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EMFLEX CAPSULES

Active substance(s): ACEMETACIN

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Emflex Capsules

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each capsule contains Acemetacin 60mg
Excipients: Each capsule contains 73.9mg lactose.
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Gelatine capsule

4

CLINICAL PARTICULARS

4.1
and

Therapeutic indications
Rheumatoid arthritis, osteoarthritis, low back pain, and post-operative pain
inflammation.

4.2

Posology and method of administration
Method of administration:

For oral administration.
To be taken preferably with or after food.

Undesirable effects may be minimised by using the lowest effective dose for the
shortest duration necessary to control symptoms (see section 4.4).
Posology:
The recommended starting dose is 120mg/day in divided doses, increasing to
180mg/day in divided doses, depending on patient response.
Special populations:
Elderly:
The elderly are at increased risk of the serious consequences of adverse reactions. If
an NSAID is considered necessary, the lowest effective dose should be used and for
the shortest possible duration. The patient should be monitored regularly for GI
bleeding during NSAID therapy.
Paediatric population:
The safety in children and adolescents is not established.

4.3

4.4

Contraindications


Hypersensitivity to the active substance, indomethacin or to any of the excipients
listed in section 6.1



Active, or history of recurrent peptic ulcer/haemorrhage (two or more distinct
episodes of proven ulceration or bleeding).



NSAIDS are contra-indicated in patients who have previously shown
hypersensitivity reactions (e.g., asthma, rhinitis, angioedema or urticaria) in
response to ibuprofen, aspirin or other non-steroidal anti-inflammatory drugs.



Severe heart failure, hepatic failure and renal failure (see section 4.4).



During the last trimester of pregnancy (see section 4.6)



History of gastrointestinal bleeding or perforation, related to previous NSAIDs
therapy.



Nasal polyps associated with angioneurotic oedema.



Blood formation disorder of unclear aetiology



Children and adolescents

Special warnings and precautions for use
Undesirable effects may be minimised by using the lowest effective dose for the
shortest duration necessary to control symptoms (see section 4.2, and GI and
cardiovascular risks below).

The use of Emflex with concomitant NSAIDS including cyclooxygenase-2 selective
inhibitors should be avoided (see section 4.5).
Elderly:
The elderly have an increased frequency of adverse reactions to NSAIDs especially
gastrointestinal bleeding and perforation which may be fatal (see section 4.2).
Respiratory disorders:
Caution is required if administered to patients suffering from, or with a previous
history of, bronchial asthma since NSAIDs have been reported to precipitate
bronchospasm in such patients. Patients who suffer from asthma, hay fever, swollen
nasal mucosae or chronic respiratory disease are at particular risk of hypersensitivity
reactions

Cardiovascular, renal and hepatic impairment:
The administration of an NSAID may cause a dose dependent reduction in
prostaglandin formation and precipitate renal failure. Patients at greatest risk of this
reaction are those with impaired renal function, cardiac impairment, liver dysfunction,
those taking diuretics and the elderly. Renal function should be monitored in these
patients (see also section 4.3). An increase in the parameters of liver and kidney
function tests has been in observed in some patients being treated with Emflex. Under
long-term treatment, monitoring of liver and kidney function is strongly
recommended.
Cardiovascular and cerebrovascular effects:
Appropriate monitoring and advice are required for patients with a history of
hypertension and/or mild to moderate congestive heart failure as fluid retention and
oedema have been reported in association with NSAID therapy.
Clinical trial and epidemiological data suggest that use of some NSAIDs (particularly
at high doses and in long term treatment) may be associated with a small increased
risk of arterial thrombotic events (for example myocardial infarction or stroke).
There are insufficient data to exclude such a risk for acemetacin.
Patients with uncontrolled hypertension, congestive heart failure, established
ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease
should only be treated with acemetacin after careful consideration. Similar
consideration should be made before initiating longer-term treatment of patients with
risk factors for cardiovascular disease (e.g., hypertension, hyperlipidaemia, diabetes
mellitus, smoking).

Gastrointestinal bleeding, ulceration and perforation:
GI bleeding, ulceration or perforation, which can be fatal, has been reported with all
NSAIDs at any time during treatment, with or without warning symptoms or a
previous history of serious GI events. Inhibition of platelet aggregation may occur.
Emflex should only be used after careful assessment of the risk/benefit ratio in
patients with a history of gastric or duodenal ulcers if not contraindicated according to
section 4.3.
The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID
doses, in patients with a history of ulcer, particularly if complicated with haemorrhage
or perforation (see section 4.3) and in the elderly. These patients should commence

treatment on the lowest dose available. Combination therapy with protective agents
(e.g. misoprostol or proton pump inhibitors) should be considered for these patients,
and also for patients requiring concomitant low dose aspirin, or other drugs likely to
increase gastrointestinal risk (see below and section 4.5).

Patients with a history of GI toxicity, particularly when elderly, should report any
unusual abdominal symptoms (especially GI bleeding) particularly in the initial stages
of treatment.
Caution should be advised in patients receiving concomitant medications which could
increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants
such as warfarin, selective serotonin-reuptake inhibitors or anti-platelet agents such as
aspirin (see section 4.5).
When GI bleeding or ulceration occurs in patients receiving acemetacin, the treatment
should be withdrawn.
In patients with an increased haemorrhagic tendency, platelet aggregation may be
affected and the tendency to bleed may be increased.
Under long term treatment haemogram and blood coagulation monitoring is strongly
recommended.
NSAIDs should be given with care to patients with a history of gastrointestinal
disease (ulcerative colitis, Crohn’s disease) as these conditions may be exacerbated
(see section 4.8).
SLE and mixed connective tissue disease:
In patients with systemic lupus erythematosus (SLE) and mixed connective tissue
disorders there may be an increased risk of aseptic meningitis (see section 4.8).
Dermatological:
Serious skin reactions, some of them fatal, including exfoliative dermatitis, StevensJohnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in
association with the use of NSAIDs (see section 4.8). Patients appear to be at highest
risk for these reactions early in the course of therapy: the onset of the reaction
occurring in the majority of cases within the first month of treatment. Emflex should
be discontinued at the first appearance of skin rash, mucosal lesions or any other sign
of hypersensitivity.
Impaired female fertility:
The use of Emflex may impair female fertility and is not recommended in women
attempting to conceive. In women who have difficulties conceiving or who are
undergoing investigation of infertility, withdrawal of Emflex should be considered.

Eye disorders:
Eye changes may occur in chronic rheumatoid disease and patients should receive
periodic ophthalmological examinations and therapy discontinued if changes occur.
Neurological:
Aggravation of psychiatric disorders, epilepsy or parkinsonism may occur.
Other:
Signs and symptoms of infection may be masked.

Emflex should only be used with careful medical observation in Varicella zoster virus
infections (chickenpox, herpes zoster) due to a possibly increased risk of severe
cutaneous complications
Special care is required when Emflex is given immediately before or after surgeries.
As this product contains lactose, patients with rare hereditary problems of galactose
intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should
not take this medicine.

4.5

Interaction with other medicinal products and other forms of interaction
Other analgesics including cyclooxygenase-2 selective inhibitors: Avoid concomitant
use of two or more NSAIDs (including aspirin, other salicylates, diflusinal) as this
may increase the risk of adverse effects (see section 4.4).
Anti-hypertensives: reduced anti-hypertensive effect.
Diuretics: Reduced diuretic effect should be considered when treating patients with
compromised cardiac function or hypertension. Diuretics can increase the risk of
nephrotoxicity of NSAIDs. Furosemide accelerates the excretion of acemetacin.
Diuretics and antihypertensives: NSAIDs may weaken the effect of diuretic agents
and hypertensive agents. In patients with impaired renal function (such as dehydrated
patients or elderly patients), concomitant use of an ACE inhibitor and/or angiotensinII receptor antagonist and a medicinal product inhibiting cyclooxygenase may lead to
further exacerbation of renal function (including the possibility of acute renal failure)
which is normally reversible. Therefore, such a combination should be used with
caution only, in particular in the elderly. These patients should be encouraged to drink
adequate liquids, and regular control of renal laboratory values should be considered
after such combination therapy has been initiated.
Hyperkalaemia has been reported with use of indomethacin and this should be
considered when administration with potassium-sparing diuretics is proposed.
Potassium concentration must be monitored frequently.
Digoxin, cardiac glycosides: NSAIDs may exacerbate cardiac failure, reduce GFR
and increase plasma glycoside levels.
Phenytoin: decreased elimination of phenytoin.
Lithium: decreased elimination of lithium.
Methotrexate: decreased elimination of methotrexate.
Ciclosporin: Increased risk of nephrotoxicity.
Mifepristone: NSAIDs should not be used for 8-12 days after mifepristone
administration as NSAIDs can reduce the effect of mifepristone.
Corticosteroids: increased risk of gastrointestinal ulceration or bleeding (see section
4.4).

Anti-coagulants: NSAIDs may enhance the effects of anti-coagulants, such as
warfarin (see section 4.4). ). In case of concomitant treatment, it is therefore
recommended to monitor the patient's blood clotting status.
Quinolone antibiotics: Animal data indicate that NSAIDs can increase the risk of
convulsions associated with quinolone antibiotics. Patients taking NSAIDs and
quinolones may have an increased risk of developing convulsions.
Penicillin antibiotics:
May delay the elimination of penicillin
Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs): Increased
risk of gastro-intestinal bleeding (see section 4.4). NSAIDS may reduce the effect of
SSRIs.
Tacrolimus: Possible increased risk of nephrotoxicity when NSAIDs are given with
tacrolimus.
Zidovudine: Increased risk of haematological toxicity when NSAIDs are given with
zidovudine. There is evidence of an increased risk of haemarthroses and haematoma
in HIV(+) haemophiliacs receiving concurrent treatment with zidovudine and
ibuprofen.
Probenecid, Sulphinpyrazone : Decreased elimination of acemetacin.
Anti-psychotics: increased drowsiness with haloperidol.
Alcohol: Under treatment with NSAIDs, concomitant consumption of alcohol may
intensify substance-related adverse effects, in particular the occult blood loss from the
gastrointestinal tract.
Antacids:
Antacids can reduce the resorption rate of acemetacin

4.6

Fertility, pregnancy and lactation
Pregnancy
Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the
embryo/foetal development. Data from epidemiological studies suggest an increased
risk of miscarriage and of cardiac malformation and gastroschisis after use of a
prostaglandin synthesis inhibitor in early pregnancy. The absolute risk for
cardiovascular malformation was increased from less than 1%, up to approximately
1.5 %. The risk is believed to increase with dose and duration of therapy. In animals,
administration of a prostaglandin synthesis inhibitor has been shown to result in
increased pre- and post-implantation loss and embryo-foetal lethality. In addition,
increased incidences of various malformations, including cardiovascular, have been
reported in animals given a prostaglandin synthesis inhibitor during the organogenetic
period. During the first and second trimester of pregnancy, acemetacin should not be
given unless clearly necessary. If acemetacin is used by a woman attempting to
conceive, or during the first and second trimester of pregnancy, the dose should be
kept as low and duration of treatment as short as possible.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may
expose the foetus to:
- cardiopulmonary toxicity (with premature closure of the ductus arteriosus and
pulmonary hypertension);
- renal dysfunction, which may progress to renal failure with oligo-hydroamniosis;
the mother and the neonate, at the end of pregnancy, to:
- possible prolongation of bleeding time, an anti-aggregating effect which may occur
even at very low doses.
- inhibition of uterine contractions resulting in delayed or prolonged labour.
Consequently, acemetacin is contraindicated during the third trimester of pregnancy.
Breast-feeding
In limited studies so far available, NSAIDs can appear in breast milk in very low
concentrations. NSAIDs should, if possible, be avoided when breastfeeding.
Fertility
See section 4.4 Special warnings and precautions for use, regarding female fertility.

4.7

Effects on ability to drive and use machines

Undesirable effects such as dizziness, drowsiness, fatigue and visual disturbances are possible
after taking NSAIDs. If affected, patients should not drive or operate machinery.
These effects will be enhanced in combination with alcohol.

4.8

Undesirable effects
Within the system organ classes, adverse reactions are listed under headings of
frequency
(number of patients expected to experience the reaction), using the following
categories:
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)
Not known (cannot be estimated from the available data)
In case of the adverse drug reactions described below it must be considered that these
are mainly dose-related and may vary inter-individually.
The most commonly observed adverse events are gastrointestinal in nature. Peptic
ulcers, perforation or gastrointestinal bleeding, sometimes fatal, particularly in the
elderly, may occur (See section 4.4).
Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain,
melaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn's
disease (See section 4.4) have been reported following administration. Less
frequently, gastritis has been observed. Pancreatitis has been reported very rarely. In
particular the risk for the occurrence of gastrointestinal bleeding depends on the dose
range and the duration of treatment.

Hypersensitivity:
Hypersensitivity reactions have been reported following treatment with NSAIDs.
These may consist of (a) non-specific allergic reactions and anaphylaxis (b)
respiratory tract reactivity comprising asthma, aggravated asthma, bronchospasm or
dyspnoea, or (c) assorted skin disorders, including rashes of various types, pruritus,
urticaria, purpura, angiodema and, more rarely exfoliative and bullous dermatoses
(including epidermal necrolysis and erythema multiforme).

Cardiovascular and cerebrovascular:
Oedema, hypertension and cardiac failure have been reported in association with
NSAID treatment.
Clinical trials and epidemiological data suggest that use of some NSAIDs (especially
when used at high doses and in long-term treatment) may be associated with a small
increase in the risk for arterial thrombotic events (for example myocardial infarction
or stroke) (See section 4.4).
Infections and infestations
In very rare cases, exacerbation of inflammation caused by infection (e.g.
development of necrotising fasciitis) has been described in a temporal relationship
with the systemic use of non-steroidal anti-inflammatory agents. This may be
associated with the mechanism of action of NSAIDs.
Therefore, the patient should contact a doctor if any symptoms of the infection recur
or become worse under treatment with Emflex. The doctor shall check whether an
anti-infectious /antibiotic therapy should be indicated.
Blood and the lymphatic system disorders
Very rare: anaemia caused by occult blood loss from the gastrointestinal tract,
haemolytic anaemia, pancytopenia (anaemia including aplastic anaemia, leucopenia,
agranulocytosis, thrombocytopenia). The initial symptoms may include: fever, sore
throat, superficial lesions in the mouth, flu-like symptoms, severe tiredness, epistaxis
and subcutaneous haemorrhage.
In these cases, use of the medicinal product must be discontinued immediately and a
doctor must be consulted. Any self-medication with analgesic agents and/or
antipyretics shall not happen.
In case of long-term treatment, the blood count should be checked at regular intervals.
An influence on thrombocytes aggregation as well as increased haemorrhagic
diathesis is possible.
Immune system disorders
Common: hypersensitivity reactions, such as skin rashes and pruritus.
Uncommon: urticaria
Very rare: severe general hypersensitivity reactions. These may manifest in the form
of: oedema of the face and the eyelids, swollen tongue, internal laryngeal oedema
with stenosis of the airways (angioneurotic oedema), respiratory distress that may
lead to an asthma attack, aggravated asthma, tachycardia, blood pressure decrease
leading to life-threatening shock.
Should the patient experience any of these phenomena (which may occur as early as
upon the first use of this medicinal product), medical assistance will be required.
Very rare: allergy-related vasculitis and pneumonitis.
Endocrine disorders

Very rare: hyperglycaemia and glucosuria.
Metabolism and nutrition disorders:
Rare: hyperkalaemia

Psychiatric disorders
Common: agitation.
Rare: irritability, confusion.
Very rare: mental disorders, disorientation, anxiety, nightmares, tremor, psychosis,
hallucination, depression and transitory loss of consciousness that may lead to coma.
Treatment with Emflex may intensify the symptoms of preexisting psychiatric
diseases.
Nervous system disorders
Common: central nervous disorders such as headache, sleepiness/fatigue, dizziness,
malaise and drowsiness.
Very rare: sensibility disorders, muscular asthenia, hyperhidrosis, dysgeusia, impaired
memory, sleep disorders, seizures, reports of aseptic meningitis (especially in patients
with existing auto-immune disorders, such as systemic lupus erythematosus, mixed
connective tissue disease) with symptoms such as stiff neck, headache, nausea,
vomiting, fever or disorientation (see section 4.4)
Administration of Emflex may intensify the symptoms of epilepsy and Parkinson's
disease.
Frequency not known: optic neuritis, paraesthesia
Eye disorders
Uncommon: In the course of long-term treatment with indometacin, the main
metabolite of acemetacin, pigment degeneration of the retina and corneal opacity
have been reported.
Blurred or double vision may be a typical symptom (see section 4.4).
Ear and labyrinth disorders
Very rare: Tinnitus and transitory hearing impairment.
Cardiac disorders
Very rare: palpitations, angina pectoris, cardiac failure
Vascular disorders
Very rare: hypertension
Frequency not known: circulatory collapse
Gastrointestinal disorders
Very common: gastrointestinal disorders such as nausea, vomiting, abdominal pain,
diarrhoea and minor haemorrhage from the gastrointestinal tract which, in exceptional
cases, can cause anaemia.
Common: dyspepsia, flatulence, abdominal cramps, loss of appetite and
gastrointestinal ulcers (sometimes accompanied by bleeding and perforation)
Uncommon: blood can appear in vomit, faeces or diarrhoea.
Very rare:stomatitis, inflammation of the tongue, lesions on the oesophagus,
complaints in the lower abdomen (e.g. non-specific, bleeding inflammation of the
colon) exacerbation of Crohn's disease or ulcerative colitis and constipation have
been reported. Formation of intestinal diaphragm-like strictures; pancreatitis.

The patient shall be instructed to discontinue the medicinal product and to consult a
doctor immediately in case of any severe abdominal pain and/or the occurrence of
meleana or haematemesis.
Hepatobiliary disorders
Common: hepatic enzyme increased
Uncommon: hepatic damage (toxic hepatitis with or without icterus, cholestasis
Very rare: taking a fulminant course in cases and at times without prodromal
symptoms).
The patient’s liver values should therefore be monitored at regular intervals.
Skin and subcutaneous tissue disorders
Uncommon: alopecia
Very rare: eczema, enanthema, erythema, photosensitivity reaction, minor and
extensive cutaneous bleeding, exfoliative dermatitis and rash with bullous eruption,
which may also take a grave course such as Stevens-Johnson syndrome and toxic
epidermal necrolysis (Lyell's syndrome).
Renal and urinary disorders
Uncommon: development of oedema (e.g. peripheral oedema), in particular in
patients with hypertension and/or impaired renal function.
Very rare: micturition disorders, increase in blood urea, acute renal insufficiency,
proteinuria, haematuria or renal damage (interstitial nephritis, nephrotic syndrome,
papillary necrosis).
Therefore, the patient's renal function should be checked at regular intervals.
Reproductive system and breast disorders
Very rare: vaginal haemorrhage.
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 professional are asked to report any suspected adverse reactions
via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard

4.9

Overdose

a)
Symptoms
Symptoms include headache, nausea, vomiting, epigastric pain,
gastrointestinal bleeding, rarely diarrhoea, disorientation, excitation, coma,
drowsiness, dizziness, tinnitus, fainting, occasionally convulsions. In cases of
significant poisoning acute renal failure and liver damage are possible.
b)
Therapeutic measures
Patients should be treated symptomatically as required.
Within one hour of ingestion of a potentially toxic amount, activated charcoal
should be considered. Alternatively, in adults, gastric lavage should be
considered within one hour of ingestion of a potentially life-threatening
overdose.

Good urine output should be ensured.
Renal and liver function should be closely monitored.
Patients should be observed for at least four hours after ingestion of potentially
toxic amounts.
Frequent or prolonged convulsions should be treated with intravenous
diazepam.
Other measures may be indicated by the patient’s clinical condition.

5

PHARMACOLOGICAL PROPERTIES

5.1
Pharmacodynamic properties
Acemetacin is a glycolic acid ester of indomethacin and the pharmacological activity
resulting from acemetacin administration in man is derived from the presence of both
acemetacin and indomethacin. The precise pharmacological mode of action of
acemetacin is not known. However, unlike other NSAIDs, acemetacin is only a
relatively weak inhibitor of prostaglandin synthetase.
Prostaglandins are known to have an antisecretory and cytoprotective effect on the
gastric mucosa. Acemetacin shows activity in many of the established in vitro tests of
anti-inflammatory activity, including inhibition of the release of a number of
mediators of inflammation.

5.2

Pharmacokinetic properties

Acemetacin is well absorbed after oral administration. Its major metabolite is
indomethacin which, after repeated administration, is present at levels in excess of
those of acemetacin. Acemetacin is bound to plasma protein to a slightly lesser extent
than indomethacin and has a relatively short plasma elimination half-life. It is
eliminated by both hepatic and renal mechanisms. The pharmacokinetics appear to be
linear at recommended therapeutic doses, unaffected by moderate renal or hepatic
impairment, and unchanged in the elderly.

5.3

Preclinical safety data

Emflex Capsules show similar toxicity to other non-steroidal antiinflammatory drugs.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Gelatine capsule (colourings: ferric (III) oxide, ferric oxide hydrate and
titanium
dioxide E171), lactose, magnesium stearate, silicon dioxide, talc.

6.2

Incompatibilities
None known.

6.3

Shelf life
5 years

6.4

Special precautions for storage
Store below 25°C.

6.5

Nature and contents of container
White polypropylene bottles with polypropylene screw caps.
Pack sizes: 90, 56, 60 and 30 capsules.
PVC/PVDC foil blister packs in cartons:
Pack sizes: 90, 60, 56, 30, 10, and 6 capsules
Not all pack sizes may be marketed.

6.6

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

7

MARKETING AUTHORISATION HOLDER
Merck Serono Ltd
Bedfont Cross, Stanwell Road
Feltham, Middlesex,
TW14 8NX, UK

8

MARKETING AUTHORISATION NUMBER(S)
PL 11648/0083

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
First registration: 26/11/90

10

DATE OF REVISION OF THE TEXT
19/05/2016

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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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