Composition

Tablets
Each film- coated tablet contains:
Domperidone Maleate equivalent to Domperidone .. 10 mg
Paracetamol .. 325 mg

Suspension
Each 5 ml of suspension contains:
Domperidone Maleate .. 5 mg
Paracetamol .. 250 mg

Dosage Forms

Tablet and Suspension for oral use

Pharamacology

Pharmacodynamics

Domperidone
Pharmacotherapeutic group: Propulsives; ATC Code: A03F A 03
Domperidone is a dopamine antagonist with anti-emetic properties. Domperidone does not readily cross the blood-brain barrier. In domperidone users, especially adults, extrapyramidal side effects are very rare, but domperidone 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 domperidone on dopamine receptors.
Studies in humans have shown oral domperidone to increase lower oesophageal pressure, improve antroduodenal motility and accelerate gastric emptying. There is no effect on gastric secretion.

Paracetamol
Analgesic - the mechanism of analgesic action has not been fully determined. Paracetamol may act predominantly by inhibiting prostaglandin synthesis in the central nervous system (CNS) and to a lesser extent, through a peripheral action by blocking the pain-impulse generation.

The peripheral action may also be due to inhibition of prostaglandin synthesis or to inhibition of the synthesis or actions of other substances that sensitize pain receptors to mechanical or chemical stimulation.

Antipyretic  - paracetamol probably produces antipyresis by acting centrally on the hypothalamic heat-regulation centre to produce peripheral vasodilation resulting in increased blood flow through the skin, sweating and heat loss. The central action probably involves inhibition of prostaglandin synthesis in the hypothalamus.

Pharmacokinetics

Domperidone
Absorption
In fasting subjects, domperidone is rapidly absorbed after oral administration, with peak plasma concentrations at 30 - 60 minutes. The low absolute bioavailability of oral domperidone (approximately 15%) is due to an extensive first-pass metabolism in the gut wall and liver. Although domperidone bioavailability is enhanced in normal subjects when taken after a meal, patients with gastrointestinal complaints should take domperidone 15 - 30 minutes before a meal. Reduced gastric acidity impairs the absorption of domperidone. Oral bioavailability is decreased by prior concomitant administration of cimetidine and 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; after 90 minutes a peak plasma level of 21ng/ml after 2 weeks of oral administration of 30 mg per day was almost the same as that of 18 ng/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, but low brain concentration. Small amounts of the drug cross the placenta in rats.

Metabolism
Domperidone undergoes rapid and extensive hepatic metabolism by hydroxylation and N-dealkylation. In vitro metabolism experiments with diagnostic inhibitors revealed that a major form of cytochrome P-450, CYP3A4 is involved in the N-dealkylation of domperidone, whereas CYP3A4, CYP1A2 and CYP2E1 are involved in domperidone 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 impairment.

Paracetamol
Paracetamol is readily absorbed from the gastrointestinal tract with peak plasma concentrations occurring about 30 minutes to 2 hours after ingestion; the time to peak effect is 1 - 3 hours and the duration of action is 3 - 4 hours. It is metabolized in the liver (90 - 95%) and excreted in the urine mainly as the glucuronide and sulphate conjugates. Less than 5% is excreted as unchanged paracetamol. The elimination half-life varies from about 1 to 4 hours. Plasma-protein binding is negligible at usual therapeutic concentrations, but increases with increasing concentrations.

A minor hydroxylated metabolite (n-acetyl-p-benzoquinoneimine) which is usually produced in very small amounts by mixed-function oxidases in the liver and which is usually detoxified by conjugation with liver glutathione may accumulate following paracetamol over dosage and cause liver damage

Indications

DOMCET tablet and suspension is indicated for the following:

Dosage and Administration

DOMCET tablets should be given as soon as a migraine attack has started or is imminent.

Adults (including the elderly)
1 - 2 tablets not more frequently than every 4 hours, and up to a maximum of 8 tablets in any 24-hour period.

DOMCET suspension

Age (years)	Average Weight (kg)	Dose (ml)
5 to 7	20 - 25	6 - 8
7 to 9	25 - 32	8 - 10
9 to 11	32 - 40	10 - 13
11 to 12	40 - 45	13 - 14

Contraindications

Domperidone plus paracetamol combination is contraindicated in the following situations:

Warnings and Precautions

General

Domperidone
Domperidone should only be taken according to the above posology.

Patients who find they have post-prandial symptoms that persist, and are having to take domperidone continuously for more than 2 weeks should be referred to their general practitioner.

Patients who find that their nausea and vomiting persist for more than 48 hours should be referred to their doctor.

The patient should be advised that Domperidone is not recommended for the treatment of motion sickness.

Domperidone is not recommended for use in patients with underlying cardiac disease, without medical supervision.

These tablets contain lactose and may be unsuitable for patients with lactose intolerance, galactosaemia or glucose/galactose malabsorption.

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

Cardiac effects
Some epidemiological studies showed that domperidone may be associated with an increased risk of serious ventricular arrhythmias or sudden cardiac death. The risk may be higher in patients older than 60 years and at daily doses of more than 30 mg. Domperidone should be used at the lowest effective dose in adults and children.

Use of domperidone and other drugs which prolong QTc intervals requires that caution be exercised in patients who have existing prolongation of cardiac conduction intervals, particularly QTc, patients with significant electrolyte disturbances or underlying cardiac diseases such as congestive heart failure.

The label will include the following:
Do not take if you are pregnant.

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

Paracetamol
Care is advised in the administration of paracetamol to patients with severe renal or severe hepatic impairment. The hazards of overdose are greater in those with non-cirrhotic alcoholic liver disease.

Do not exceed the stated dose.

Contains Paracetamol.

Do not take with any other paracetamol-containing products.

If symptoms persist for more than 3 days or get worse consult your doctor.
Immediate medical advice should be sought in the event of an overdose, even if you feel well.

Drug Interactions

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

Separate in vivo pharmacokinetic/pharmacodynamic interaction studies with oral ketoconazole or oral erythromycin in healthy subjects confirmed a marked inhibition of domperidone's CYP3 A4 mediated first pass metabolism by these drugs. With the combination of oral 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 oral 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. In these studies domperidone monotherapy at 10 mg 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 (200 mg twice daily) and erythromycin monotherapy (500 mg three times daily) led to increases in QTc of 3.8 and 4.9 msec, respectively, over the observation period.

Paracetamol
Cholestyramine: The speed of absorption of paracetamol is reduced by cholestyramine. Therefore, the cholestyramine should not be taken within 1 hour if maximal analgesia is required.

Metoclopramide: The absorption of paracetamol is increased by metoclopramide. However, concurrent use need not be avoided.

Warfarin: The anticoagulant effect of warfarin and other coumarins may be enhanced by prolonged regular use of paracetamol with increased risk of bleeding; occasional doses have no significant effect.

Chloramphenicol: Increased plasma concentration of chloramphenicol.

Pregnancy

Domperidone
There are limited post-marketing data on the use of domperidone in pregnant women. Therefore, domperidone should only be used during pregnancy when justified by the anticipated therapeutic benefit.

Paracetamol
Epidemiological studies in human pregnancy have shown no ill effects due to paracetamol used in the recommended dosage, but patients should follow the advice of their doctor regarding its use.

Lactation

Domperidone
Studies have shown that domperidone enters breast milk. It is not known whether this is harmful to the newborn. Therefore, breast feeding is not recommended for mothers who are taking domperidone.

Paracetamol
Paracetamol is excreted in breast milk but not in a clinically significant amount. Available published data do not contraindicate breast feeding.

Undesirable Effects

Domperidone
The safety of domperidone was evaluated in 1275 patients with dyspepsia, gastro-oesophageal reflux disorder, Irritable Bowel Syndrome, 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 base. The median total daily dose was 30 mg (range 10 - 80 mg), and median duration of exposure was 28 days (range 1 - 28 days).

Studies in diabetic gastroparesis or symptoms secondary to chemotherapy or parkinsonism were excluded.

The following terms and frequencies have been applied: very common (?1/10), common (?1/100 to <1/10), uncommon (?1/1000 to <1/100), rare (?1/10,000 to <1/1000), and very rare (<1/10,000).

Where frequency cannot be estimated from clinical trials data, it is recorded as “Not known”.

System Organ Class	Adverse Drug Reaction Frequency
	Common	Uncommon
Psychiatric disorders		Loss of libido Anxiety
Nervous system disorders		Somnolence Headache
Gastrointestinal disorders	Dry mouth	Diarrhoea
Skin and subcutaneous tissue disorders		Rash Pruritus
Reproductive system and breast disorders		Galactorrhoea Breast pain Breast tenderness
General disorders and administration site conditions		Asthenia

Post-marketing experience
In addition to the adverse effects reported during clinical studies and listed above, the following adverse drug reactions have been reported.

Immune system disorders
Not known	Anaphylactic reaction (including anaphylactic shock)
Psychiatric disorders
Not known	Agitation, nervousness
Nervous system disorders
Not known	Convulsion, extrapyramidal disorder
Eye disorders
Not known	Oculogyric crisis
Cardiac disorders
Not known	Ventricular arrhythmias, sudden cardiac death, QTc prolongation
Skin and subcutaneous tissue disorders
Not known	Urticaria, angio-oedema
Renal and urinary disorders
Not known	Urinary retention
Reproductive system and breast disorders
Not known	Gynaecomastia, amenorrhoea
Investigations
Not known	Liver function test abnormal, blood prolactin increased

Extrapyramidal disorder occurs primarily in neonates and infants.
Other CNS-related effects of convulsion and agitation also are primarily reported in infants and children.

Paracetamol
Adverse effects of paracetamol are rare; however, hypersensitivity including skin rash may occur. There have been reports of blood dyscrasias including thrombocytopenia and agranulocytosis, but these were not necessarily causally related to paracetamol.

Overdosage

Domperidone

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

Treatment
There is no specific antidote to domperidone; in the event of overdose, gastric lavage as well as the administration of activated charcoal may be useful. Close medical supervision and supportive therapy are recommended. Anticholinergic and anti-parkinson drugs may be helpful in controlling the extrapyramidal reactions.

Paracetamol

Liver damage is possible in adults who have taken 10g or more of paracetamol. Ingestion of 5g or more of paracetamol may lead to liver damage if the patient has risk factors (see below).

Risk Factors
If the patient

Symptoms
Symptoms of paracetamol over dosage in the first 24 hours are pallor, nausea, vomiting, anorexia and abdominal pain. Liver damage may become apparent 12 - 48 hours after ingestion. Abnormalities of glucose metabolism and metabolic acidosis may occur. In severe poisoning, hepatic failure may progress to encephalopathy, haemorrhage, hypoglycaemia, cerebral oedema, and death. Acute renal failure with acute tubular necrosis, strongly suggested by loin pain, haematuria and proteinuria, may develop even in the absence of severe liver damage. Cardiac arrhythmias and pancreatitis have been reported.

Management
Immediate treatment is essential in the management of paracetamol overdose. Despite a lack of significant early symptoms, patients should be referred to a hospital urgently for immediate medical attention. Symptoms may be limited to nausea or vomiting and may not reflect the severity of overdose or the risk of organ damage. Management should be in accordance with established treatment guidelines.

Treatment with activated charcoal should be considered if the overdose has been taken within 1 hour. Plasma paracetamol concentration should be measured at 4 hours or later after ingestion (earlier concentrations are unreliable).

Treatment with N-acetylcysteine may be used up to 24 hours after ingestion of paracetamol however; the maximum protective effect is obtained up to 8 hours post ingestion.

If required the patient should be given intravenous-N-acetylcysteine, in line with the established dosage schedule. If vomiting is not a problem, oral methionine may be a suitable alternative for remote areas, outside hospital.

Management of patients who present with serious hepatic dysfunction beyond 24 hours from ingestion should be discussed with the doctor.

Packaging Information

DOMCET Tablets: Blister Pack of 10 Tablets
DOMCET Suspension: 30 ml bottle