Arthrotec 50 modified-release tablets

Ireland - English - HPRA (Health Products Regulatory Authority)

Buy It Now

Active ingredient:
Diclofenac sodium; Misoprostol
Available from:
Pfizer Healthcare Ireland
ATC code:
M01AB; M01AB55
INN (International Name):
Diclofenac sodium; Misoprostol
Dosage:
50 mg/0.2 milligram(s)
Pharmaceutical form:
Modified-release tablet
Prescription type:
Product subject to prescription which may not be renewed (A)
Therapeutic area:
Acetic acid derivatives and related substances; diclofenac, combinations
Authorization status:
Marketed
Authorization number:
PA0822/112/001
Authorization date:
1993-06-16

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Package leaflet: Information for the patient

Arthrotec

®

50 modified-release tablets

diclofenac sodium, misoprostol

Read all of this leaflet carefully before you start taking this medicine because it contains important

information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor or pharmacist.

This medicine has been prescribed for you only. Do not pass it on to others. It may harm

them, even if their signs of illness are the same as yours.

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side

effects not listed in this leaflet. See section 4.

What is in this leaflet

1.

What Arthrotec is and what it is used for

2.

What you need to know before you take Arthrotec

3.

How to take Arthrotec

4.

Possible side effects

5.

How to store Arthrotec

6.

Contents of the pack and other information

1. What Arthrotec is and what it is used for

Arthrotec helps to relieve the pain and swelling of rheumatoid arthritis and osteoarthritis, and may

help to protect patients at risk of irritation or ulceration of the stomach or intestines.

Arthrotec contains diclofenac and misoprostol. Diclofenac belongs to a group of medicinal products

called Non-Steroidal Anti-Inflammatory drugs (NSAIDs).

Although NSAIDs relieve the pain, they can reduce the amount of natural protective substances called

prostaglandins in the stomach lining.

This means that NSAIDs can lead to stomach upsets or stomach ulcers. Arthrotec also contains

misoprostol which is very similar to these prostaglandins and may help protect your stomach.

2. What you need to know before you take Arthrotec

Do not take Arthrotec

If you:

think you may be allergic to diclofenac sodium, aspirin (acetylsalicylic acid), ibuprofen or any other

NSAIDs,

misoprostol

another

prostaglandin

medicine,

other

ingredients of

Arthrotec (see section 6). Signs of a hypersensitivity reaction include a skin rash, swelling or

itchiness of the skin, swelling of the face and mouth (angioedema), severe nasal congestion, asthma

(breathing problems), chest pain, wheezing or any other allergic type reaction.

currently have an ulcer or perforation (hole) in your stomach or intestines

currently suffer from bleeding in your stomach, intestines or brain

are undergoing or you have just had coronary artery bypass graft (CABG) surgery

have severe kidney or liver failure

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have established heart disease and/or cerebrovascular disease e.g. if you have had a heart attack,

stroke, mini-stroke (TIA) or blockages to blood vessels to the heart or brain or an operation to clear

or bypass blockages

have or have had problems with your blood circulation (peripheral arterial disease)

are pregnant, or trying to become pregnant, because it may cause a miscarriage. Women who have

not reached the menopause should use reliable contraception while they are taking Arthrotec

are a woman of childbearing age and you are not using an effective contraceptive method to avoid

becoming pregnant (see section on ‘Pregnancy’ for further information)

Warnings and precautions

Talk to your doctor or pharmacist before taking Arthrotec

If you:

have other health problems such as a disease of the liver or kidneys. Do not take Arthrotec if you have

severe kidney or liver failure

previously had an ulcer or bleeding in your stomach or intestines. Do not take Arthrotec if you

currently have an ulcer or bleeding in your stomach or intestines

bleed or bruise easily

have inflammation of the intestines (ulcerative colitis or Crohn’s disease)

have, or have ever had asthma or an allergic disease

have an infection, as Arthrotec may mask a fever or other signs of infection

are dehydrated

are over the age of 65 as your doctor will want to monitor you regularly

are pregnant or plan to become pregnant (see section on “Pregnancy”). Due to the risk to the foetus, your

treatment with Arthrotec must be discontinued immediately

are a woman of childbearing age (see also section on “Pregnancy”). It is important to use effective

contraception while you are taking this medicine

recently had or you are going to have a surgery of the stomach or intestinal tract before

receiving/taking/using Arthrotec, as Arthrotec can sometimes worsen wound healing in your gut after

surgery

NSAID medicines such as Arthrotec can cause bleeding or ulceration. If this occurs, treatment should

be stopped. Use of Arthrotec with another NSAID other than aspirin (e.g. ibuprofen) may also increase

frequency of ulcers or bleeding in your stomach or intestines.

Arthrotec may cause serious side effects, especially stomach and intestinal complications, if you are

using a corticosteroid (e.g. prednisone), an oral anticoagulant, or a Selective Serotonin Re-uptake

Inhibitor (e.g. sertraline) or if you drink alcohol.

Make sure your doctor knows, before you are given Arthrotec

If you:

smoke

have diabetes

have angina, blood clots, high blood pressure, raised cholesterol or raised triglycerides

Medicines such as Arthrotec may be associated with a small increased risk of heart attack (myocardial

infarction) or stroke. Any risk is more likely with high doses and prolonged treatment. Do not exceed the

recommended dose or duration of treatment.

Side effects may be minimised by using the lowest effective dose for the shortest duration necessary.

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As with other NSAIDs (e.g. ibuprofen) Arthrotec may lead to an increase in blood pressure, and so your

doctor may ask to monitor your blood pressure on a regular basis.

If you have heart, liver or kidney problems, your doctor will want to monitor you regularly.

Other medicines and Arthrotec

Some medicines can affect the way other medicines work. Tell your doctor or pharmacist if you are

taking, have recently taken or might take any other medicines, including:

Aspirin (acetylsalicylic acid) or other NSAIDs (e.g. ibuprofen)

Medicines used to treat osteoarthritis or rheumatoid arthritis known as cyclo-oxygenase-2 (COX-2)

inhibitors

Diuretics (used to treat excess fluid in the body)

Ciclosporin or tacrolimus (used for immune system suppression e.g. after transplants)

Lithium (used to treat some types of depression)

Digoxin (a medicine for an irregular heart beat and/or heart failure)

Warfarin or other oral anticoagulants (blood-thinning agents that reduce blood clotting, e.g. aspirin)

Medicines used to treat anxiety and depression known as Selective Serotonin Re-uptake Inhibitors

(SSRIs)

Medicines used to control your blood sugar (oral hypoglycaemics for diabetes)

Methotrexate (used to treat rheumatoid arthritis, psoriasis and leukaemia)

Steroid medications (e.g. corticosteroids, which are often used as anti-inflammatory medicines)

Medicines for high blood pressure (anti-hypertensives)

Magnesium containing antacids (used to treat heartburn, indigestion)

Quinolone antibiotics (used to treat some infections)

Ketoconazole, fluconazole, miconazole and voriconazole (used to treat some fungal infections)

Amiodarone (used to treat an abnormal heart beat)

Sulfinpyrazole (used to treat gout)

If you have taken a medicine called mifepristone (used to terminate pregnancy) within the last 12 days.

Arthrotec should not be taken within 8-12 days of taking mifepristone

Pregnancy, breast-feeding and fertility

Pregnancy

Do not take Arthrotec if you are pregnant, think you may be pregnant or trying to become pregnant.

You should tell your doctor if you are planning to become pregnant. Due to the possible risk of damage

to the foetus, you must make sure you are not pregnant before starting treatment. Women who have not

reached menopause must use reliable contraception while they are taking Arthrotec.

Your doctor will make you aware of the risks if you do become pregnant while taking Arthrotec as it

may cause a miscarriage, premature birth, abnormal formation of the foetus (birth defects). You should

NEVER take this medicine if you are pregnant, as it can also have severe consequences on your child,

especially on the heart, lungs and/or kidneys, including death. If you have received treatment with this

medicine during pregnancy, talk with your doctor. If you decide to continue with the pregnancy, careful

ultrasound scan monitoring of the pregnancy, with special attention to the limbs and head must be

carried out.

Breast-feeding

Ask your doctor or pharmacist for advice before taking this medicine if you are breast-feeding. Do not

use Arthrotec while you are breast-feeding.

Driving and using machines

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If you feel dizzy or drowsy after taking Arthrotec, do not drive and do not use any tools or machines

until these effects have worn off.

Arthrotec contains

Lactose (a type of sugar). If you have been told by your doctor that you have an intolerance to some

sugars, contact your doctor before taking Arthrotec.

3. How to take Arthrotec

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or

pharmacist if you are not sure.

The recommended dose is one tablet two or three times a day, as directed by your doctor.

Arthrotec should be swallowed whole with a drink of water (not chewed), taken during or after

mealtimes.

In the elderly and patients with liver or kidney disorders, your doctor may want to monitor you

more closely. No change in dose is needed.

Use in children: Arthrotec is for adults only, it is not for use in children (under 18 years).

If you take more Arthrotec than you should

You should not take more tablets than your doctor tells you to. If you take too many tablets contact

your doctor, pharmacist or hospital as soon as possible, and take your medicine with you.

If you forget to take Arthrotec

If you forget to take a tablet, take it as soon as you remember. Do not take a double dose to make up for

a forgotten dose.

If you stop taking Arthrotec

Do not stop taking Arthrotec unless your doctor tells you to. If you have any further questions on the

use of this medicine, ask your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

If you are worried about side effects, ask your doctor. It is important that you know what can happen, so that

you can take action if Arthrotec does have a side effect. Arthrotec sometimes causes side effects but these

usually go away during treatment as your body gets used to the medicine.

If any of the following happen, stop taking Arthrotec and tell your doctor immediately:

If you have

Weakness of or inability to move one side of body, slurred speech (stroke) or chest pain (heart

attack) or heart failure or palpitations (awareness of your heartbeat) – the occurrence is uncommon

Shortness of breath – the occurrence is uncommon

Arthrotec can cause a decrease in a type of white blood cell (these help protect the body from

infection and disease) and lead to infections with symptoms like chills, sudden fever, sore throat or

flu-like symptoms – the occurrence is uncommon

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Severe stomach pain or any sign of bleeding or rupture in the stomach or intestines, such as passing

black or bloodstained stools – the occurrence is uncommon, or vomiting blood – this occurs rarely

A serious skin reaction such as rash, blistering or peeling of the skin (Stevens-Johnson syndrome,

exfoliative dermatitis and toxic epidermal necrolysis) – this occurs very rarely

A serious allergic reaction such as skin rash, swelling of the face, wheezing or difficulty breathing

(anaphylactic shock)

this occurs rarely

Jaundice (your skin or the whites of your eyes look yellow) this occurs rarely

Reduction in the number of blood platelets (increased chance of bleeding or bruising) it is not

known how often this occurs

Symptoms of meningitis (stiff neck, headache, nausea (feeling sick), vomiting, fever or loss of

consciousness) – it is not known how often this occurs

Chest pain, which can be a sign of a potentially serious allergic reaction called Kounis syndrome - it

is not known how often this occurs

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side

effects not listed in this leaflet.

Very common: may affect more than 1 in 10 people

Stomach ache, diarrhoea, nausea (feeling sick), indigestion

Diarrhoea is the most common problem and is occasionally severe. You have less chance of getting

diarrhoea if you take Arthrotec with food. If you use an antacid (something to reduce acid in the

stomach) you should avoid antacids with magnesium in them as these may make diarrhoea worse. Your

pharmacist can help you choose a suitable antacid. If this diarrhoea continues and is severe tell your

doctor.

Common: may affect up to 1 in 10 people

Rash, itching

Vomiting, wind, constipation, burping, gastritis (indigestion, stomach ache, vomiting)

Ulcers in the stomach or intestines

Headache, dizziness

Difficulty sleeping

Changes in blood tests relating to the liver

Inflammation of the digestive tract, including the intestines, such as nausea, diarrhoea, abdominal

pain

Abnormal formation of foetus

Uncommon: may affect up to 1 in 100 people

Swelling of the mouth

Fluid build-up in the body that can cause swollen ankles and legs

Abnormal or unexpected bleeding from the vagina, menstrual disturbances

Reduction in the number of blood platelets (increased chance of bleeding or bruising)

Purpura (purple spots on the skin)

Urticaria (raised itchy rash)

Infection of the vagina (itching, burning, soreness, pain especially during intercourse and/or

urination)

Blurred vision

High blood pressure

Loss of appetite

Menstrual disorders such as usually heavy or light bleeding, or delayed periods

Chills or fever

Drowsiness, tiredness, feeling shaky

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Ringing in the ears

Depression and feeling anxious

Tingling or pricking (pins and needles)

Mouth ulcers and dry mouth

Rare: may affect up to 1 in 1,000 people

Inflammation of the liver (possible yellow discoloration of skin, headache, fever, chills, general

weakness)

Inflammation of the pancreas, which causes severe pain in the abdomen and back

Inflammation of the lung such as coughing, increased sputum

Breast pain

Vomiting blood

Worsening of ulcerative colitis (inflammation of lower intestine)

Damage to the gullet

Swelling of the tongue

Low blood pressure

Hair loss

Increased sensitivity to light

Nightmares

Very rare: may affect up to 1 in 10,000 people

Severe liver disorders including liver failure

Not known: frequency cannot be estimated from the available data

Worsening of Crohn’s disease (inflammation of the intestines)

Kidney problems

Seizures

Inflamed blood vessels (can cause fever, aches, purple blotches)

Psychotic disorder (mental disorder that features loss of contact with reality)

Mood swings, irritability, memory problems, feeling confused

Difficulty seeing, changes in the way things taste

Inflammation

Abnormal contractions of the womb, rupture in the womb, retained placenta after giving birth, a

life-threatening reaction in the mother due to the passage of amniotic fluid (fluid covering the

fetus) or other fetal material into the maternal blood stream, bleeding in the womb, miscarriage,

death of the unborn baby, premature birth

Anaemia (low number of red blood cells) which can lead to pale skin and cause weakness or

breathlessness

Painful menstrual/period cramps

Decreased fertility in females

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not

listed in this leaflet. You can also report side effects directly via HPRA Pharmacovigilance, Earlsfort

Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail:

medsafety@hpra.ie. By reporting side effects you can help provide more information on the safety of

this medicine.

5. How to store Arthrotec

Keep this medicine out of the sight and reach of children.

Do not store above 25°C. Store in the original packaging.

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Do not use this medicine after the expiry date which is stated on the blister and carton. The expiry date

refers to the last day of that month.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to

throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What Arthrotec 50 contains

The active substances are diclofenac sodium and misoprostol.

One tablet contains 50 mg diclofenac sodium and 0.2 mg misoprostol.

The other ingredients are:

Lactose monohydrate, microcrystalline cellulose, maize starch, povidone, magnesium stearate,

methylacrylic acid copolymer type C, sodium hydroxide, talc, triethyl citrate, hypromellose,

crospovidone, hydrogenated castor oil and colloidal silicon dioxide.

What Arthrotec looks like and contents of the pack

Arthrotec is available as white, round, biconvex tablets, marked '1411' and 'Searle' on one side with four

‘A’s on the other side.

The tablets are packed in blister strips and supplied in boxes of 60 tablets.

Marketing Authorisation Holder

Pfizer Healthcare Ireland, 9 Riverwalk, National Digital Park, Citywest Business Campus, Dublin 24,

Ireland.

Manufacturer

Piramal Pharma Solutions (Dutch) B.V.

Level, 7e verdieping

Bargelaan 200

2333 CW

Leiden

Netherlands

Piramal Healthcare UK Limited

Morpeth

Northumberland

NE61 3YA

United Kingdom

For any information about this medicine, please contact:

Pfizer Healthcare Ireland Limited, 9 Riverwalk, National Digital Park, Citywest Business Campus,

Dublin 24, Ireland.

Telephone: 1800 633 363.

This leaflet was last revised in 06/2020.

Ref: AE 23_1

Health Products Regulatory Authority

30 June 2020

CRN009LDH

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Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Arthrotec 50 modified-release tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet consists of a gastro-resistant core containing 50 milligrams diclofenac sodium surrounded by an outer mantle

containing 200 micrograms misoprostol.

Excipient(s) with known effect:

Each tablet contains 13.0 mg lactose monohydrate.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Modified-release tablet.

White round biconvex tablet marked ‘1411’ and ‘Searle’ on one side with four ‘A’s on the reverse.

4 CLINICAL PARTICULARS

4.1 Therapeutic Indications

Arthrotec 50 is indicated for patients who require the non-steroidal anti-inflammatory drug diclofenac together with

misoprostol.

The diclofenac component of Arthrotec 50 is indicated for the symptomatic treatment of osteoarthritis and rheumatoid

arthritis. The misoprostol component of Arthrotec 50 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

Posology

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control

symptoms (see section 4.4 Special warnings and precautions for use).

Adults

One tablet to be taken with food, two or three times daily. Tablets should be swallowed whole, not chewed.

Elderly/renal, cardiac 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, cardiac or hepatic impairment should be closely monitored (see section 4.4 and section 4.8).

Paediatric population

The safety and efficacy of Arthrotec 50 in children under 18 years has not been established.

4.3 Contraindications

Arthrotec 50 is contraindicated in:

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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.

Women of childbearing potential who are not using effective contraception (see sections 4.4, 4.6 and 4.8).

Patients with a known hypersensitivity to diclofenac, acetylsalicylic acid, 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 acetylsalicylic acid 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.

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 systemic NSAIDs including COX-2 inhibitors should be avoided, except for

patients requiring low dose acetylsalicylic acid – caution is advised in such patients with close monitoring. Concomitant use of

a systemic NSAID and another systemic NSAID may increase frequency of gastrointestinal ulcers and bleeding.

In women of childbearing potential (see also section 4.3)

Arthrotec 50 must not be used 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 women of childbearing potential 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 impairment

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 Arthrotec 50 should be used only in exceptional circumstances

and with close clinical monitoring: advanced liver disease, severe dehydration.

In a large trial where patients received diclofenac for a mean of 18 months, ALT/AST elevations were observed in 3.1% of

patients. ALT/AST elevations usually occur within 1-6 months. In clinical trials, hepatitis has been observed in patients who

received diclofenac, and in postmarketing experience, other hepatic reactions have been reported, including jaundice and

hepatic failure. During diclofenac/misoprostol therapy, liver function should be monitored periodically. If

diclofenac/misoprostol is used in the presence of impaired liver function, close monitoring is necessary. If abnormal liver tests

persist or worsen, if clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur

treatment with diclofenac should be discontinued.

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 overt renal disease, and the elderly. Such patients should be carefully monitored while receiving

NSAID therapy.

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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.

with

NSAIDS,

diclofenac/misoprostol

lead

onset

hypertension

worsening

pre-existing

hypertension,

either

which

contribute

increased

incidence

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 significant risk factors for cardiovascular events (e.g. 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 should be used. The patient's

need for symptomatic relief and response to therapy should be re-evaluated periodically.

Clinical trial and epidemiological data suggest that use of diclofenac, particularly at high dose (150 mg 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 acetylsalicylic acid, corticosteroids, selective serotonin

reuptake inhibitors, patients who consume alcohol 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).

NSAIDs, including diclofenac, may be associated with increased risk of gastro-intestinal anastomotic leak. Close medical

surveillance and caution are recommended when using diclofenac after gastro-intestinal surgery.

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, selective serotonin-reuptake inhibitors or

anti-platelet agents such as aspirin (see section 4.5). The concomitant use of NSAIDs, including Arthrotec 50, with oral

anticoagulants increases the risk of GI and non-GI bleeding and should be given with caution. Oral anticoagulants include

warfarin/coumarin-type and novel oral anticoagulants (e.g. apixaban, dabigatran, rivaroxaban). Anticoagulation/INR should be

monitored in patients taking a warfarin/coumarin-type anticoagulant (see section 4.5).

Arthrotec 50 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

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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.

As with other NSAIDs, allergic reactions, including anaphylactic/anaphylactoid reactions, can also occur in rare cases with

diclofenac without earlier exposure to the drug. Hypersensitivity reactions can also progress to Kounis syndrome, a serious

allergic reaction that can result in myocardial infarction. Presenting symptoms of such reactions can include chest pain

occurring in association with an allergic reaction to diclofenac.

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.

Arthrotec 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 interactions

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, NSAIDs such as diclofenac may increase the nephrotoxicity of ciclosporin.

When co-administered with ciclosporin, there is a two‑fold increase in diclofenac systemic exposure. It is prudent to start with

the lowest dose of Arthrotec 50 and to monitor closely for signs of toxicity.

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 Arthrotec 50 with anti-coagulants.

NSAIDs may enhance the effects of anti-coagulants, such as warfarin, antiplatelet agents, such as acetylsalicylic acid, and

serotonin re-uptake inhibitors (SSRIs) thereby increasing the risk of gastrointestinal bleeding (see section 4.4).

When diclofenac was administered with acetylsalicylic acid, the protein binding of diclofenac was reduced, although the

clearance of the free diclofenac was not altered. The clinical significance of this interaction is not known; however, as with other

NSAIDs, concomitant administration of diclofenac/misoprostol and acetylsalicylic acid is not generally recommended because

of the potential risk of increased gastrointestinal adverse effects.

Cases of hypo and hyperglycaemia have been reported when diclofenac was associated with antidiabetic agents

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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, especially in patients receiving high doses of

methotrexate.

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, angiotensin II antagonists (AIIA) and

beta-blockers: NSAIDs can reduce the efficacy of diuretics and other antihypertensive drugs, including ACE inhibitors, AIIA and

beta‑blockers.

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 and/or diuretics 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 and/or

diuretics.

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.

Caution is recommended when co-prescribing diclofenac with mild CYP2C9 inhibitors (such as sulfinpyrazone and

voriconazole), which could result in a significant increase in peak plasma concentrations and exposure to diclofenac due to

inhibition of diclofenac metabolism. Caution is also recommended when co-prescribing diclofenac with moderate CYP2C9

inhibitors (such as fluconazole, miconazole and amiodarone). Concomitant administration of diclofenac with these moderate

CYP2C9 inhibitors has not been studied, but is expected to lead to a larger magnitude of interaction.

Voriconazole increased C

and AUC of diclofenac (50 mg single dose) by 114% and 78%, respectively.

4.6 Fertility, pregnancy and lactation

Fertility

Based on the mechanism of action, the use of NSAIDs, including diclofenac/misoprostol, may delay or prevent rupture of

ovarian follicles, which has been associated with reversible infertility in some women. In women who have difficulties

conceiving or who are undergoing investigation of infertility, withdrawal of NSAIDs, including diclofenac/misoprostol, should

be considered.

Women of childbearing potential

Women of childbearing potential must be informed about the risk of teratogenicity prior to treatment with

diclofenac-misoprostol. Treatment must not be initiated until pregnancy is excluded, and women should be fully counselled on

the importance of adequate contraception while undergoing treatment. If pregnancy is suspected, treatment must be

immediately discontinued (see sections 4.3, 4.4 and 4.8).

Pregnancy

Arthrotec 50 is contraindicated in pregnant women and in women planning a pregnancy.

Misoprostol:

Misoprostol

induces

uterine

contractions

associated

with

abortion,

premature

birth,

foetal

death

foetal

malformations. Approximately a 3-fold increased risk of malformations was reported in pregnancies exposed to misoprostol

during the first trimester, compared to a control group incidence of 2%. In particular, prenatal exposure to misoprostol has

been associated with Moebius syndrome (congenital facial paralysis leading to hypomimia, troubles of suckling and deglutition

and eye movements, with or without limb defects); amniotic band syndrome (limb deformities/ amputations, especially

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clubfoot, acheiria, olygodactyly, cleft palate inter alia) and central nervous system anomalies (cerebral and cranial anomalies as

anencephaly, hydrocephaly, cerebellar hypoplasia, neural tube defects). Other defects including arthrogryposis have been

observed.

Consequently:

Women should be informed of the risk of teratogenicity.

Should the patient wish to continue with her pregnancy after exposure of misoprostol in utero, a careful ultrasound

scan monitoring of the pregnancy, with special attention to the limbs and head must be carried out.

Diclofenac:

Inhibition of prostaglandin synthesis might adversely affect 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

prostaglandin synthesis inhibitors 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 prostaglandin synthesis inhibitors 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 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;

Breast-feeding

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. Arthrotec 50 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

Summary of the safety profile

In the table below the incidence of adverse drug reactions reported in controlled clinical studies where Arthrotec was

administered to more than 2000 patients are listed. Additionally, adverse drug reactions have been identified during

post-marketing surveillance and the frequency of some ADRs cannot be estimated from the available data. The most

commonly observed adverse events are gastrointestinal in nature. In general, the adverse event profile of

diclofenac/misoprostol in patients 65 years of age and older (556 subjects) was similar to that of younger patients (1564

subjects). The only clinically relevant differences were that patients 65 years of age and older appeared to be less tolerant to

the gastrointestinal effects of diclofenac/misoprostol given three times a day.

Tabulated list of adverse reactions

Organ System

Very Common

(≥ 1/10)

Common

(≥1/100

Uncommon

(≥1/1,000

Rare

(≥1/10,000 and

Very Rare

(<1/10,000)

Not Known

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and <1/10)

and <1/100)

<1/1,000)

Infections and

infestations

Vaginal infection

Blood and

lymphatic

system disorders

Thrombo-cytope

nia, leucopenia

Aplastic anaemia,

agranulocytosis,

haemolytic

anaemia, platelet

aggregation

inhibition

Immune system

disorders

Hypersensitivity

Anaphylactic

reaction

Metabolism and

nutrition

disorders

Decreased

appetite

Fluid retention

Psychiatric

disorders

Insomnia

Depression,

anxiety

Nightmares

Psychotic disorder,

disorientation,

mood altered,

irritability

Nervous system

disorders

Headache,

dizziness

Cerebrovascular

accident,

somnolence,

tremor,

paraesthesia

Meningitis aseptic

convulsion,

memory

impairment,

dysgeusia

Eyes disorders

Vision blurred

Visual impairment

Ear and

labyrinth

disorders

Tinnitus

Cardiac

disorders

Cardiac failure,

myocardial

infarction,

palpitations

Kounis syndrome

Vascular

disorders

Hypertension

Hypotension

Shock, vasculitis

Respiratory,

thoracic and

mediastinal

disorders

Dyspnoea

Pneumonitis

Asthma

Gastrointestinal

disorders

Abdominal

pain,

diarrhoea

nausea,

dyspepsia

Gastritis,

vomiting,

flatulence,

eructation,

constipation,

peptic ulcer,

gastrointestinal

inflammation,

gastrointestinal

ulcer,

duodenitis,

oesophagitis

Stomatitis,

melaena, mouth

ulceration, dry

mouth,

gastrointestinal

bleeding

Pancreatitis,

haematemesis,

colitis,

oesophageal

disorder,

glossitis

Gastrointestinal

perforation

Crohn's disease,

tongue oedema

Hepatobiliary

disorders

Hepatitis,

jaundice

Hepatic

failure

Hepatitis fulminant

Skin and

subcutaneous

tissue disorders

Rash, pruritus

Purpura, urticaria

Angioedema,

dermatitis

bullous,

photosensitivity

reaction,

alopecia

Erythema

multiforme, toxic

epidermal

necrolysis

Stevens-Johnson

syndrome

dermatitis

exfoliative

, Henoch

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Schonlein purpura,

mucocutaneous

rash, rash vesicular

Renal and

urinary

disorders

Renal failure, renal

failure acute, renal

papillary necrosis,

tubulointerstitial

nephritis, nephrotic

syndrome,

proteinuria,

haematuria,

glomerulonephritis,

glomerulonephritis

minimal lesion,

glomerulonephritis

membranous, renal

impairment

Pregnancy,

puerperium and

perinatal

conditions

Foetal death,

abortion

incomplete,

premature baby,

anaphylactoid

syndrome of

pregnancy, retained

placenta or

membranes, uterine

contractions

abnormal

Reproductive

system and

breast disorders

Menorrhagia,

metrorrhagia,

vaginal

haemorrhage,

post-menopausal

haemorrhage,

menstrual

disorder

Breast pain,

dysmenorrhea

Uterine

haemorrhage,

uterine spasm,

infertility (female

fertility decreased)

Congenital,

familial and

genetic

disorders

Foetal

malformations

General

disorders and

administration

site conditions

Chest pain, face

oedema,

oedema

, pyrexia,

chills, fatigue

Inflammation

Investigations

Alanine

amino-transfera

se increased,

blood alkaline

phosphatase

increased,

haematocrit

decreased

Blood bilirubim

increased,

aspartate

aminotransferase

increased

Injury,

poisoning and

procedural

complications

Uterine rupture,

uterine perforation

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.

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Diarrhoea is usually mild to moderate and transient and can be minimised by taking Arthrotec 50 with food and by avoiding

the use of predominantly magnesium-containing antacids.

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

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

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

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 by the MAH (approximately 45% of all case reports in

the company safety database) followed by cutaneous/hypersensitivity-type reactions, which is in agreement with the known

side effects profile of the NSAIDs drug class.

Description of selected adverse reactions

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).

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 HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971

; Fax: +353 1 6762517

. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

4.9 Overdose

The toxic dose of Arthrotec 50 has not been determined and there is minimal experience of overdosage. Intensification of the

pharmacological effects may occur with overdosage.

Symptoms

Clinical signs that may indicate diclofenac overdose include gastrointestinal complaints, confusion, drowsiness, headache,

dizziness, disorientation, excitation, coma, tinnitus, fainting or convulsions. In the case of significant poisoning acute renal

failure and liver damage are possible. Clinical signs that may indicate misoprostol overdose are sedation, tremor, convulsions,

dyspnoea, abdominal pain, diarrhoea, fever, palpitations, hypotension, or bradycardia.

Management

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.

Induced diuresis may be beneficial because diclofenac and misoprostol metabolites are excreted in the urine, provided that the

patient does not develop renal failure at diclofenac overdose . Special measures such as haemodialysis or haemoperfusion are

probably unlikely to be helpful in accelerating the elimination of diclofenac and misoprostol, due to the high protein binding

and extensive metabolism.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group (ATC code): M01AB55

Arthrotec 50 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 anti-inflammatory and analgesic properties.

Arthrotec 50 also contains the gastroduodenal mucosal protective component misoprostol, which is a synthetic prostaglandin

analogue that enhances several of the factors that maintain gastroduodenal mucosal integrity.

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5.2 Pharmacokinetic properties

The pharmacokinetic profiles of diclofenac and misoprostol administered as Arthrotec 50 are similar to the profiles when the

two drugs are administered as separate tablets and there are no pharmacokinetic interactions between the two components.

Diclofenac metabolism is predominantly mediated via cytochrome P450 CYP2C9 in the liver. Patients who are known or

suspected to be poor CYP2C9 metabolizers based on previous history/experience with other CYP2C9 substrates should be

administered diclofenac with caution as they may have abnormally high plasma levels due to reduced metabolic clearance.

Misoprostol is rapidly and extensively absorbed, and it undergoes rapid metabolism to its active metabolite, misoprostol acid,

which is eliminated with an elimination t

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 73 % of the administered dose is excreted in the urine, mainly as biologically inactive

metabolites. In patients with mild-to-moderate renal impairment, t

, and AUC were increased compared to controls, but

there was no clear correlation between the degree of renal impairment and AUC. In patients with total renal failure, AUC was

approximately doubled in four of six patients.

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

Magnesium stearate

Mantle/Coat:

Methylacrylic acid copolymer type C

Sodium Hydroxide

Talc

Triethyl citrate

Hypromellose

Crospovidone

Hydrogenated castor oil

Colloidal silicon dioxide

Microcrystalline cellulose.

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Do not store above 25°C. Keep blister in the outer carton.

6.5 Nature and contents of container

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