Dotilium

Dotilium Suspension is indicated in adults and children for the relief of the symptoms of nausea and vomiting.

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

It is recommended to take Dotilium Oral Suspension 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.

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

10 ml (of 1mg/ml oral suspension) up to three times per day with a maximum dose of 30ml per day.

Neonates, infants and children (under 12 years of age and weighing less than 35kg)

The dose is 0.25mg/kg. This should be given up to three times per day with a maximum dose of 0.75mg/kg per day. For example, for a child weighing 10kg, the dose is 2.5mg and this can be given three times per day toa maximum dose of 7.5mg per day.

Hepatic Impairment

Dotilium Oral Suspension is contraindicated in moderate or severe hepatic impairment. Dose modification in mild hepatic impairment is however not needed.

Renal Impairment

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

Dotilium suspension is contraindicated in the following situations:

-

- 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.

- 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 QT-prolonging drugs, with the exception of apomorphine

- co-administration with potent CYP3A4 inhibitors (regardless of their QT prolonging effects)

Precautions for use

Renal impairment:

The elimination half-life of Dotilium is prolonged in severe renal impairment. For repeated administration, the dosing frequency of Dotilium should be reduced to once or twice daily depending on the severity of the impairment. The dose may also need to be reduced.

Cardiovascular effects:

Dotilium 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 Dotilium. These reports included patients with confounding risk factors, electrolyte abnormalities and concomitant treatment which may have been contributing factors.

Epidemiological studies showed that Dotilium was associated with an increased risk of serious ventricular arrhythmias or sudden cardiac death. A higher risk was observed in patients older than 60 years, patients taking daily doses greater than 30mg, and patients concurrently taking QT_prolonging drugs or CYP3A4 inhibitors.

Dotilium should be used at the lowest effective dose in adults and children.

Dotilium 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. Electrolyte disturbances (hypokalaemia, hyperkalaemia, hypomagnesaemia) or bradycardia are known to be conditions increasing the proarrythmic risk.

Treatment with Dotilium 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 in infants:

Although neurological side effects are rare , the risk of neurological side effects is higher in young children since metabolic functions and the blood-brain barrier are not fully developed in the first months of life. Overdosing may cause extrapyramidal symptoms in children, but other causes should be taken into consideration.

Use with Potent CYP3A4 Inhibitors:

Co-administration with oral ketoconazole, erythromycin or other potent CYP3A4 inhibitors that prolong the QTc interval should be avoided.

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 Dotilium was taken concomitantly with levodopa.

Use with apomorphine:

Dotilium 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.

Dotilium suspension contains 400mg of liquid sorbitol (non-crystallising, E420) per ml, which may have a mild laxative effect. Patients with rare hereditary problems of fructose intolerance should not take this medicine.

Dotilium suspension contains methyl hydroxybenzoate (E218) and propyl hydroxybenzoate (E216), which may cause allergic reactions (possibly delayed).

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

Tabulated list of adverse reactions

The safety of Dotilium 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 Dotilium (Dotilium 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”.

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

In 45 studies where Dotilium 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 convulsion and agitation also are primarily reported in infants and children.

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 at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Symptoms

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

Treatment

There is no specific antidote to Dotilium, but in the event of overdose, standard symptomatic treatment should be given immediately. 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.

Pharmacotherapeutic group: Propulsives

ATC code: A03F A03

Mechanism of action

Dotilium is a dopamine antagonist with anti-emetic properties, Dotilium does not readily cross the blood-brain barrier. In Dotilium users, especially in adults, extrapyramidal side effects are very rare, but Dotilium promotes the release of prolactin from the pituitary. Its anti-emetic effect may be due to a combination of peripheral (gastrokinetic) effects and antagonism of dopamine receptors in the chemoreceptor trigger zone, which lies outside the blood-brain barrier in the area postrema. Animal studies, together with the low concentrations found in the brain, indicate a predominantly peripheral effect of Dotilium on dopamine receptors.

Studies in man have shown oral Dotilium to increase lower oesophaegeal pressure, improve antroduodenal motility and accelerate gastric emptying. There is no effect on gastric secretion.

In accordance with ICH—E14 guidelines, a thorough QT study was performed. This study included a placebo, an active comparator and a positive control and was conducted in healthy subjects with up to 80 mg per day 10 or 20 mg administered 4 times a day of Dotilium. This study found a maximal difference of QTc between Dotilium and placebo in LS-means in the change from baseline of 3.4 msec for 20 mg Dotilium administered 4 times a day on Day 4. The 2-sided 90 % CI (1.0 to 5.9 msec) did not exceed 10 msec. No clinically relevant QTc effects were observed in this study when Dotilium was administered at up to 80 mg/day (i.e., more than twice the maximum recommended dosing).

However, two previous drug-drug interaction studies showed some evidence of QTc prolongation when Dotilium was administered as monotherapy (10 mg 4 times a day).The largest time-matched mean difference of QTcF between Dotilium and placebo was 5.4 msec (95 % CI: -1.7 to 12.4) and 7.5 msec (95 % CI: 0.6 to 14.4), respectively.

Absorption

Dotilium is rapidly absorbed after oral administration, with peak plasma concentrations occurring at approximately 1hr after dosing. The Cmax and AUC values of Dotilium increased proportionately with dose in the 10mg to 20mg dose range. A 2- to 3-fold accumulation of Dotilium AUC was observed with repeated four times daily (every 5 hr) dosing of Dotilium for 4 days.

Although Dotilium's bioavailability is enhanced in normal subjects when taken after a meal, patients with gastro-intestinal complaints should take Dotilium 15 - 30 minutes before a meal. Reduced gastric acidity impairs the absorption of Dotilium. Oral bioavailability is decreased by prior concomitant administration of cimetidine and sodium bicarbonate.

Distribution

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

Biotransformation

Dotilium 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 Dotilium, whereas CYP3A4, CYP1A2 and CYP2E1 are involved in Dotilium aromatic hydroxylation.

Excretion

Urinary and faecal excretions amount to 31 and 66% of the oral dose respectively. The proportion of the drug excreted unchanged is small (10% of faecal excretion and approximately 1% of urinary 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.

Hepatic impairment

In subjects with moderate hepatic impairment (Pugh score 7 to 9, Child-Pugh rating B), the AUC and C_max of Dotilium is 2.9- and 1.5-fold higher, respectively, than in healthy subjects. The unbound fraction is increased by 25%, and the terminal elimination half-life is prolonged from 15 to 23 hours. Subjects with mild hepatic impairment have a somewhat lower systemic exposure than healthy subjects based on C_max and AUC, with no change in protein binding or terminal half-life. Subjects with severe hepatic impairment were not studied. Dotilium should not be used in patients with moderate or severe hepatic impairment.

Renal impairment

In subjects with severe renal insufficiency (creatinine clearance<30 ml/min/1.73m2) the elimination half-life of Dotilium was increased from 7.4 to 20.8 hours, but plasma drug levels were lower than in healthy volunteers.

Since very little unchanged drug (approximately 1%) is excreted via the kidneys, it is unlikely that the dose of a single administration needs to be adjusted in patients with renal insufficiency.

However, on repeated administration, the dosing frequency should be reduced to once or twice daily depending on the severity of the impairment, and the dose may need to be reduced.

Paediatric population

No pharmacokinetic data are available in the paediatric population.

Not applicable.

No special requirements.

How to use the oral syringe

1. Shake the bottle well making sure the cap is firmly on the bottle.

2. Remove the cap. Note: keep the cap nearby to close the bottle after each use.

3. Push the plastic adapter into the neck of the bottle. Note: the adapter must always stay in the bottle.

4. Take the syringe and check the plunger is fully down.

5. Keep the bottle upright and insert the oral syringe firmly into the plastic adapter.

6. Turn the whole bottle with the syringe upside down.

7. Slowly pull the plunger down fully so that the syringe fills with medicine. Push the plunger back up completely to expel any large air bubbles that may be trapped inside the oral syringe.

8. Then pull the plunger slowly back to the volume you need for your dose.

9. Turn the whole bottle with the syringe the right way up and take the syringe out of the bottle.

10. The dose of medicine can now be swallowed directly from the oral syringe. Please ensure that you are sitting upright and the plunger must be pushed slowly to allow you to swallow the dose.

11. Replace the child resistant cap after use, leaving the adapter in place.

12. To clean the oral syringe, take apart by removing the plunger completely. Pull straight out of the barrel. The barrel and plunger can be washed with soap and water, rinsed, and allowed to dry. Do not wash the oral syringe in the dishwasher.