomitant use of the following substances is not recommended with domperidone: moderate CYP3A4 inhibitors i.e. diltiazem, verapamil and some macrolides.

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.

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

Caution with bradycardia and hypokalaemia-inducing drugs, as well as with the following macrolides involved in QT interval prolongation: azithromycin and roxithromycin.

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 C_max 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.

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. Domperidone should only be used during pregnancy when justified by the anticipated therapeutic benefit.

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.

Domperidone has no or negligible influence on the ability to drive and use machines.

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 domperidone (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 (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), Where frequency can not be estimated from clinical trials data, it is recorded as “Not known”.

Immune system disorders

Not known: Anaphylactic reaction (including anaphylactic shock)

Psychiatric disorders

Uncommon: Loss of libido, Anxiety

Not known: Agitation, Nervousness

Nervous system disorders

Uncommon: Somnolence, Headache

Not known: Convulsion, Extrapyramidal disorder

Eye disorders

Not known: Oculogyric crisis

Cardiac disorders

Not known: Ventricular arrhythmias, Sudden cardiac death, QTc prolongation, Torsade de Pointes

Gastrointestinal disorders

Common: Dry mouth

Uncommon: Diarrhoea

Skin and subcutaneous tissue disorder

Uncommon: Rash, Pruritus

Not known: Urticaria, Angioedema

Renal and urinary disorders

Not known: Urinary retention

Reproductive system and breast disorders

Uncommon: Galactorrhoea, Breast pain, Breast tenderness

Not known: Gynaecomastia, Amenorrhoea

General disorders and administration site conditions

Uncommon: Asthenia

Investigations

Not known: Liver function test abnormal, Blood prolactin increased

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.

Paediatric population

Extrapyramidal disorder occurs primarily in neonates and infants

Other central nervous system-related effects of convulsionand agitation alsoare primarily reported in infants and children.