MIGRAMAX 900MG/10MG POWDER FOR ORAL SOLUTION

Active substance: METOCLOPRAMIDE HYDROCHLORIDE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Migramax 900mg/10mg Powder for oral solution

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Active ingredients

Per sachet
DL-lysine acetylsalicylate
equivalent to acetylsalicylic acid
Metoclopramide (INN) hydrochloride EP
equivalent in terms of the anhydrous substance to:

3

1,620mg
900mg
10.54mg
10mg

PHARMACEUTICAL FORM
Sachet containing powder for oral solution.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Adult population
MigraMax is indicated for the treatment of migraine-associated symptoms
such as headache, nausea and vomiting.

4.2

Posology and method of administration
For oral administration only.
MigraMax must be dissolved completely in some water before taking.
Renal and hepatic insufficiency

Caution should be exercised in significant renal or hepatic impairment.
Metoclopramide is metabolised in the liver and eliminated mainly via the
kidney. A dose reduction may be necessary.
Adults (aged 18 years and older) and elderly: One sachet should be taken at
the first warning of a migraine attack. A second sachet may be taken two
hours later if the symptoms have not resolved. Do not exceed three sachets in
a 24 hour period.
Paediatric population including adolescents
Use in children less than 1 year of age is contraindicated (see section 4.3)
Use in children and adolescents between the ages of 1 and 18 years is not
recommended.
Treatment should not exceed 3 months due to the presence of metoclopramide
(see sections 4.4 and 4.8)

4.3

Contraindications

-

-

-

4.4

Hypersensitivity to metoclopramide, salicylates or any of the components.
Patients with pre-existing mastocytosis, in whom the use of acetylsalicyclic acid
may induce severe hypersensitivity reactions (including circulatory shock with
flushing, hypotension, tachycardia and vomiting). In these patients, aspirin has
the potential to induce anaphylaxis either on its own or in combination with food
and/or exercise.
Active, chronic or recurrent gastric or duodenal ulcers.
Congenital or acquired bleeding disorders; obstruction, haemorrhage or
perforation of the GI tract.
Known or suspected phaeochromocytoma.
Third trimester of pregnancy.
Metoclopramide should not be used in the immediate post-operative period (up to
3-4 days) following pyloroplasty or gut anastomosis, as vigorous gastro-intestinal
contractions may adversely affect healing.
Use in children less than 1 year of age due to increased risk of extrapyramidal
disorders (see section 4.4).
Patients with severe hepatic insufficiency

Special warnings and precautions for use
If vomiting persists the patient should be reassessed to exclude the possibility
of an underlying disorder e.g. cerebral irritation.
As salicylates may induce asthma attacks in susceptible individuals MigraMax
should be avoided in patients at risk of developing sensitivity reactions. These
include individuals with asthma or rhinitis, a history of atopy or nasal polyps,
and also patients who have been sensitive to other salicylates or NSAIDs.

Use with caution in patients with a history of gastroduodenal ulcer or GI
haemorrhage, or with mild and moderate hepatic impairment, gout,
menorrhagia, or epilepsy. Care should be taken in patients using intra-uterine
contraceptive devices and patients who have a high alcohol intake.
There is a possible association between aspirin and Reye’s syndrome when
given to children with a fever. Reye’s syndrome is a very rare disease which
affects the brain and liver, and can be fatal. For this reason aspirin should not
be given to children under 12 years and should be avoided up to and including
16 years of age if feverish. MigraMax is contraindicated in patients under 20
years of age (see section 4.3).
As total clearance of metoclopramide is reduced and elimination prolonged in
patients with renal failure use in patients with significant degrees of renal
impairment should be approached with caution.
Metoclopramide may induce an acute hypertensive response in patients with
phaeochromocytoma.
Due to the risk of tardive dyskinesia with metoclopramide, treatment should
not exceed 3 months (see also sections 4.2 and 4.8).
Extrapyramidal disorders, (drowsiness, decreased level of consciousness,
confusion and hallucination) (see section 4.8) may occur, particularly in
children and young adults and/or when high doses are used (see section 4.8).
These adverse reactions resolve completely after treatment discontinuation. A
symptomatic treatment may be necessary (benzodiazepines in children and/or
anti-cholinergic anti-parksonian drugs in adults).
Neuroleptic Malignant Syndrome (NMS), a potentially fatal symptom
complex with hyperthermia, muscle rigidity, extrapyramidal symptoms,
altered mental status and autonomic dysfunction, may occur.
The
management of NMS should include 1) immediate discontinuation of the
product, 2) intensive symptomatic treatment and medical monitoring, and 3)
treatment of any concomitant serious medical problems for which specific
treatments are available.
Methaemoglobinemia has been reported with metoclopramide. In case of
methaemoglobinemia, MigraMax should be immediately and permanently
discontinued and appropriate measures initiated.
Metoclopramide is not recommended in epileptic patients as benzamides may
decrease the epileptic threshold.
Care should be exercised when using MIGAMAX SACHETS in patients with
a history of atopy (including asthma) or porphyria.
4.5

Interaction with other medicinal products and other forms of interaction
Metoclopramide-related interactions

Alcohol:
Alcohol potentiates the sedative effect of metoclopramide
Anticholinergics and morphine derivatives:
Anticholinergics and morphine derivatives antagonise the effects of
metoclopramide on gastrointestinal motility.
CNS depressants (morphine derivatives, hypnotics, anxiolytics, sedative H1
antihistamines, sedative antidepressants, barbiturates, clonidine and related):
Combination of CNS depressants with metoclopramide may result in
potentiation of sedative effects.
Antipsychotics:
Combination of antipsychotics with metoclopramide may result in potentiation
of extrapyramidal effects.
Due to the promotion of gastric emptying and normal peristalsis (see section
5.1) caused by metoclopramide, the absorption of certain drugs may be
modified:
Digoxin:
Metoclopramide decreased the gastric absorption of digoxin. Therefore, dose
adjustment may be required.
Ciclosporin:

Metoclopramide increases ciclosporin bioavailability. Dose adjustment may be
required. In one study, dosing requirements for ciclosporin were reported to be
reduced by 20% when metoclopramide was administered concomitantly. To avoid
toxicity, careful monitoring of ciclosporin plasma concentration is required.

Levodopa:
Levodopa and metoclopramide have a mutual antagonism. Concomitant use
should be avoided.
Salicylate-related interactions
Anti-coagulants:
Salicylates may enhance the effects of anti-coagulants.
Oral anti-diabetic agents:
Salicylates may enhance the effects of oral anti-diabetic agents.
Anti-epileptics:
Salicylates may enhance the effects of phenytoin, sodium valproate.
Antimetabolites:
Salicylates may enhance the effects of methotrexate

Immunomodulating agents:
Salicylates may inhibit the action of alpha interferon
Salicylates may interact with other NSAIDs, antacids and glucorticosteroids,
which may lower blood salicylate concentration during treatment and result in
high levels when treatment is stopped.
The effects of diuretics and uricosurics may also be affected by salicylates.
Other anti-platelet drugs
Salicylates may increase risk of bleeding with clopidogrel and ticlopidine.
Leukotriene antagonists
Aspirin may increase plasma concentration of zafirlukast
Mifepristone
Based on theoretical grounds, mifepristone may interact with salicylates.

4.6

Pregnancy and lactation
Although teratogenic effects of acetylsalicylic acid have been recorded in
animals, no such effects have been observed in humans.
No teratogenic effects have been observed with metoclopramide: data on
pregnant patients (> 1000) indicate no malformative nor foeto/ neonatal
toxicity during 1rst trimester of pregnancy. A limited amount of data on
pregnant patients (> 300) indicate no neonatal toxicity in other trimesters.
Animal studies do not indicate reproductive toxicity.
In the third trimester, the use of prostaglandin synthesis inhibitors such as
acetylsalicylic acid may expose the foetus to premature closure of the ductus
arteriosus. MigraMax is therefore contra-indicated during the third trimester.
Like all drugs avoid use in the first and second trimester unless the physician
believes the benefits outweigh the risk.
MigraMax is not recommended during lactation because acetylsalicylic acid and
metoclopramide are excreted in breast milk and adverse reactions in the breast-fed
baby cannot be excluded. A decision should be made whether to discontinue breastfeeding or to abstain from Migramax treatment.

4.7

Effects on ability to drive and use machines
MigraMax may cause drowsiness. This effect can be potentiated by CNS
depressants or alcohol. If affected, patients should not drive or operate
machinery.

4.8

Undesirable effects
Nervous system and psychiatric disorders
The following reactions, sometimes associated, occur more frequently when
high doses are used:
- Extrapyramidal symptoms: acute dystonia and dyskinesia, Parkinsonian
syndrome, akathisia may occur even following administration of a single
dose of the drug particularly in children, young adults and the elderly (see
section 4.4).
Extrapyramidal reactions include spasm of the facial muscles, trismus, rhythmic
protrusion of the tongue, a bulbar type of speech, spasm of extraocular muscles
including oculogyric crises, unnatural positioning of the head and shoulders and
opisthotonos. There may be a generalised increase in muscle tone. The majority
of reactions occur within 36 hours of starting treatment and the effects usually
disappear within 24 hours of withdrawal of the drug. Should treatment of a
dystonic reaction be required, a benzodazepine or an anticholinergic antiParkinsonian drug may be used.
- Drowsiness, decreased level of consciousness, confusion, hallucination.

Other reactions may occur:
- Tardive dyskinesia, particularly in elderly patients and during or after
- prolonged treatment (see also sections 4.2 and 4.4).
- Metoclopramide may cause lethargy, insomnia, dizziness
- Depression
- Restlessness, anxiety
- Seizures
- Neuroleptic malignant syndrome
- Intracranial haemorrhage
Endocrine disorders
Hyperprolactinaemia causing amenorrhea, galactorrhea, gynaecomastia.
Blood and Lymphatic system disorders
Metoclopramide may cause:
-

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
sulfur-releasing drugs.
Aspirin may increase bleeding time, decrease platelet adhesiveness, and in large doses
cause hypothrombinaemia.
It may cause other blood disorders, including
thrombocytopenia, iron deficiency or haemolytic anaemia and rarely agranulocytosis.
Cardiac and Vascular disorders
Bradycardia and heart block have been reported with metoclopramide, particularly
the intravenous formulation.
Respiratory, thoracic and mediastinal disorders
Frequency not known:

-

Non-cardiogenic pulmonary oedema with chronic use and in the context of a
hypersensitivity reaction due to acetylsalicyclic acid

Gastrointestinal disorders
Diarrhoea, flatulence
The most common side effects occurring with therapeutic doses of salicylates are
gastrointestinal disturbances such as gastric irritation with blood loss, nausea,
dyspepsia, vomiting and gastric ulceration. The gastrointestinal haemorrhaging is
occasionally severe but in most cases blood loss is not significant.
Frequency not known:
- Upper gastrointestinal disorders: oesophagitis, erosive duodenitis, erosive
gastritis, esophageal ulceration, perforation
- Lower gastrointestinal disorders: small (jejunum and ileum) and large (colon and
rectum) intestinal ulcers, colitis and intestinal perforation
These reactions may or may not be associated with haemorrhage, and may occur at
any dose of acetylsalicyclic acid and in patients with or without warning symptoms or
a previous history of serious GI events
Hepatobiliary disorders
Elevation of hepatic enzymes, liver injury mainly hepatocellular
General disorders and administration site conditions
Very rarely hypersensitivity, including anaphylaxis has been reported.
Salicylates may induce hypersensitivity especially in those individuals with asthma or
rhinitis, and a history of atopy or nasal polyps. The observed hypersensitivity
reactions include anaphylaxis, urticaria and bronchospasm.
Asthenia
Ear and labyrinth disorders
Tinnitus
Renal and urinary disorders
Other reported effects of salicylates include urate kidney stones.

4.9

Overdose
In cases of overdose, toxic reactions are mainly ascribable to aspirin.
Salicylate poisoning is usually associated with plasma concentrations >350 mg/L
(2.5mmol/L). Most adult deaths occur in patients whose concentrations exceed 700
mg/L (95.1mmol/L). Single doses less than 100 mg/kg are unlikely to cause serious
poisoning.
Symptoms
Common features include vomiting, dehydration, tinnitus, vertigo, deafness,
sweating, warm extremities with bounding pulses, increased respiratory rate and
hyperventilation. Some degree of acid-base disturbance is present in most cases. A
mixed respiratory alkalosis and metabolic acidosis with normal or high arterial pH
(normal or reduced hydrogen ion concentration) is usual in adults and children over
the age of 4 years. In children aged 4 years or less, a dominant metabolic acidosis
with low arterial pH (raised hydrogen ion concentration) is common. Acidosis may
increase salicylate transfer across the blood brain barrier. Uncommon features include

haematemesis, hyperpyrexia, hypoglycaemia, hypokalaemia, thrombocytopaenia,
increased INR/PTR, intravascular coagulation, renal failure and non-cardiac
pulmonary oedema.
Central nervous system features including confusion, disorientation, coma and
convulsions are less common in adults than in children.
Non-cardiogenic pulmonary oedema can
acetylsalicyclic acid overdose (see section 4.8)

occur

with

acute

and

chronic

Management
Give activated charcoal if an adult presents within one hour of ingestion of more than
250 mg/kg. The plasma salicylate concentration should be measured, although the
severity of poisoning cannot be determined from this alone and the clinical and
biochemical features must be taken into account. Elimination is increased by urinary
alkalinisation, which is achieved by the administration of 1.26% sodium bicarbonate.
The urine pH should be monitored. Correct metabolic acidosis with intravenous 8.4%
sodium bicarbonate (first check serum potassium). Forced diuresis should not be used
since it does not enhance salicylate excretion and may cause pulmonary
oedema. Haemodialysis is the treatment of choice for severe poisoning and should be
considered in patients with plasma salicylate concentrations >700 mg/L (5.1
mmol/L), or lower concentrations associated with severe clinical or metabolic
features. Patients under 10 years or over 70 have increased risk of salicylate toxicity
and may require dialysis at an earlier stage.
Metoclopramide overdose may cause extrapyramidal disorders and drowsiness,
decreased level of consciousness, confusion, hallucinations and convulsions.
Decreased level of consciousness, confusion and hallucinations resolve after
metoclopramide withdrawal.
Treatment for extrapyramidal disorders caused by metoclopramide overdose is only
symptomatic (benzodiazepines in children and/or anticholinergic anti-parkinsonian
drugs in adults).

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
The pharmacological properties of this product are those of the two active
ingredients ie. an analgesic and an antiemetic.
Acetylsalcylic acid has analgesic, antipyretic and anti-inflammatory
properties. It inhibits prostaglandin synthesis so that the prostaglandininduced sensitivity of peripheral nerve endings to kinins and other mediators
of pain and inflammation is reduced. Acetylsalicylic acid also exerts a
powerful inhibition on platelet aggregation by blocking thromboxane A2
synthesis in the platelets.
Metoclopramide is an effective anti-emetic, although its exact mechanism(s)
of action is not fully established. It is a cholinergic agonist acting peripherally

to enhance the action of acetylcholine at muscarinic synapses and in the CNS
by blocking dopamine receptors in the chemoreceptor trigger zone for
vomiting.
Local effects include the promotion of gastric emptying and normal peristalsis,
impairment of which are a common feature of migraine attacks.

5.2

Pharmacokinetic properties
Lysine acetylsalicylate
Absorption of lysine acetylsalicylate as a solution is rapid in healthy subjects.
Lysine acetylsalicylate dissociates into lysine and acetylsalicylic acid which is
rapidly hydrolysed to salicylic acid. The plasma peak of acetylsalicylic acid is
achieved within 20 minutes.
Plasma salicylates are essentially bound to plasma proteins and are converted
to inactive metabolites in the liver. Salicylic acid and its metabolites are
excreted via the kidneys. Clearance increases with increasing urinary pH.
The elimination half-life of salicylic acid is dose-dependent owing to the
saturable nature of salicylic acid conjugation and ranges from as little as 2
hours after a single dose of 500 mg, lengthening to as long as 20 hours in
overdosage.
Metoclopramide
The plasma peak of metoclopramide is reached within an average time of 40
minutes following oral administration. Peak plasma concentrations are 32 and
70 g/L for 10 and 20 mg doses.
Bioavailability is 80% per os. Interindividual variations are related to a 20%
first-pass effect. Metoclopramide is rapidly and extensively distributed in
tissues. The volume of distribution is 2.2 - 3.4 1/kg. Metoclopramide has a
low degree of binding to plasma proteins (30%). The plasma elimination halflife of metoclopramide is 5 - 6 hours. Total clearance is 0.4 - 0.7 1/min.
Metoclopramide is only partially metabolised in humans; urinary excretion
occurs essentially as the unchanged and sulphoconjugated compounds (50% of
the dose administered).
Renal insufficiency significantly reduces the clearance of metoclopramide and
increases the plasma elimination half-life.
Combination
When administered as an oral solution, lysine acetylsalicylate and
metoclopramide are rapidly absorbed.

In subjects not suffering from migraine, plasma concentrations of total
salicylates, acetylsalicylic acid and metoclopramide do not differ from those
recorded following both drugs administered singly.
The elimination half-life of salicylates and metoclopramide is unaffected in
subjects suffering from migraine receiving the two drugs in combination
compared with normal subjects.

5.3

Preclinical safety data
No data of therapeutic relevance.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Aspartame, glycine, lemon flavour (essential oil of lemon absorbed on a
maltodextrin substrate).

6.2

Incompatibilities
No known major incompatibilities.

6.3

Shelf life
1 year

6.4

Special precautions for storage
Store at or below 25°C.

6.5

Nature and contents of container

Pack sizes:

Carton containing 2 sachets
Carton containing 6 sachets
Carton containing 20 sachets

MigraMax is packaged in sachets made of a paper-polyethylene-aluminium
complex, containing one unit dose and heat-sealed.

6.6

Special precautions for disposal
Consult the patient leaflet before use.
Do not use after the stated expiry date on the sachet or carton.
To be taken orally when the powder is completely dissolved.

7

MARKETING AUTHORISATION HOLDER
Winthrop Pharmaceuticals UK Limited
One Onslow Street
Guildford
Surrey
GU1 4YS, UK
Trading as: Winthrop Pharmaceuticals, PO Box 611, Guildford, Surrey, GU1
4YS, UK
Or
Trading as: Zentiva, One Onslow Street, Guildford, Surrey, GU1 4YS, UK

8

MARKETING AUTHORISATION NUMBER(S)
PL 17780/0552

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
16/03/2011

10

DATE OF REVISION OF THE TEXT
11/11/2014

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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