Arthrotec

PACKAGE LEAFLET: INFORMATION FOR THE USER

Warning! Keep this leaflet, information on the outer packaging in a foreign language!
Arthrotec
50 mg + 0.2 mg, tablets
Diclofenacum natricum + Misoprostolum
Please read this leaflet carefully before using the medicine, as it contains
important information for the patient.

• Keep this leaflet, as you may need to read it again.
• If you have any questions, please consult your doctor or pharmacist.
• This medicine has been prescribed for a specific individual. Do not pass it on to others. The medicine may harm another person, even if their symptoms are the same.
• If you experience any adverse reactions, including any not listed in this leaflet, inform your doctor or pharmacist. See section 4.

Table of contents

1. What Arthrotec is and what it is used for
2. Important information before taking 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 is a non-steroidal anti-inflammatory drug (NSAID).
Arthrotec is indicated for use in patients requiring concomitant administration of a non-steroidal anti-inflammatory drug (diclofenac) with misoprostol.
Diclofenac contained in Arthrotec is indicated for symptomatic treatment of osteoarthritis and rheumatoid arthritis. Misoprostol is indicated for the prevention of gastric and/or duodenal ulceration associated with NSAID therapy in patients requiring such protection.

2. Important information before using Arthrotec

When not to use Arthrotec

• if the patient is allergic to diclofenac, acetylsalicylic acid, nonsteroidal anti-inflammatory drugs (NSAIDs), misoprostol, other prostaglandins, or any of the other ingredients of this medicine (listed in section 6). Symptoms of hypersensitivity include, among others, chest pain;
• in case of active gastric and/or duodenal ulcer, perforation or bleeding;
• in the case of other active bleeding, e.g. cerebrovascular haemorrhage;
• during pregnancy or in women planning pregnancy;
• if the patient is of childbearing age and is not using an effective method of contraception to prevent pregnancy (for additional information see section "Pregnancy");
• in patients in whom NSAIDs cause asthma attacks, urticaria or acute rhinitis;
• for perioperative pain management in coronary artery bypass graft (CABG) surgery;
• if the patient has heart disease and/or cerebrovascular disease, e.g. moderate or severe congestive heart failure, myocardial infarction, stroke, transient ischaemic attack (TIA), or arterial embolism of the heart or brain, or following revascularisation or bypass surgery of blocked vessels;
• if the patient has current or previous circulatory disorders (peripheral vascular disease);
• in patients with severe renal or hepatic insufficiency.

Warnings and precautions
Before starting to take Arthrotec, discuss this with your doctor or pharmacist. If the patient:

• is pregnant or planning to become pregnant (see section "Pregnancy"); due to the risk to the foetus, treatment with Arthrotec should be discontinued immediately.
• is of childbearing age (see section "Pregnancy"); due to the risk to the foetus, it is important to use an effective method of contraception during treatment.

Exercise special caution when using Arthrotec

• in patients with impaired renal, hepatic or serious cardiac function, and in elderly patients. In cases of severe hepatic dysfunction or significant dehydration, Arthrotec should only be used in exceptional circumstances and under strict monitoring of the patient's condition (see section "When not to use Arthrotec");
• when diclofenac is used at high doses (150 mg daily) or for long-term treatment, as this may be associated with an increased risk of serious arterial thrombotic events (e.g. myocardial infarction or stroke). The doctor should inform the patient about symptoms and/or signs of serious cardiovascular toxicity and actions to take if such symptoms occur;
• in patients with a history of gastrointestinal toxicity or gastric and/or duodenal ulcer disease. In particular, elderly patients should report any unusual gastrointestinal symptoms (especially gastrointestinal bleeding), especially during the initial phase of treatment. If gastrointestinal bleeding or ulcers occur, the doctor will decide to discontinue treatment with the combination medicine containing diclofenac and misoprostol;
• in patients with haematological disorders or impaired coagulation, and in patients with a history of cerebrovascular haemorrhage, as, like other NSAIDs, Arthrotec may reduce platelet aggregation and prolong bleeding time;
• in patients taking anticoagulants: warfarin and/or coumarin derivatives, and new oral anticoagulants (e.g. apixaban, dabigatran, rivaroxaban), due to increased risk of gastrointestinal bleeding and other haemorrhages;
• in patients with ulcerative colitis or Crohn's disease, as Arthrotec may exacerbate symptoms of these diseases;
• in patients with bronchial asthma or allergic disease, current or past, as NSAIDs may cause bronchospasm in patients with bronchial asthma or allergic disease;
• in patients with hypertension and/or mild congestive heart failure, as fluid retention and oedema associated with NSAID use have been observed in these patients. The doctor will provide information on monitoring and other special recommendations.

Concomitant use of Arthrotec and other systemic NSAIDs, other than acetylsalicylic acid, including selective COX-2 inhibitors (e.g. rofecoxib, celecoxib), should be avoided due to increased frequency of gastrointestinal ulcers and bleeding.
Before using Arthrotec, inform the doctor if the patient has recently undergone or is scheduled for surgery of the stomach or gastrointestinal tract, as Arthrotec may impair intestinal wound healing after surgical procedures.
Arthrotec may cause serious gastrointestinal adverse effects, including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, and large intestine, which may be fatal. If gastrointestinal bleeding or ulceration occurs, treatment should be discontinued. These events may occur at any time during treatment, with or without warning symptoms, or in patients with a history of serious gastrointestinal adverse events.
Patients at highest risk of gastrointestinal complications associated with Arthrotec include those receiving high doses of the drug, elderly patients, patients with cardiovascular disorders, patients concurrently taking acetylsalicylic acid, corticosteroids, selective serotonin reuptake inhibitors (SSRIs), patients consuming alcohol, or patients with gastrointestinal diseases, active or in history, such as ulceration, gastrointestinal bleeding, or inflammatory mucosal conditions.
Therefore, Arthrotec should be used cautiously in these patients, starting treatment with the lowest effective dose.
Arthrotec should not be used in women of childbearing age unless they use effective contraception and have been informed of the risks associated with use during pregnancy. The packaging carries the warning: “Do not use in women of childbearing age unless they use effective contraception.”
Use of medicines such as Arthrotec may be associated with a small increased risk of heart attack (myocardial infarction) or stroke. This risk increases with long-term use of high doses. Do not exceed recommended doses or duration of treatment.
Severe skin reactions have been very rarely observed during treatment with NSAIDs, including the combination medicine containing diclofenac and misoprostol. The patient should immediately report any skin changes to the treating physician. The doctor may decide to discontinue treatment with Arthrotec at the first occurrence of skin rash, mucosal lesions, or any other signs of hypersensitivity.
In patients with systemic lupus erythematosus or connective tissue diseases, Arthrotec may increase the risk of aseptic meningitis.
During long-term treatment with high doses of analgesic and/or anti-inflammatory drugs, headache may occur, which should not be treated by administering further doses of the medicine or other NSAIDs.
Arthrotec may mask fever and thus the underlying disease.
The medicine may impair fertility. If the patient plans to become pregnant or has difficulty conceiving, she should inform her doctor.
Arthrotec may cause visual disturbances. If visual disturbances occur, consult an ophthalmologist.
Before taking the medicine, inform the doctor:

• if the patient smokes
• if the patient has diabetes
• if the patient has angina pectoris, thrombosis, hypertension, elevated cholesterol or elevated triglycerides.

The occurrence of adverse effects can be minimized by using the medicine at the lowest effective dose and for no longer than necessary.
Arthrotec and other medicines
Inform the doctor if the patient is taking any of the following medicines:

• diuretics (water tablets): NSAIDs may reduce the effectiveness of diuretics. When potassium-sparing diuretics are used concomitantly, serum potassium levels may increase;
• cyclosporine (immunosuppressive agents used, among others, in transplant patients): diclofenac may increase the nephrotoxicity of cyclosporine; it is important that treatment with Arthrotec in patients taking cyclosporine is initiated at the lowest dose and the patient is carefully monitored for signs of toxicity;
• tacrolimus (an immunosuppressive agent used, among others, in atopic dermatitis): concomitant use of NSAIDs with tacrolimus may increase the risk of nephrotoxicity;
• lithium preparations, digoxin, ketoconazole: Arthrotec may increase steady-state serum concentrations of lithium and digoxin, and decrease ketoconazole levels;
• antidiabetic medicines: NSAIDs may enhance the effect of oral antidiabetic agents. Concomitant use may result in risk of hypoglycaemia or hyperglycaemia;
• anticoagulants such as warfarin, antiplatelet agents such as acetylsalicylic acid. Concomitant use of Arthrotec with acetylsalicylic acid is not recommended;
• selective serotonin reuptake inhibitors (SSRIs) (some medicines used to treat depression): NSAIDs may potentiate the effects of these medicines, thereby increasing the risk of gastrointestinal bleeding;
• methotrexate: NSAIDs may enhance methotrexate toxicity due to increased serum concentrations, particularly in patients receiving high doses of methotrexate;
• other NSAIDs and corticosteroids: concomitant use of these medicines with Arthrotec may increase the frequency of gastrointestinal ulcers or bleeding and other adverse effects;
• antihypertensive medicines, including diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists (AIIA), and ß-blockers: NSAIDs may reduce their effectiveness. In patients with impaired renal function (e.g. dehydrated patients or elderly patients with impaired renal function), concomitant use of ACE inhibitors or AIIA and/or diuretics with cyclooxygenase inhibitors may lead to renal dysfunction, including acute renal failure, which is usually reversible;
• antacids: these may delay absorption of diclofenac. Antacids containing magnesium may exacerbate diarrhoea caused by misoprostol;
• quinolones: in patients taking NSAIDs and quinolones, there may be an increased risk of seizures;
• mifepristone (an abortion medicine not available in Poland): NSAIDs may reduce its effectiveness. NSAIDs should be used at least 8 to 12 days after administration of mifepristone;
• voriconazole (an antifungal medicine);
• sulfinpyrazone (a medicine used in the treatment of gout).

Inform your doctor or pharmacist about all medicines currently or recently used, as well as any medicines the patient plans to use.
Arthrotec with food and drink
Take tablets with food.
Pregnancy, breastfeeding and fertility
Pregnancy
The patient should not take Arthrotec if she is pregnant, suspects she may be pregnant, or is trying to become pregnant. The patient should inform her doctor about planned pregnancy. Due to the potential risk of foetal harm, the patient must ensure she is not pregnant before starting treatment with this medicine. Women of childbearing age must use an effective method of contraception during treatment with this medicine.
The doctor must inform the patient about the risks associated with becoming pregnant during treatment with Arthrotec, as the medicine may cause miscarriage, premature birth or abnormal foetal development (congenital malformations). If the patient is pregnant, she should NEVER take this medicine, as it may seriously affect the child, particularly its heart, lungs and/or kidneys, up to causing death. If the patient took this medicine during pregnancy, she should discuss it with her doctor. If the patient decides to continue the pregnancy, careful monitoring by ultrasound should be performed, with particular attention to the assessment of foetal limbs and head.
Diclofenac may cause premature closure of the ductus arteriosus.
NSAIDs, when used during the second or third trimester of pregnancy, may cause renal dysfunction in the foetus, which may lead to reduced amniotic fluid volume or, in severe cases, oligohydramnios. These effects may appear soon after starting treatment and are usually reversible. Amniotic fluid volume should be closely monitored in pregnant women taking NSAIDs.
Breastfeeding
If the patient is breastfeeding, she should consult her doctor or pharmacist before taking this medicine. Do not use Arthrotec during breastfeeding. Misoprostol is converted to misoprostolic acid, which passes into breast milk and may cause adverse effects in breastfed infants, such as diarrhoea.
Driving and operating machinery
Patients who experience dizziness or other central nervous system disturbances during treatment with NSAIDs should not drive or operate machinery.
Arthrotec contains lactose monohydrate
If the patient has previously been diagnosed with intolerance to certain sugars, the patient should consult a doctor before taking the medicine.
Arthrotec contains sodium
The medicine contains less than 1 mmol (23 mg) of sodium per tablet, i.e. the medicine is considered "sodium-free".
Arthrotec contains hydrogenated castor oil
The medicine contains hydrogenated castor oil, which may cause indigestion and diarrhoea.

3. How to use Arthrotec

This medicine should always be taken exactly as directed by your doctor. In case of doubt, consult your
doctor or pharmacist.
Tablets should be swallowed whole, not chewed.
Adults
The recommended dose is one tablet taken with food once to three times daily.
Use in elderly patients
Dose adjustment is not necessary; however, elderly patients should be closely monitored.
Use in patients with renal impairment
Dose adjustment is not necessary in patients with mild or moderate renal impairment, but they should be closely monitored.
Use in patients with hepatic impairment
Dose adjustment is not necessary in patients with mild or moderate hepatic impairment, but they should be closely monitored.
Use in children and adolescents
Safety and efficacy have not been established in children and adolescents under 18 years of age.
Overdose of Arthrotec
In case of overdose, contact your doctor or pharmacist immediately.
Treatment of acute poisoning with NSAIDs consists of supportive and symptomatic therapy. Measures aimed at reducing absorption of the recently ingested drug should be initiated, such as inducing vomiting, gastric lavage, or administration of activated charcoal.
Clinical signs that may indicate mizoprostol overdose include: sedation, tremor, seizures, dyspnea, abdominal pain, diarrhea, fever, palpitations, hypotension, or bradycardia (slow heart rate). Inducing diuresis (urine excretion) may be beneficial, as metabolites of Arthrotec are excreted in urine.
Missed dose of Arthrotec
Do not take a double dose to make up for a missed dose.
Discontinuation of Arthrotec
The decision to discontinue treatment should be made by your doctor. If you feel the effect of the medicine is too strong or too weak, consult your doctor.
If you have any further questions about the use of this medicine, consult your doctor or pharmacist.

4. Possible adverse reactions

Like all medicines, this medicine can cause adverse reactions, although not everyone experiences them.

Very common (occurring in more than 1 in 10 patients):

• abdominal pain, diarrhoea, nausea, indigestion

Common (occurring in more than 1 in 100 and less than 1 in 10 patients):

• insomnia
• headache, dizziness
• gastrointestinal ulceration*, duodenitis, gastritis, oesophagitis, gastrointestinal inflammation*, vomiting, constipation, flatulence, belching with regurgitation of gastric contents
• rash*, itching
• increased alanine aminotransferase activity, decreased haematocrit value, increased alkaline phosphatase activity in blood
• abnormal fetal development*

Uncommon (occurring in more than 1 in 1,000 and less than 1 in 100 patients):

• vaginitis
• thrombocytopenia* (low platelet count)
• stroke*
• blurred vision*
• myocardial infarction*, heart failure*
• arterial hypertension*
• dyspnoea*
• gastrointestinal haemorrhage*, oral mucositis*
• urticaria*, purpura
• irregular or intermenstrual menstrual bleeding, excessive menstrual bleeding, vaginal haemorrhage (including postmenopausal bleeding), menstrual disorders
• fever*, oedema*, chills*
• increased aspartate aminotransferase activity

Rare (occurring in less than 1 in 1,000 patients):

• anaphylactic reaction*
• nightmares*
• pancreatitis*
• hepatitis*
• bullous dermatitis*, angioedema*
• breast pain, dysmenorrhoea

Frequency not known (cannot be estimated from available data):

• haemolytic anaemia*, agranulocytosis*, inhibition of platelet aggregation*
• fluid retention*
• mood changes*
• aseptic meningitis* (characterised by symptoms such as neck stiffness, headache, nausea, vomiting, fever or altered consciousness)
• vasculitis*
• gastrointestinal perforation*
• liver failure*, jaundice*
• toxic epidermal necrolysis*, Stevens-Johnson syndrome* (blisters of the mucous membranes of the mouth and genital organs), erythema multiforme*, exfoliative dermatitis*, mucocutaneous reactions*, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome)
• renal failure*, renal function disorders*, renal papillary necrosis*, nephrotic syndrome*, interstitial nephritis*, membranous glomerulonephritis*, submicroscopic glomerulonephritis*, glomerulonephritis*
• fetal death*, amniotic fluid embolism*, incomplete abortion*, premature delivery*, abnormal uterine contractions*, retained placenta or fetal membranes*
• uterine haemorrhage*, uterine contractions, female infertility (reduced fertility in women)*
• uterine rupture*, uterine perforation*

* Adverse reactions reported after marketing authorization.
Patients should immediately inform their doctor if they experience chest pain, which may be a symptom of a potentially serious allergic reaction called Kounis syndrome.
Adverse reactions from controlled clinical trials lasting up to 24 months are mainly related to the gastrointestinal system. Diarrhoea and abdominal pain are usually mild or moderate in severity and transient; these symptoms occur early in treatment and may last for several days. Diarrhoea and abdominal pain resolve spontaneously during treatment with Arthrotec.
When using NSAIDs, in very rare cases, worsening of infection-related inflammatory conditions has been observed.
After marketing authorization, the most commonly reported adverse reactions were gastrointestinal disorders (approximately 45% of all reported cases), followed by skin and hypersensitivity reactions, which is consistent with the adverse reaction profile of NSAIDs.
Use of diclofenac, particularly at high doses (150 mg daily) and during long-term treatment, may be associated with a slightly increased risk of serious arterial thrombotic events (e.g. myocardial infarction or stroke).

Reporting of adverse reactions
If any adverse reactions occur, including any possible adverse reactions not listed in this leaflet, patients should inform their doctor or pharmacist. Adverse reactions can be reported directly to the Department of Monitoring Adverse Drug Reactions of the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
Al. Jerozolimskie 181C
02-222 Warsaw
Tel.: + 48 22 49 21 301
Fax: + 48 22 49 21 309
Website: https://smz.ezdrowie.gov.pl
Reporting adverse reactions helps to provide more information on the safety of the medicine.

5. How to store Arthrotec

Keep the medicine out of the sight and reach of children.
Do not store above 25°C.
Store in the original packaging to protect from moisture.
Do not use this medicine after the expiry date stated on the carton after: EXP. The expiry date refers to the last day of the stated month.
Medicines must not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. This will help protect the environment.

6. Contents of the packaging and other information

What Arthrotec contains

• The active substances in this medicine are diclofenac sodium and misoprostol.

Each enteric-coated tablet contains a core resistant to gastric fluid, which includes
50 mg of diclofenac sodium, surrounded by an outer coating containing 0.2 mg
of misoprostol.
Other ingredients are: monohydrate lactose, microcrystalline cellulose, maize starch,
povidone K 30, magnesium stearate, methacrylic acid copolymer (type C), sodium hydroxide
(see section 2 "Arthrotec contains sodium"), triethyl citrate, crospovidone, colloidal anhydrous silica,
hydrogenated castor oil (see section 2 "Arthrotec contains hydrogenated castor oil"), talc.

What Arthrotec looks like and contents of the pack
White, round, biconvex tablets, marked with "A" on one side and "Searle 1411" on the other side.
Packaging contains: 10 tablets (1 blister), 20 tablets (2 blisters of 10 tablets each), 30 tablets (3 blisters of 10 tablets each), or 60 tablets (6 blisters of 10 tablets each). Outer packaging: cardboard box.
For more detailed information, please contact the marketing authorization holder or the parallel importer.

Marketing Authorization Holder in Portugal, country of export:
Laboratórios Pfizer, Lda.
Lagoas Park
Edifício 10
2740-271 Porto Salvo
Portugal

Manufacturer:
Piramal Pharma Solutions (Dutch) B.V.
Level, 7e verdieping
Bargelaan 200
2333 CW Leiden
The Netherlands

Parallel Importer:
Medezin Sp. z o.o.
ul. Zbąszyńska 3
91-342 Łódź
Poland

Repackaged by:
Medezin Sp. z o.o.
ul. Zbąszyńska 3
91-342 Łódź
Poland

Marketing Authorization number in Portugal, country of export: 4632782
Parallel Import Authorization number: 263/23