Arthrotec

Patient Information Leaflet

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 taking the medicine, as it contains important information for the patient.

• Keep this leaflet so that you can read it again if necessary.
• If you have any doubts, please consult your doctor or pharmacist.
• This medicine has been prescribed for a specific individual. Do not pass it on to others. It may harm other people, 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 ulcers associated with NSAID therapy.

2. Important information before using ARTHROC

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 case of any other active bleeding, e.g. cerebrovascular bleeding;
• during pregnancy or in women planning pregnancy;
• in women of childbearing potential who are 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 cardiovascular disease and/or cerebrovascular disease, e.g. moderate or severe congestive heart failure, previous myocardial infarction, stroke, transient ischemic attack (TIA), or arterial embolism in the heart or brain, or following revascularization or bypass surgery of blocked vessels;
• if the patient has existing or previous circulatory disorders (peripheral vascular disease);
• in patients with severe renal or hepatic impairment.

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 "Pregnacy"); due to the risk to the fetus, treatment with ARTHROTEC should be discontinued immediately;
• is of childbearing potential (see section "Pregnancy"); due to the risk to the fetus, 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 impairment or significant dehydration, ARTHROTEC should be used only 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 symptoms 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 ulceration occurs, the doctor will decide to discontinue treatment with the combination drug containing diclofenac and misoprostol;
• in patients with hematopoietic system disorders or impaired coagulation, and in patients with a history of cerebrovascular bleeding, since, 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 hemorrhages;
• in patients with ulcerative colitis or Crohn's disease, as ARTHROTEC may exacerbate symptoms of these conditions;
• in patients with bronchial asthma or allergic disease, currently or in the past, since 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 edema associated with NSAID use have been observed in these patients. The doctor will provide information on monitoring tests and other special recommendations.

Concomitant use of ARTHROTEC and other systemically administered 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 sometimes 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 greatest risk of gastrointestinal complications associated with ARTHROTEC use include those receiving high doses of the drug, elderly patients, patients with cardiovascular disorders, patients concurrently taking acetylsalicylic acid, corticosteroids, or 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 of the gastrointestinal tract.
Therefore, ARTHROTEC should be used cautiously in these patients, starting treatment with the lowest effective dose possible.
ARTHROTEC should not be used in premenopausal women 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 potential 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 use higher doses or longer treatment duration than recommended.
Severe skin reactions have been very rarely observed during treatment with NSAIDs, including the combination drug containing diclofenac and misoprostol. The patient should immediately report any skin changes to the treating physician. The doctor may decide to discontinue ARTHROTEC treatment at the first sign of skin rash, mucosal changes, or any other hypersensitivity symptoms.
In patients with systemic lupus erythematosus and 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 drug or other NSAIDs.
ARTHROTEC may mask fever and thus the underlying disease.
The drug 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, contact 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 lowest effective dose for the shortest duration necessary.
ARTHROTEC and other medicines
Inform your doctor or pharmacist about all medicines currently or recently used, as well as any medicines you plan to use.
Inform the doctor if the patient is taking the following medicines:

• diuretics (water tablets): NSAIDs may reduce the effectiveness of diuretics. Concomitant use of potassium-sparing diuretics may lead to increased serum potassium levels;
• cyclosporine (immunosuppressive drugs used, among others, in transplant patients): diclofenac may increase cyclosporine nephrotoxicity; it is important to start ARTHROTEC at the lowest dose and carefully monitor the patient for signs of toxicity;
• tacrolimus (an immunosuppressive drug used, among others, in atopic dermatitis): concomitant use of NSAIDs with tacrolimus may increase the risk of nephrotoxic effects;
• lithium preparations, digoxin, ketoconazole: ARTHROTEC may increase steady-state serum concentrations of lithium and digoxin, and decrease ketoconazole levels;
• antidiabetic drugs: NSAIDs may potentiate the effect of oral antidiabetic drugs. Concomitant administration may result in risk of hypoglycemia or hyperglycemia;
• 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 drugs used to treat depression): NSAIDs may potentiate the effect of these drugs, thereby increasing the risk of gastrointestinal bleeding;
• methotrexate: NSAIDs may enhance methotrexate toxicity due to increased serum levels, especially in patients receiving high doses of methotrexate;
• other NSAIDs and corticosteroids: concomitant use with ARTHROTEC may increase the frequency of gastrointestinal ulcers or bleeding and other adverse effects;
• antihypertensive drugs, including diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists (AIIA), and β-blockers: NSAIDs may reduce their effectiveness. In patients with impaired renal function (e.g. dehydrated patients or elderly patients with impaired renal function), concomitant administration of an ACE inhibitor or AIIA drugs and/or diuretics with a cyclooxygenase inhibitor may lead to renal dysfunction, including acute renal failure, which is usually reversible;
• antacids: these may delay diclofenac absorption. Antacids containing magnesium may exacerbate diarrhea caused by misoprostol;
• quinolones: in patients taking NSAIDs and quinolones, there may be an increased risk of seizures;
• mifepristone (an abortion drug not available in Poland): NSAIDs may reduce its effectiveness. NSAIDs should be used at least 8 to 12 days after mifepristone administration;
• voriconazole (an antifungal drug);
• sulfinpyrazone (a drug used in the treatment of gout).

ARTHROTEC with food and drink
Tablets should be taken with food.
Pregnancy, breastfeeding, and effects on 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 the doctor about planned pregnancy.
Due to the possible risk of fetal harm, the patient must ensure she is not pregnant before starting this medicine. Women of childbearing potential 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 while taking ARTHROTEC, as it may cause miscarriage, premature delivery, or abnormal fetal development (congenital malformations). If the patient becomes pregnant, she should NEVER take this medicine, as it may seriously affect the child, particularly the heart, lungs, and/or kidneys, up to causing death. If the patient has taken this medicine during pregnancy, she should discuss it with her doctor. If the patient decides to continue the pregnancy, careful monitoring by ultrasound, particularly assessing fetal limbs and head, is required.
Diclofenac may cause premature closure of the ductus arteriosus.
NSAIDs used during the second or third trimester of pregnancy may cause renal dysfunction in the fetus, which may lead to reduced amniotic fluid volume or, in severe cases, oligohydramnios. These effects may occur 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 a 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 diarrhea.
Driving and operating machinery
Patients who experience dizziness or other central nervous system disturbances while taking NSAIDs should not drive or operate machinery.
ARTHROTEC contains lactose monohydrate.
If the patient has previously been diagnosed with intolerance to certain sugars, he or she should consult a doctor before taking the medicine.
ARTHROTEC contains sodium
The medicine contains less than 1 mmol (23 mg) of sodium per tablet, meaning the medicine is considered "sodium-free".
ARTHROTEC contains hydrogenated castor oil
The medicine contains hydrogenated castor oil, which may cause indigestion and diarrhea.

3. How to use ARTHROTEC

This medicine should always be taken as prescribed by the doctor. If in doubt, consult your
doctor or pharmacist.
Tablets should be swallowed whole, not chewed.
Adults
The recommended dose is one tablet taken with food one to three times daily.
Use in elderly patients
Dose adjustment is not necessary; however, 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.
Taking more ARTHROTEC than recommended
If more than the recommended dose is taken, contact your doctor or pharmacist immediately.
Treatment of acute NSAID poisoning consists of supportive and symptomatic therapy. Measures aimed at reducing absorption of the recently ingested drug, such as administration of activated charcoal, are recommended.
Clinical signs that may indicate mizoprostol overdose include: sedation, tremor, seizures, dyspnea, abdominal pain, diarrhea, fever, palpitations, hypotension, or bradycardia (slow heart rate).
Missed dose of ARTHROTEC
Do not take a double dose to make up for a missed dose.
Stopping ARTHROTEC treatment
The decision to discontinue treatment should be made by the 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 effects

Like all medicines, this medicine can cause adverse effects, although not everybody will experience them.
If the patient experiences any of the following symptoms, treatment with
ARTHROTEC must be discontinued and immediate medical help sought:

• weakness or inability to move one side of the body, slurred speech (stroke)*, chest pain (heart attack)*, or heart failure* – occur uncommonly
• shortness of breath* – occurs uncommonly
• infections with symptoms such as chills*, fever* – occur uncommonly
• severe abdominal pain or any signs of gastrointestinal bleeding* (occur uncommonly), or perforation* (frequency unknown), such as black or bloody stools, or vomiting blood
• severe allergic reaction such as skin rash, facial swelling, wheezing or difficulty breathing [anaphylactic reaction (shock)]*, or swelling under the skin (angioedema)* – occur rarely
• jaundice (yellowing of the skin or whites of the eyes)* – frequency unknown
• decrease in platelet count (increased risk of bleeding or bruising)* – occurs uncommonly
• symptoms of meningitis [stiff neck, headache, nausea, vomiting, fever or altered consciousness]* – frequency unknown
• chest pain, which may be a symptom of a potentially serious allergic reaction called Kounis syndrome – frequency unknown
• severe skin reaction such as rash, blistering (e.g. in the mucous membranes of the mouth and genital organs) or peeling of the skin (DRESS syndrome, Stevens-Johnson syndrome*, toxic epidermal necrolysis*, erythema multiforme*, exfoliative dermatitis*) – frequency unknown

Other adverse effects

Very common (may affect more than 1 in 10 people)

• abdominal pain, diarrhoea, nausea, dyspepsia

Common (may affect up to 1 in 10 people)

• insomnia
• headache, dizziness
• gastrointestinal ulceration*, duodenitis, gastritis, oesophagitis, gastrointestinal inflammation*, vomiting, constipation, flatulence with passage of gas, regurgitation of gastric contents
• rash*, pruritus
• increased alanine aminotransferase activity, decreased red blood cell count in blood tests (reduced haematocrit), increased alkaline phosphatase activity in blood
• abnormal fetal development*

Uncommon (may affect up to 1 in 100 people)

• vaginal inflammation
• blurred vision*
• hypertension*
• inflammation of the mucous membrane of the mouth*
• urticaria*, purpura
• irregular or intermenstrual menstrual bleeding, excessive menstrual bleeding, vaginal haemorrhage (including postmenopausal bleeding), menstrual disorders

Rare (may affect up to 1 in 1,000 people)

• nightmares*
• pancreatitis*
• hepatitis*
• blisters on the skin (bullous dermatitis)*
• breast pain, painful menstruation

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

• haemolytic anaemia*, agranulocytosis*, inhibition of platelet aggregation*
• fluid retention*
• mood changes*
• vasculitis*
• liver failure*
• mucocutaneous reactions*
• 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*
• abnormal uterine bleeding (uterine haemorrhage)*, uterine spasm, female infertility (reduced fertility in women)*
• uterine rupture*, uterine perforation*

* Adverse effects reported after marketing authorization. Adverse effects from controlled clinical trials lasting up to 24 months mainly involve the gastrointestinal system. Diarrhoea and abdominal pain are usually mild or moderate in intensity and transient; these symptoms occur early in treatment and may last for several days. Diarrhoea and abdominal pain resolve spontaneously during continued ARTHROTEC therapy. During treatment with NSAIDs, exacerbation of inflammatory conditions related to infection has been observed in very rare cases. After marketing authorization, the most frequently reported adverse effects were gastrointestinal disorders (approximately 45% of all reported cases), followed by skin reactions and hypersensitivity, consistent with the adverse effect 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 effects
If any adverse effects occur, including any not listed in this leaflet, please inform your doctor or pharmacist. Adverse effects can be reported directly to the Department of Monitoring of Adverse Drug Reactions, 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 effects helps to 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 to protect from moisture.
Do not use this medicine after the expiry date stated on the packaging. The expiry date refers to the last day of the stated month.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. Such measures help protect the environment.

6. Contents of the pack and other information

What ARTHROTEC contains

• The active substances in this medicine are diclofenac and misoprostol. Each enteric-coated tablet consists of a core resistant to gastric juice, containing 50 mg of diclofenac sodium, coated with an outer layer containing 0.2 mg of misoprostol.
• Other ingredients are: lactose monohydrate, 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.
Pack contents: 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 authorisation holder or parallel importer.
Marketing Authorisation 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:
InPharm Sp. z o.o.
ul. Strumykowa 28/11
03-138 Warsaw
Poland
Repackaged in:
InPharm Sp. z o.o. Services sp. k.
ul. Chełmżyńska 249
04-458 Warsaw
Marketing Authorisation Number in Portugal, country of export: 4632782
Parallel Import Authorisation Number: 439/15