Skip to Content

UK Edition. Click here for US version.

MISOFEN 50MG/200MICROGRAM MODIFIED RELEASE TABLETS

Active substance(s): DICLOFENAC SODIUM / MISOPROSTOL

View full screen / Print PDF » Download PDF ⇩
Transcript
SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Misofen 50mg/200microgram modified release tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet consists of a gastro-resistant core containing 50 mg diclofenac sodium
surrounded by an outer mantle containing 200 micrograms misoprostol.
Excipient(s):
Each tablet contains 20.0 mg lactose monohydrate.
For a full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Modified Release Tablet
White circular, biconvex uncoated tablets plain one side and embossed with “DM2”
on the other side.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Misofen tablets are indicated for patients who require the non-steroidal antiinflammatory drug diclofenac together with misoprostol.
The diclofenac component of Misofen Tablets is indicated for the symptomatic
treatment of osteoarthritis and rheumatoid arthritis. The misoprostol component of
Misofen Tablets is indicated for patients with a special need for the prophylaxis of
NSAID-induced gastric and duodenal ulceration.

4.2

Posology and method of administration
Adults
One tablet to be taken with food, two or three times daily. Tablets should be
swallowed whole, not chewed.
Elderly/Renal and Hepatic Impairment
No adjustment of dosage is necessary in the elderly or in patients with hepatic
impairment or mild to moderate renal impairment as pharmacokinetics are not altered
to any clinically relevant extent. Nevertheless, elderly patients and patients with renal
or hepatic impairment should be closely monitored (see section 4.4 and section 4.8).
Children (under 18 years)
The safety and efficacy of Misofen Tablets in children has not been established.
Undesirable effects may be minimised by using the lowest effective dose for the
shortest duration necessary to control symptoms (see section 4.4).

4.3 Contraindications
Misofen Tablets are contraindicated in:
- Patients with active peptic ulcer/haemorrhage or perforation or who have active GI bleeding or
other active bleedings e.g. cerebrovascular bleedings.
- Pregnant women and in women planning a pregnancy.
- Patients with a known hypersensitivity to diclofenac, aspirin, other NSAIDs, misoprostol, other
prostaglandins, or any other ingredient of the product.
- Patients in whom, attacks of asthma, urticaria or acute rhinitis are precipitated by aspirin or other
non-steroidal anti-inflammatory agents.
- Treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery.
- Patients with severe renal and hepatic failure.
- Patients with established congestive heart failure (NYHA II-IV), ischemic heart disease,peripheral
arterial disease and/or cerebrovascular disease

4.4 Special warnings and precautions for use
Warnings
The use of diclofenac/misoprostol with concomitant NSAIDs including COX-2 inhibitors should be
avoided.
Use in pre-menopausal women (see also section 4.3)
Misofen Tablets should not be used in pre-menopausal women unless they use effective
contraception and have been advised of the risks of taking the product if pregnant (see section 4.6).
The label will state: 'Not for use in pre-menopausal women unless using effective contraception'.
Precautions
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).
Renal/Cardiac/Hepatic
In patients with renal, cardiac or hepatic impairment and in the elderly, caution is required since the
use of NSAIDs may result in deterioration of renal function. In the following conditions, Misofen
Tablets should be used only in exceptional circumstances and with close clinical monitoring:
advanced cardiac failure, advanced kidney failure, advanced liver disease, severe dehydration.
Diclofenac metabolites are eliminated primarily by the kidneys (see section 5.2). The extent to
which the metabolites may accumulate in patients with renal failure has not been studied. As with
other NSAIDs, metabolites of which are excreted by the kidney, patients with significantly
impaired renal function should be more closely monitored.
In rare cases, NSAIDs, including diclofenac/misoprostol, may cause interstitial nephritis,
glomerulitis, papillary necrosis and the nephrotic syndrome. NSAIDs inhibit the synthesis of renal
prostaglandin which plays a supportive role in the maintenance of renal perfusion in patients whose
renal blood flow and blood volume are decreased. In these patients, administration of an NSAID
may precipitate overt renal decompensation, which is typically followed by recovery to pretreatment state upon discontinuation of NSAID therapy. Patients at greatest risk of such a reaction
are those with congestive heart failure, liver cirrhosis, nephrotic syndrome and overt renal disease.

Such patients should be carefully monitored while receiving NSAID therapy.
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.
As with all NSAIDS, diclofenac/misoprostol can lead to the onset of new hypertension or
worsening of pre-existing hypertension, either of which may contribute to the increased incidence
of cardiovascular events. NSAIDs, including diclofenac/misoprostol, should be used with caution
in patients with hypertension. Blood pressure should be monitored closely during the initiation of
therapy with diclofenac/misoprostol and throughout the course of therapy.
Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart
disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with
diclofenac after careful consideration. Patients with significant risk factors for cardiovascular
events (eg. hypertension, hyperlipidaemia, diabetes mellitus, smoking) should only be treated with
diclofenac after careful consideration. As the cardiovascular risks of diclofenac may increase with
dose and duration of exposure, the shortest duration possible and the lowest effective daily dose
may be used. The patient’s need for symptomatic relief and response to therapy should be reevaluated periodically.
Clinical trial and epidemiological data suggest that use of diclofenac, particularly at high dose
(150mg daily) and in long term treatment may be associated with a small increased risk of serious
arterial thrombotic events (for example myocardial infarction or stroke).
Physicians and patients should remain alert for the development of such events, even in the absence
of previous cardiovascular symptoms. Patients should be informed about the signs and/or
symptoms of serious cardiovascular toxicity and the steps to take if they occur (see section 4.3).
Blood system/Gastrointestinal
NSAIDs, including diclofenac/misoprostol, can cause serious gastrointestinal (GI) adverse events
including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or
large intestine, which can be fatal. When GI bleeding or ulceration occurs in patients receiving
diclofenac/misoprostol, the treatment should be withdrawn. These events can occur at any time
during treatment, with or without warning symptoms or in patients with a previous history of
serious GI events.
Patients most at risk of developing these types of GI complications with NSAIDs are those treated
at higher doses, the elderly, patients with cardiovascular disease, patients using concomitant
aspirin, or patients with a prior history of, or active, gastrointestinal disease, such as ulceration, GI
bleeding or inflammatory conditions.
Therefore, diclofenac/misoprostol should be used with caution in these patients and commence on
treatment at the lowest dose available (see section 4.3).
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 medicines 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).
Misofen Tablets in common with other NSAIDs, may decrease platelet aggregation and prolong
bleeding time. Extra supervision is recommended in haematopoietic disorders or in conditions with
defective coagulation or in patients with a history of cerebrovascular bleeding.

Caution is required in patients suffering from ulcerative colitis or Crohn's Disease as these
conditions may be exacerbated (see section 4.8).
Care should be taken in elderly patients and in patients treated with corticosteroids, other NSAIDs,
or anti-coagulants (see section 4.5).
Skin Reactions
Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson
syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the
use of NSAIDs, including diclofenac/misoprostol (see section 4.8). Patients appear to be at highest
risk for these events early in the course of therapy, the onset of the event occurring in the majority
of cases within the first month of treatment. Diclofenac/misoprostol should be discontinued at the
first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.
Hypersensitivity
NSAIDs may precipitate bronchospasm in patients suffering from, or with a history of bronchial
asthma or allergic disease.
Long-term treatment
All patients who are receiving long-term treatment with NSAIDs should be monitored as a
precautionary measure (e.g. renal, hepatic function and blood counts). During long-term, high dose
treatment with analgesic/anti-inflammatory drugs, headaches can occur which must not be treated
with higher doses of the medicinal product.
• Misofen Tablets may mask fever and thus an underlying infection.
• 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
NSAIDs may attenuate the natriuretic efficacy of diuretics due to inhibition of
intrarenal synthesis of prostaglandins. Concomitant treatment with potassium-sparing
diuretics may be associated with increased serum potassium levels; hence serum
potassium should be monitored.
Because of their effect on renal prostaglandins, cyclo-oxygenase inhibitors such as
diclofenac can increase the nephrotoxicity of ciclosporin. There is a possible
increased risk of nephrotoxicity when NSAIDs are given with tacrolimus.
Steady state plasma lithium and digoxin levels may be increased and ketoconazole
levels may be decreased.
Pharmacodynamic studies with diclofenac have shown no potentiation of oral
hypoglycaemic and anticoagulant drugs. However, as interactions have been reported
with other NSAIDs, caution and adequate monitoring are, nevertheless advised (see
statement on platelet aggregation in Precautions).
Because of decreased platelet aggregation caution is advised when using Misofen
Tablets with anti-coagulants. NSAIDs may enhance the effects of anti-coagulants,
such as warfarin, antiplatelet agents, such as aspirin, and serotonin re-uptake
inhibitors (SSRIs) thereby increasing the risk of gastrointestinal bleeding (see section
4.4).
Cases of hypo and hyperglycaemia have been reported when diclofenac was
associated with antidiabetic agents.
Caution is advised when methotrexate is administered concurrently with NSAIDs
because of possible enhancement of its toxicity by the NSAID as a result of increase
in methotrexate plasma levels.
Concomitant use with other NSAIDs or with corticosteroids may increase the
frequency of gastrointestinal ulceration or bleeding and of side effects generally.

Anti-hypertensives including diuretics, angiotensin-converting enzyme (ACE)
inhibitors and angiotensin II antagonists (AIIA): NSAIDs can reduce the efficacy of
diuretics and other antihypertensive drugs.
In patients with impaired renal function (e.g. dehydrated patients or elderly patients
with compromised renal function), the co-administration of an ACE inhibitor or an
AIIA with a cyclo-oxygenase inhibitor can increase the deterioration of the renal
function, including the possibility of acute renal failure, which is usually reversible.
The occurrence of these interactions should be considered in patients taking
diclofenac/misoprostol with an ACE inhibitor or an AIIA.
Antacids may delay the absorption of diclofenac. Magnesium-containing antacids
have been shown to exacerbate misoprostol-associated diarrhoea.
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.
NSAIDs should not be used for 8-12 days after mifepristone administration as
NSAIDs can reduce the effect of mifepristone.

4.6

Fertility, pregnancy and lactation
Pregnancy
Misofen Tablets are contraindicated in pregnant women and in women planning a
pregnancy because misoprostol induces uterine contractions and is associated with
abortion, premature birth, and foetal death. Use of misoprostol has been associated
with birth defects. Also diclofenac may cause premature closure of the ductus
arteriosus.
Women of childbearing potential should not be started on diclofenac/misoprostol
until pregnancy is excluded, and should be fully counselled on the importance of
adequate contraception while undergoing treatment. If pregnancy is suspected, use of
the product should be discontinued.
Lactation
Misoprostol is rapidly metabolised in the mother to misoprostol acid, which is
biologically active and is excreted in breast milk. Diclofenac is excreted in breast
milk in very small quantities. In general, the potential effects on the infant from any
exposure to misoprostol and its metabolites via breast feeding are unknown.
However, diarrhoea is a recognised side effect of misoprostol and could occur in
infants of nursing mothers. Misofen Tablets should therefore not be administered to
nursing mothers.

4.7

Effects on ability to drive and use machines
Patients who experience dizziness or other central nervous system disturbances while
taking NSAIDs should refrain from driving or operating machinery.

4.8

Undesirable effects
In the table below the incidence of adverse drug reactions reported in controlled
clinical studies where diclofenac/misoprostol was administered to more than 2000
patients are listed. Additionally, adverse drug reactions reported during postmarketing surveillance are whose frequency cannot be estimated from the available
data, such as spontaneous reports, have been listed at frequency ‘unknown’. The most
commonly observed adverse events are gastrointestinal in nature.

Organ System

Very
Common
(

1/10)

Common

Uncommon

( 1/100 and ( 1/1,000 and
<1/10)
<1/100)

Infections and
infestations

Rare
( 1/10,000,
and
<1/1,000)

Frequency:
Unknown
(Post-marketing
experience)
Aseptic
meningitis1

Blood and
lymphatic
system
disorders

Thrombocytopaenia

Immune system
disorders

Aplastic
anaemia,
agranulocytosis,
haemolytic
anaemia,
leucopenia
Anaphylactic Hypersensitivity
reaction

Metabolism and
nutrition
disorders

Anorexia

Psychiatric
disorders

Insomnia

Psychotic
reaction,
disorientation,
depression,
anxiety,
nightmares,
mood change,
irritability

Nervous system
disorders

Headache,
dizziness

Convulsions,
memory
disturbance,

drowsiness,
tremor, taste
disturbance,
paraesthesia
Eyes disorders

Visual
disturbances,
blurred vision

Ear and
labyrinth
disorders

Tinnitus

Cardiac
disorders

Cardiac failure,
palpitations

Vascular
disorders

Shock,
hypertension,
hypotension,
vasculitis

Respiratory,
thoracic and
mediastinal
disorders

Asthma,
pneumonitis,
dyspnoea

Gastrointestinal Abdominal Gastritis,
Stomatitis
pain,
vomiting,
disorders
diarrhoea2 flatulence,
, nausea,
eructation,
dyspepsia constipation,
peptic ulcer

GI perforation3 ,
gastrointestinal
bleeding3 ,
melaena,
haematemesis,
colitis, Crohn's
disease,
oesophageal
disorder, mouth
ulceration,
glossitis, tongue
odema, dry
mouth

Hepato-biliary
disorders

Alanine
aminotransferase
increased

Skin and
subcutaneous
tissue disorders

Erythema
multiforme,
rash,

Hepatitis,
jaundice

Purpura,
urticaria

Hepatitis
fulminant,
aspartate
aminotransferase
increased, blood
bilirubin
increased

Angioedema Toxic epidermal
necrolysis4 ,
Stevens-Johnson

syndrome4 ,
dermatitis
exfoliative4 ,
dermatitis
bullous, Henoch
Schönlein
purpura,
mucocutaneous
rash, rash
vesicular,
photosensitivity
reaction,
alopecia,
urticaria

pruritus

Renal and
urinary
disorders

Renal failure,
acute renal
failure, renal
papillary
necrosis,
nephritis
interstitial,
nephrotic
syndrome,
proteinuria,
haematuria

Pregnancy,
puerperium and
perinatal
conditions

Intra-uterine
death, uterine
rupture,
incomplete
abortion,
premature baby,
anaphylactoid
syndrome of
pregnancy,
retained placenta
or membranes,
uterine
contractions
abnormal

Reproductive
system and
breast
disorders

Congenital,

Menorrhagia,
metrorrhagia,
vaginal
haemorrhage,
postmenopausal
haemorrhage

Uterine
haemorrhage

Birth defects

familial and
genetic
disorders
Oedema5 , chest
pain, face
oedema, fatigue,
pyrexia, chills,
inflammation

General
disorders and
administration
site conditions

Investigations

Blood
alkaline
phosphatase
increased

Injury,
poisoning and
procedural
complications

Decreased
haemoglobin

Uterine
perforation

1

Symptoms of aseptic meningitis (stiff neck, headache, nausea, vomiting, fever or
impaired consciousness) have been reported during treatment with NSAIDs. Patients
suffering from autoimmune disease (e.g. lupus erythematosus, mixed connective
tissue disorders) seem to be more susceptible.

2

Diarrhoea is usually mild to moderate and transient and can be minimised by taking
Misofen Tablets with food and by avoiding the use of predominantly magnesiumcontaining antacids.

3

GI perforation or bleeding can sometimes be fatal, particularly in the elderly (see
section 4.4).

4

Serious skin reactions, some of them fatal, have been reported very rarely (see
section 4.4).
5

Especially in patients with hypertension or impaired renal function (see section 4.4).

Given the lack of precise and/or reliable denominator and numerator figures, the
spontaneous adverse event reporting system through which post marketing safety data
are collected does not allow for a medically meaningful frequency of occurrence of
any undesirable effects.
With regard to the relative frequency of reporting of adverse reactions during post
marketing surveillance, the undesirable effects at the gastrointestinal level were those
received most frequently followed by cutaneous/hypersensitivity-type reactions,
which is in agreement with the known side effects profile of the NSAIDs drug class.
Clinical trial and epidemiological data consistently point towards an increased risk of
arterial thrombotic events (for example myocardial infarction or stroke) associated
with the use of diclofenac, particularly at high dose (150mg daily) and in long term

treatment. (see section 4.3 and 4.4 for Contraindications and Special warnings and
special precautions for use).

4.9

Overdose
The toxic dose of Misofen Tablets has not been determined and there is no experience
of overdosage. Intensification of the pharmacological effects may occur with
overdosage. Management of acute poisoning with NSAIDs essentially consists of
supportive and symptomatic measures. It is reasonable to take measures to reduce
absorption of any recently consumed drug by forced emesis, gastric lavage or
activated charcoal.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: Anti-inflammatory and antirheumatic products,
ATC code: M01BX
Misofen Tablets is a non-steroidal, anti-inflammatory drug, which is effective in
treating the signs and symptoms of arthritic conditions.
This activity is due to the presence of diclofenac, which has been shown to have antiinflammatory and analgesic properties.
Misofen Tablets also contain the gastroduodenal mucosal protective component
misoprostol, which is a synthetic prostaglandin E1 analogue that enhances several of
the factors that maintain gastroduodenal mucosal integrity.

5.2

Pharmacokinetic properties
The pharmacokinetic profiles following oral administration of a single dose or
multiple doses of diclofenac sodium and misoprostol administered as Misofen Tablets
are similar to the profiles when the two drugs are administered as separate tablets.
There are no pharmacokinetic interactions between the two components.
Diclofenac sodium is completely absorbed from the gastrointestinal (GI) tract after
fasting oral administration. Only 50 % of the absorbed dose is systemically available
due to first pass metabolism. Peak plasma levels are achieved in 2 hours (range 1-4
hours), when given as a single dose under fasting conditions.The area-under-the
plasma-concentration curve (AUC) is dose proportional within the range of 25 mg to
150 mg.

The terminal half-life is approximately 2 hours. Clearance and volume of distribution
are about 350 ml/min and 550 ml/kg, respectively. More than 99 % of diclofenac
sodium is reversibly bound to human plasma albumin, and this has been shown not to
be age dependent.
Diclofenac sodium is eliminated through metabolism and subsequent urinary and
biliary excretion of the glucuronide and the sulfate conjugates of the metabolites.
Approximately 65 % of the dose is excreted in the urine and 35 % in the bile. Less
than 1 % of the parent drug is excreted unchanged.
Misoprostol is rapidly and extensively absorbed, and it undergoes rapid metabolism
to its active metabolite, misoprostol acid, which is eliminated with an elimination t½
of about 30 minutes. No accumulation of misoprostol acid was found in multiple-dose
studies, and plasma steady state was achieved within 2 days. The serum protein
binding of misoprostol acid is less than 90 %. Approximately 70 % of the
administered dose is excreted in the urine, mainly as biologically inactive
metabolites.

5.3

Preclinical safety data
In co-administration studies in animals, the addition of misoprostol did not enhance
the toxic effects of diclofenac. The combination was also shown not to be teratogenic
or mutagenic. The individual components show no evidence of carcinogenic
potential.
Misoprostol in multiples of the recommended therapeutic dose in animals has
produced gastric mucosal hyperplasia. This characteristic response to E-series
prostaglandins reverts to normal on discontinuation of the compound.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Core:
lactose monohydrate
microcrystalline cellulose
maize starch
povidone K-30
magnesium stearate
purified talc

Mantle/Coat:
hypromellose
methylacrylic acid copolymer type C
purified talc
triethylcitrate
sodium starch glycolate
hydrogenated castor oil
microcrystalline cellulose

6.2

Incompatibilities
Not applicable.

6.3

Shelf life
2 years

6.4

Special precautions for storage
This medicine product does not require any special storage instructions.

6.5

Nature and contents of container
Misofen Tablets are presented in packs composed of OPA-ALU-PVC blisters with
aluminium foil.
Pack size: 7, 10, 14, 15, 20, 28, 30, 50, 60, 90, 100, 140 tablets
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
No special requirements.
Any unused product or waste material should be disposed of in accordance with local
requirements.

7

MARKETING AUTHORISATION HOLDER
Marketing Authorisation Holder:
Morningside Healthcare Limited
115 Narborough Road
Leicester, LE3 0PA
UK

8

MARKETING AUTHORISATION NUMBER(S)
PL 20117/0187

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
10/10/2012

10

DATE OF REVISION OF THE TEXT
07/02/2014

Expand view ⇕

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.

Hide