Metoclopramide Orion

Document: Metoclopramide Orion film-coated tablet ENG SmPC change

SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

Metoclopramide Orion 10 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 10 mg metoclopramide hydrochloride.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL form

Film-coated tablet (tablet)

White to off-white, circular, 7 mm diameter, biconvex film-coated tablets with break line on both sides.

The tablet can be divided into equal doses.

4. Clinical particulars

4.1 Therapeutic indications

Adult population

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

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

4.2 Posology and method of administration

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

Age	Body weight	Dose	Frequency
1–3 years	10–14 kg	1 mg	Up to 3 times daily
3–5 years	15–19 kg	2 mg	Up to 3 times daily
5–9 years	20–29 kg	2.5 mg	Up to 3 times daily
9–18 years	30–60 kg	5 mg	Up to 3 times daily
15–18 years	Over 60 kg	10 mg	Up to 3 times daily

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

Tablets are not suitable for use in children weighing less than 30 kg. Other pharmaceutical forms/strengths may be more appropriate for administration to this population.

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).

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Gastrointestinal haemorrhage, mechanical obstruction or gastro‑intestinal perforation for which 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).

4.4 Special warnings and precautions for use

_N_e_u_r_o_l_og_i_c_al_d_i_s_o_r_d_e_r_s

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.

Methaemoglobinaemia

Methaemoglobinaemia 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 to those taking other drugs known to prolong QT interval.

Intravenous doses should be administered as a slow bolus injection (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).

4.5 Interaction with other medicinal products and other forms of interaction

Contraindicated combination

Levodopa or dopaminergic agonists and metoclopramide have a mutual antagonism (see section 4.3).

Combination to be avoided

Alcohol potentiates the sedative effect of metoclopramide.

Combination to be taken into account

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

_A_n_t_i_c_ho_li_n_e_r_g_i_c_s_and _m_o_r_ph_i_ne_d_e_r_i_v_a_t_i_v_e_s

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

Centralnervoussystemdepressants(morphinederivatives,anxiolytics, sedativeH1 antihistamines, sedativeantidepressants,barbiturates, clonidineand related substances)

Sedative effects of Central nervous system depressants and metoclopramide are potentiated.

_N_e_u_r_o_l_e_p_t_i_c_s

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

_S_e_r_o_t_on_e_r_g_i_c_d_r_u_gs

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

_D_i_go_x_i_n

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

_C_yc_l_o_s_po_r_i_ne

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

_M_i_v_a_c_u_r_i_um_and _s_u_x_a_m_e_t_hon_i_um

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

_S_t_r_ong _C_Y_P₂_D₆_i_nh_i_b_i_t_o_r_s

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.

4.6 Fertility, pregnancy and lactation

Pregnancy

A large amount of data on pregnant women (more than 1,000 exposed outcomes) indicates no malformative toxicity nor foetotoxicity. Metoclopramide can be used during pregnancy if clinically needed. Due to pharmacological properties (as 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 breast-fed infants cannot be excluded. Therefore the use of metoclopramide is not recommended during breastfeeding. Discontinuation of metoclopramide in breastfeeding women should be considered.

4.7 Effects on ability to drive and use machines

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

Undesirable effects

Adverse reactions are listed by system organ class. Frequencies are defined using the following convention: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1,000, < 1/100), rare (≥ 1/10,000, < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data).

System organ class	Frequency		Adverse reactions
Blood and lymphatic system disorders
	Not known		Methaemoglobinaemia, which could be related to NADH cytochrome b5 reductase deficiency, particularly in neonates (see section 4.4). Sulfhaemoglobinaemia, mainly with concomitant administration of high doses of sulphur-releasing medicinal products
Cardiac disorders
	Uncommon		Bradycardia, particularly with intravenous formulation
	Not known		Cardiac arrest occurring shortly after injectable use; and which can be subsequent to bradycardia (see section 4.4); atrioventricular block; sinus arrest particularly with intravenous formulation; Electrocardiogram QT prolonged; torsade de pointes
Endocrine disorders*
	Uncommon		Amenorrhoea, hyperprolactinaemia
	Rare		Galactorrhoea
	Not known		Gynecomastia
Gastrointestinal disorders
	Common		Diarrhoea
General disorders and administration site conditions
	Common		Asthenia
Immune system disorders
	Uncommon	Hypersensitivity
	Not known	Anaphylactic reaction (including anaphylactic shock particularly with intravenous formulation)
Nervous system disorders
	Very common	Somnolence
	Common	Extrapyramidal disorders (particularly in children and young adults and/or when the recommended dose is exceeded, even following administration of a single dose of the drug) (see section 4.4), parkinsonism, akathisia
	Uncommon	Dystonia, dyskinesia, depressed level of consciousness
	Rare	Convulsion especially in epileptic patients
	Not known	Tardive dyskinesia which may be persistent, during or after prolonged treatment, particularly in elderly patients (see section 4.4); neuroleptic malignant syndrome (see section 4.4)
Psychiatric disorders
	Common	Depression
	Uncommon	Hallucination
	Rare	Confusional state
Vascular disorders
	Common	Hypotension, particularly with intravenous formulation
	Not known	Shock, syncope after injectable use, acute hypertension in patients with phaeochromocytoma (see section 4.3), transient increase in blood pressure

* 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 this medicinal product, particularly in children and young adults (see section 4.4).
Drowsiness, decreased level of consciousness, confusion, hallucinations.

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 national reporting system listed in Appendix V.

4.9 Overdose

Symptoms

Extrapyramidal disorders, drowsiness, decreased level of consciousness, confusion, hallucinations, 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.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Propulsives, ATC code: A03FA01

Metoclopramide is a procainamide derivate. Metoclopramide is a dopamine receptor blocker. Metoclopramide has a centrally acting antiemetic effect and a motility-enhancing effect in the area of the stomach, duodenum and small intestine. Metoclopramide synchronizes antral and duodenal contractions. In patients with gastroesophageal reflux metoclopramide increases the tone of the cardiac sphincter, increases peristalsis in the lower oesophagus and reduces the number of acid reflux episodes.

5.2 Pharmacokinetic properties

Oral bioavailability has been reported to be 32–97%. Large individual differences exist. The volume of distribution of metoclopramide is about 3.5 L/kg. The terminal half-life is 4‒6 hours and can be prolonged in patients with renal impairment. Metoclopramide is mainly excreted in the urine. About 85% of the dose is eliminated within 72 hours, 20‒30% as unchanged metoclopramide and the rest as sulphate or glucuronide conjugates, or other metabolites. About 5% is excreted in the faeces via the bile.

_R_e_nal_i_m_pa_i_r_m_e_nt

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

5.3 Preclinical safety data

Besides the data in other sections of this summary of product characteristics, there are no preclinical data relevant to the assessment of safety.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tabletcore

Maize starch

Starch, pregelatinised

Cellulose, microcrystalline

Silica, colloidal anhydrous

Stearic acid

Tabletcoating

Hypromellose

Macrogol

Titanium dioxide (E171)

Talc

6.2 Incompatibilities

Notapplicable.

6.3 Shelf life

4 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

Nature and contents of container

ClearPVDC coatedPVC/aluminiumblister.

Pack sizes: 20, 30, 40, 50, 100 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

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

7. MARKETING AUTHORISATION HOLDER

[To be completed nationally]

8. MARKETING AUTHORISATION NUMBER(S)

[To be completed nationally]

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation:

10. DATE OF REVISION OF THE TEXT

2016-10-25