Metoclopramide Hydrochloride 5mg/5ml Oral Solution

Adult population

Metoclopramide is indicated in adults for:

- Prevention of delayed chemotherapy induced nausea and vomiting (CINV).

- Prevention of radiotherapy induced nausea and vomiting (RINV).

- Symptomatic treatment of nausea and vomiting, including acute migraine induced nausea and vomiting. Metoclopramide can be used in combination with oral analgesics to improve the absorption of analgesics in acute migraine.

Paediatric population

Metoclopramide is indicated in children (aged 1-18 years) for:

- Prevention of delayed chemotherapy induced nausea and vomiting (CINV) as a second line option.

Method of Administration.

For oral use.

Suitable for administration via nasogastric (NG) or percutaneous endoscopic gastrostomy (PEG) tubes. For further instructions see section 6.6.

Posology.

All indications (adult patients)

The recommended single dose is 10 mg, repeated up to three times daily.

The maximum recommended daily dose is 30 mg or 0.5 mg/kg body weight.

The maximum recommended treatment duration is 5 days.

Prevention of delayed chemotherapy induced nausea and vomiting (CINV) (paediatric patients aged 1-18 years)

The recommended dose is 0.1 to 0.15 mg/kg body weight, repeated up to three times daily by oral route. The maximum dose in 24 hours is 0.5 mg/kg body weight.

Dosing table

The maximum treatment duration is 5 days for prevention of delayed chemotherapy induced nausea and vomiting (CINV).

Method of administration:

A minimal interval of 6 hours between two administrations is to be respected, even in case of vomiting or rejection of the dose (see section 4.4).

Special population

Elderly

In elderly patients a dose reduction should be considered, based on renal and hepatic function and overall frailty.

Renal impairment:

In patients with end stage renal disease (Creatinine clearance ≤ 15 ml/min), the daily dose should be reduced by 75%.

In patients with moderate to severe renal impairment (Creatinine clearance 15-60 ml/min), the dose should be reduced by 50% (see section 5.2).

Hepatic impairment:

In patients with severe hepatic impairment, the dose should be reduced by 50% (see section 5.2).

Paediatric population

Metoclopramide is contraindicated in children aged less than 1 year (see section 4.3).

- Hypersensitivity to metoclopramide hydrochloride or any of the excipients listed in section 6.1

- Patients hypersensitive to procaine and procainamide may show cross-sensitivity

- Metoclopramide should not be used during the first three to four days following operations such as pyloroplasty or gut anastomosis as vigorous muscular contractions may not help healing

- Gastrointestinal haemorrhage, mechanical obstruction or gastro-intestinal perforation for which the stimulation of gastrointestinal motility constitutes a risk

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

- History of neuroleptic or metoclopramide-induced tardive dyskinesia

- Epilepsy (increased crises frequency and intensity)

- Parkinson's disease

- Combination with levodopa or dopaminergic agonists (see section 4.5)

- Known history of methaemoglobinaemia with metoclopramide, or of NADH cytochrome-b5 deficiency

- Use in children less than 1 year of age due to an increased risk of extrapyramidal disorders (see section 4.4).

If, despite treatment, vomiting persists, the patient must be re-assessed to exclude the possibility of an underlying disorder, i.e. cerebral irritation.

Care should be exercised when using metoclopramide in patients with a history of atopy (including asthma) or porphyria.

Patients receiving this drug for the disorders associated with delayed gastric emptying should be reviewed at an early stage for response to treatment.

Metoclopramide may cause elevation of serum prolactin levels.

Neurological Disorders

Extrapyramidal disorders may occur, particularly in children and young adults, and/or when high doses are used. These reactions occur usually at the beginning of the treatment and can occur after a single administration. Metoclopramide should be discontinued immediately in the event of extrapyramidal symptoms. These effects are generally completely reversible after treatment discontinuation, but may require a symptomatic treatment (benzodiazepines in children and/or anticholinergic anti-Parkinsonian medicinal products in adults).

The time interval of at least 6 hours specified in section 4.2 should be respected between each metoclopramide administration, even in case of vomiting and rejection of the dose, in order to avoid overdose.

Prolonged treatment with metoclopramide may cause tardive dyskinesia, potentially irreversible, especially in the elderly. Treatment should not exceed 3 months because of the risk of tardive dyskinesia (see section 4.8). Treatment must be discontinued if clinical signs of tardive dyskinesia appear.

Neuroleptic malignant syndrome has been reported with metoclopramide in combination with neuroleptics as well as with metoclopramide monotherapy (see section 4.8). Metoclopramide should be discontinued immediately in the event of symptoms of neuroleptic malignant syndrome and appropriate treatment should be initiated.

Special care should be exercised in patients with underlying neurological conditions and in patients being treated with other centrally-acting drugs (see section 4.3).

Symptoms of Parkinson's disease may also be exacerbated by metoclopramide.

Methaemoglobinemia

Methaemoglobinemia which could be related to NADH cytochrome b5 reductase deficiency has been reported. In such cases, metoclopramide should be immediately and permanently discontinued and appropriate measures initiated (such as treatment with methylene blue).

Cardiac Disorders

There have been reports of serious cardiovascular undesirable effects including cases of circulatory collapse, severe bradycardia, cardiac arrest and QT prolongation following administration of metoclopramide by injection, particularly via the intravenous route (see section 4.8).

Special care should be taken when administering metoclopramide, particularly via the intravenous route to the elderly population, to patients with cardiac conduction disturbances (including QT prolongation), patients with uncorrected electrolyte imbalance, bradycardia and those taking other drugs known to prolong QT interval.

Intravenous doses should be administered as a slow bolus (at least over 3 minutes) in order to reduce the risk of adverse effects (e.g. hypotension, akathisia).

Renal and Hepatic Impairment

In patients with renal impairment or with severe hepatic impairment, a dose reduction is recommended (see section 4.2).

Excipient Warnings

• Methyl and propyl parahydroxybenzoates are contained in this product which may cause allergic reactions (possibly delayed).

• Sorbitol. This medicine contains 227.3mg sorbitol (E420) in each 5ml.

The additive effect of concomitantly administered products containing sorbitol (or fructose) and dietary intake of sorbitol (or fructose) should be taken into account. The content of sorbitol in medicinal products for oral use may affect the bioavailability of other medicinal products for oral use administered concomitantly.

Patients with hereditary fructose intolerance (HFI) should not take/be given this medicinal product.

• Propylene glycol. This medicine contains 259mg propylene glycol (E1520) in each 5ml.

Co-administration with any substrate for alcohol dehydrogenase such as ethanol may induce adverse effects in children less than 5 years old.

While propylene glycol has not been shown to cause reproductive or development toxicity in animals or humans, it may reach the foetus and was found in milk. As a consequence, administration of propylene glycol to pregnant or lactating patients should be considered on a case by case basis.

Medical monitoring is required in patients with impaired renal or hepatic functions because various adverse events attributed to propylene glycol have been reported such as renal dysfunction (acute tubular necrosis), acute renal failure and liver dysfunction.

Contraindicated combination

Levodopa or dopaminergic agonists (including apomorphine, bromocriptine and pergolide) and metoclopramide have a mutual antagonism (see section 4.3).

Combination to be avoided

Alcohol potentiates the sedative effect of metoclopramide; concurrent use may also accelerate gastric emptying of alcohol and thus may promote the rate and extent of absorption from the small intestine.

Combination to be taken into account

Due to the prokinetic effect of metoclopramide, the absorption of certain drugs may be modified.

Anticholinergics and morphine derivatives

Anticholinergics and morphine derivatives may have both a mutual antagonism with metoclopramide on the digestive tract motility.

Central nervous system depressants (morphine derivatives, anxiolytics, sedative H1 antihistamines, sedative antidepressants, barbiturates, clonidine and related)

Sedative effects of Central Nervous System depressants and metoclopramide are potentiated.

Neuroleptics

Metoclopramide may have an additive effect with other neuroleptics on the occurrence of extrapyramidal disorders.

Serotonergic drugs

The use of metoclopramide with serotonergic drugs such as SSRIs may increase the risk of serotonin syndrome.

Digoxin

Metoclopramide may decrease digoxin bioavailability. Careful monitoring of digoxin plasma concentration is required.

Ciclosporin

Metoclopramide increases ciclosporin bioavailability (Cmax by 46% and exposure by 22%). Careful monitoring of ciclosporin plasma concentration is required. The clinical consequence is uncertain.

Mivacurium and suxamethonium

Metoclopramide injection may prolong the duration of neuromuscular block (through inhibition of plasma cholinesterase).

Strong CYP2D6 inhibitors

Metoclopramide exposure levels are increased when co-administered with strong CYP2D6 inhibitors such as fluoxetine and paroxetine. Although the clinical significance is uncertain, patients should be monitored for adverse reactions.

Extrapyramidal reaction causing drugs (such as phenothiazines and tetrabenazine)

Concurrent use with metoclopramide may increase the frequency and severity of extrapyramidal side effects. Care should be exercised in the event of co-administration of these drugs.

Mexiletine

Concurrent use with metoclopramide may accelerate absorption of mexiletine.

Diagnostic interference

With Gonadorelin test, concurrent use with metoclopramide may blunt the response to gonaderelin by increasing serum prolactin concentrations. Concurrent metoclopramide therapy may increase aldosterone and serum prolactin levels.

Aspirin and paracetamol

The absorption of any concurrently administered oral drug may be modified by the effect of metoclopramide on gastric motility. Drugs known to be affected in this way include aspirin and paracetamol.

Atovaquone

Metoclopramide may reduce plasma concentrations of atovaquone.

Pregnancy

A large amount of data on pregnant women (more than 1000 exposed outcomes) indicates neither malformative toxicity nor foetotoxicity. Metoclopramide can be used during pregnancy if clinically needed. Due to pharmacological properties (as with other neuroleptics), in case of metoclopramide administration at the end of pregnancy, extrapyramidal syndrome in newborn cannot be excluded. Metoclopramide should be avoided at the end of pregnancy. If metoclopramide is used, neonatal monitoring should be undertaken.

Breastfeeding

Metoclopramide is excreted in breast milk at low level. Adverse reactions in the breast-fed baby cannot be excluded. Therefore metoclopramide is not recommended during breastfeeding. Discontinuation of metoclopramide in breastfeeding women should be considered.

Metoclopramide may cause drowsiness, dizziness, dyskinesia and dystonias which can affect the vision and also interfere with the ability to drive and operate machinery.

Adverse reactions listed by System Organ Class. Frequencies are defined using the following convention: very common (≥ 1/10), common (≥ 1/100, <1/10), uncommon (≥ 1/1000, <1/100), rare (≥ 1/10000, <1/1000), very rare (<1/10000), not known (cannot be estimated from the available data).

* Endocrine disorders during prolonged treatment in relation with hyperprolactinaemia (amenorrhoea, galactorrhoea, gynaecomastia).

The following reactions, sometimes associated, occur more frequently when high doses are used:

- Extrapyramidal symptoms: acute dystonia and dyskinesia, parkinsonian syndrome, akathisia, even following administration of a single dose of the medicinal product, particularly in children and young adults (see section 4.4).

- Drowsiness, decreased level of consciousness, confusion, hallucination.

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

Extrapyramidal Disorder (muscle spasms, especially of jaw, neck, back, shuffling walk, tic like (jerky) movements of head and face, trembling and shaking of hands), drowsiness, decreased level of consciousness, confusion, hallucination and cardio-respiratory arrest may occur.

Management

In case of extrapyramidal symptoms related or not to overdose, the treatment is only symptomatic (benzodiazepines in children and/or anticholinergic anti-parkinsonian medicinal products in adults).

A symptomatic treatment and a continuous monitoring of the cardiovascular and respiratory functions should be carried out according to clinical status.

Metoclopramide is a dopaminergic blocker, acting as a delayed gastro-intestinal emptying adjunct and as a peristaltic stimulant. The exact mechanism of action is unknown; it is believed that metoclopramide inhibits gastric smooth muscle relaxation produced by dopamine thus enhancing cholinergic responses of the gastrointestinal smooth muscles. Accelerates intestinal transit and gastric emptying by preventing relaxation of gastric body and increasing the phasic activity of antrum. At the same time, this action is accompanied by relaxation of the upper small intestine, resulting in an improved co-ordination between the body and the antrum of the stomach and the upper small intestine. Decreases reflux into the oesophagus by increasing the resting pressure of the lower oesophageal sphincter and improves acid clearance from the oesophagus by increasing amplitude of oesophageal peristaltic contractions.

As an anti-emetic; the dopamine antagonist action raises the threshold of activity in the chemoreceptor trigger zone and decreases the input from afferent visceral nerves.

Metoclopramide also stimulates prolactin secretion.

Animal studies have shown metoclopramide to bind to plasma protein (13% - 22%), especially plasma albumin. Biotransformation is by the hepatic route.

Metoclopramide has a half life of four to six hours. The onset of action, by oral route of administration, is from 30 to 60 minutes. The duration on action is 1 to 2 hours.

Elimination is by the renal route, approximately 85% of an oral dose appears in the urine as unchanged drug and as sulfate and glucuronide conjugates.

Renal impairment

The clearance of metoclopramide is reduced by up to 70% in patients with severe renal impairment, while the plasma elimination half-life is increased (approximately 10 hours for a creatinine clearance of 10-50 mL/minute and 15 hours for a creatinine clearance <10 mL/minute).

Hepatic impairment

In patients with cirrhosis of the liver, accumulation of metoclopramide has been observed, associated with a 50% reduction in plasma clearance.

None stated

Methyl parahydroxybenzoate (E218), propyl parahydroxybenzoate (E216), propylene glycol (E1520), sorbitol solution (non crystallising) (E420), glycerol (E422), citric acid monohydrate (E330), lime and lemon flavours, sodium citrate (E331) and purified water.

Not applicable

24 months

1 month once opened

Store below 25° C and protect from light.

Keep out of the sight and reach of children.

Any unused product or waste material should be disposed of in accordance with local requirements.

Instructions for using the oral dosing syringe:

• Open the bottle: press the cap and turn it anticlockwise (Figure 1).

• Insert the syringe adaptor into the bottle neck (Figure 2).

• Take the syringe and put it in the adaptor opening (Figure 3).

• Turn the bottle upside down (Figure 4).

• Fill the syringe with a small amount of solution by pulling the piston down (Figure 4A). Then push the piston upward in order to remove any possible bubbles (Figure 4B). Finally, pull the piston down to the graduation mark corresponding to the quantity in millilitres (ml) prescribed by your doctor (Figure 4C).

• Turn the bottle the right way up (Figure 5A).

• Remove the syringe from the adaptor (Figure 5B).

• Put the end of the syringe into your mouth and push the piston slowly back in to take the medicine.

• Wash the syringe with water and let it dry before you use it again (Figure 6).

• Close the bottle with the plastic screw cap - leave the syringe adaptor in the bottle.

Instruction for administration via nasogastric (NG) or percutaneous endoscopic gastrostomy (PEG) tubes:

Ensure that the enteral feeding tube is free from obstruction before administration.

1. Flush the enteral tube with 5mL of water.

2. Administer the required dose of Metoclopramide Hydrochloride Oral Solution with a suitable measuring device.

3. Flush the enteral tube with 5mL of water.

This product has not been tested with latex NG or PEG tubes and therefore should not be used with tubes made from latex.