Arthrotec forte

PACKAGE LEAFLET: INFORMATION FOR THE USER

Warning! Keep the leaflet, information on the immediate packaging in a foreign language!
Arthrotec Forte (Arthrotec 75 mg/0.2 mg)
75 mg + 0.2 mg, enteric-coated tablets
Diclofenacum natricum + Misoprostolum
Arthrotec Forte and Arthrotec 75 mg/0.2 mg are different trade names for the same medicinal product.
Please read this leaflet carefully before taking the medicine, as it contains
important information for the patient.

• Keep this leaflet, so you can read it again if necessary.
• If you have any questions, consult your doctor or pharmacist.
• This medicine has been prescribed for a specific individual. Do not pass it on to others. It may harm someone else, even if their symptoms are similar.
• If you experience any adverse reactions, including those not listed in this leaflet, inform your doctor or pharmacist. See section 4.

Table of contents of the leaflet

1. What Arthrotec Forte is and what it is used for
2. Important information before taking Arthrotec Forte
3. How to take Arthrotec Forte
4. Possible side effects
5. How to store Arthrotec Forte
6. Contents of the pack and other information

1. What Arthrotec Forte is and what it is used for

Arthrotec Forte is a non-steroidal anti-inflammatory drug (NSAID).
Arthrotec Forte is indicated for use in patients requiring concomitant administration of a non-steroidal anti-inflammatory drug (diclofenac) and misoprostol.
Diclofenac contained in Arthrotec Forte is indicated for the symptomatic treatment of osteoarthritis and rheumatoid arthritis. Misoprostol is indicated for the prevention of gastric and/or duodenal ulcers associated with the use of NSAIDs.

2. Important information before using Arthrotec Forte

When not to use Arthrotec Forte

• if the patient is allergic to diclofenac, acetylsalicylic acid, non-steroidal 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 or (and) duodenal ulcer, perforation or bleeding;
• in case of any 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 have caused 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, previous myocardial infarction, stroke, transient ischaemic attack (TIA), or arterial embolism in 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 treatment with Arthrotec Forte, 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 Forte must 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 Forte

• in patients with impaired renal, hepatic or severe cardiac function, and in elderly patients. In cases of severe hepatic dysfunction or significant dehydration, Arthrotec Forte should be used only in exceptional circumstances and under strict patient monitoring (see section "When not to use Arthrotec Forte");
• 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 or (and) 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 medicine containing diclofenac and misoprostol;
• in patients with haematopoietic system disorders or impaired coagulation, and in patients with a history of cerebrovascular haemorrhage, as like other NSAIDs, Arthrotec Forte 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 and other bleeding;
• in patients with ulcerative colitis or Crohn's disease, as Arthrotec Forte may exacerbate symptoms of these diseases;
• in patients with bronchial asthma or allergic disease, currently or in the 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 this patient group. The doctor will provide the patient with information on monitoring tests and other special recommendations.

Concomitant use of Arthrotec Forte 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 Forte, inform the doctor if the patient has recently undergone or is scheduled for stomach or gastrointestinal surgery, as Arthrotec Forte may occasionally impair intestinal wound healing after surgical procedures.
Arthrotec Forte 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, and in patients with a history of serious gastrointestinal adverse events.
Patients at highest risk of gastrointestinal complications associated with Arthrotec Forte include those receiving high doses of the medicine, elderly patients, patients with cardiovascular disorders, patients taking acetylsalicylic acid, corticosteroids or selective serotonin reuptake inhibitors (SSRIs) concomitantly, patients consuming alcohol, and patients with active or past gastrointestinal diseases such as ulceration, gastrointestinal bleeding or inflammatory mucosal conditions of the gastrointestinal tract.
Therefore, Arthrotec Forte should be used cautiously in these patients, starting treatment with the lowest effective dose.
Arthrotec Forte 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 contraceptive methods.”
Use of medicines such as Arthrotec Forte 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.
Very rarely, severe skin reactions have been 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 Forte at the first sign of skin rash, mucosal lesions or any other symptoms of hypersensitivity.
In patients with systemic lupus erythematosus or connective tissue diseases, Arthrotec Forte 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 Forte 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 Forte 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 lowest effective dose for the shortest duration necessary.
Arthrotec Forte and other medicines
Inform your 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 agents used, among others, in transplant patients): diclofenac may increase the nephrotoxicity of cyclosporine; it is important that treatment with Arthrotec Forte in patients receiving cyclosporine begins with the lowest dose and that the patient is carefully monitored for signs of toxic effects;
• tacrolimus (an immunosuppressive agent used, among others, in atopic dermatitis): concomitant use of NSAIDs with tacrolimus may increase the risk of nephrotoxic effects;
• lithium preparations, digoxin, ketoconazole: Arthrotec Forte may increase steady-state serum levels of lithium and digoxin, and decrease ketoconazole levels;
• antidiabetic medicines: NSAIDs may enhance the effect of oral antidiabetic drugs. Concomitant administration with antidiabetic medicines may result in risk of hypoglycaemia or hyperglycaemia;
• anticoagulants such as warfarin, antiplatelet agents such as acetylsalicylic acid. Concomitant use of Arthrotec Forte with acetylsalicylic acid is not recommended;
• selective serotonin reuptake inhibitors (SSRIs) (some medicines used in depression treatment): NSAIDs may enhance the effect of these medicines, thereby increasing the risk of gastrointestinal bleeding;
• methotrexate: NSAIDs may enhance methotrexate toxicity due to increased serum methotrexate levels, particularly in patients receiving high-dose methotrexate;
• other NSAIDs and corticosteroids: concomitant use of these medicines with Arthrotec Forte 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 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 and (or) diuretics with a cyclooxygenase inhibitor may lead to renal impairment, including acute renal failure, which is usually reversible;
• antacids: these may delay absorption of diclofenac. Antacids containing magnesium may worsen misoprostol-induced diarrhoea;
• quinolones: in patients taking NSAIDs and quinolones, there may be an increased risk of seizures;
• mifepristone (an early abortion medicine 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 medicine);
• sulfinpyrazone (a medicine used in the treatment of gout).

Inform your doctor or pharmacist about all medicines currently or recently taken, as well as any medicines the patient plans to take.
Arthrotec Forte with food and drink
Take tablets with food.
Pregnancy, breastfeeding and fertility
Pregnancy
The patient should not take Arthrotec Forte 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 possible 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 Forte, as this 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 the heart, lungs and (or) kidneys, up to causing death. If the patient has taken this medicine during pregnancy, she should discuss this with her doctor. If the patient decides to continue the pregnancy, careful monitoring with ultrasound examination is required, with particular attention to assessment of foetal limbs and head.
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 foetus, which may lead to reduced amniotic fluid volume or, in severe cases, oligohydramnios. Such 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 Forte 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 Forte contains monohydrate lactose
If the patient has previously been diagnosed with intolerance to certain sugars, he or she should consult a doctor before taking the medicine.
Arthrotec Forte contains sodium
The medicine contains less than 1 mmol (23 mg) of sodium per tablet, meaning the medicine is considered "sodium-free".
Arthrotec Forte contains hydrogenated castor oil
The medicine contains hydrogenated castor oil, which may cause indigestion and diarrhoea.

3. How to use Arthrotec Forte

This medicine should always be used as directed by a physician. In case of doubt, consult a doctor or pharmacist.
Tablets should be swallowed whole, not chewed.

Adults
The recommended dose is one tablet taken with food once or twice daily.

Use in elderly patients
Dosage adjustment is not necessary; however, patients should be closely monitored.

Use in patients with renal function impairment
Dosage adjustment is not necessary in patients with mild or moderate renal function impairment, but they should be closely monitored.

Use in patients with hepatic function impairment
Dosage adjustment is not necessary in patients with mild or moderate hepatic function impairment, but these patients 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.

Use of a higher than recommended dose of Arthrotec Forte
If more medicine has been taken than recommended, contact a 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: drowsiness, tremor, seizures, shortness of breath, abdominal pain, diarrhea, fever, palpitations, hypotension, or bradycardia (slow heart rate). Inducing diuresis (urine excretion) may be beneficial, as metabolites of Arthrotec Forte are excreted in urine.

Missed dose of Arthrotec Forte
Do not take a double dose to make up for a missed dose.

Discontinuation of Arthrotec Forte
The decision to discontinue treatment should be made by a physician. If you feel the effect of the medicine is too strong or too weak, contact your doctor.

If you have any further questions regarding 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 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
• fetal developmental abnormalities*.

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

• vaginitis
• thrombocytopenia* (deficiency of blood platelets)
• stroke*
• blurred vision*
• myocardial infarction*, heart failure*
• hypertension*
• dyspnoea*
• gastrointestinal haemorrhage*, stomatitis*
• urticaria*, purpura
• irregular or intermenstrual 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 the available data):

• haemolytic anaemia*, agranulocytosis*, inhibition of blood platelet aggregation*
• fluid retention*
• mood changes*
• aseptic meningitis* (characterized by symptoms such as neck stiffness, headache, nausea, vomiting, fever or altered consciousness)
• vasculitis*
• gastrointestinal perforations*
• liver failure*, jaundice*
• toxic epidermal necrolysis*, Stevens-Johnson syndrome* (blisters of the oral and genital mucosa), 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 effects reported after marketing authorization of the medicine.
Inform the doctor immediately if the patient experiences chest pain, which may be a symptom of a potentially serious allergic reaction called Kounis syndrome.
Adverse effects from controlled clinical studies 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 Forte.
When using NSAIDs, exacerbation of infection-related inflammation has been observed in very rare cases.
After marketing authorization of the medicine, the most frequently reported adverse effects were gastrointestinal disorders (approximately 45% of all reported cases), followed by skin and hypersensitivity reactions, which is consistent with the adverse effect profile of NSAIDs.
The 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 possible adverse effects not listed in this leaflet, inform your doctor or pharmacist. Adverse effects 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 effects helps to provide more information on the safety of the medicine.

5. How to store Arthrotec Forte

Keep this medicine out of sight and reach of children.
Store below 25ºC in the original packaging.
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 must 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 packaging and other information

What Arthrotec Forte contains

• The active substances are diclofenac and misoprostol. Each enteric-coated tablet consists of a gastric juice-resistant core containing 75 mg of sodium diclofenac, coated with an outer layer containing 0.2 mg of misoprostol (in the form of a dispersion: Misoprostol : Hypromellose 3 mPa·s, 1:100).
• Other ingredients are: monohydrate lactose, microcrystalline cellulose, corn starch, povidone K 30, magnesium stearate, methacrylic acid copolymer (type C), sodium hydroxide (for pH adjustment) (see section 2 “Arthrotec Forte contains sodium”), triethyl citrate, crospovidone, colloidal anhydrous silica, hydrogenated castor oil (see section 2 “Arthrotec Forte contains hydrogenated castor oil”), talc.

What Arthrotec Forte looks like and contents of the pack
White, round, biconvex tablets marked with “A” and “75” on one side and “Searle 1421” on the other side.
Pack contents: 10 tablets (1 blister) or 20 tablets (2 blisters of 10 tablets each).
Outer packaging: cardboard box.
For more detailed information, please contact the responsible party or parallel importer.
Responsible party in Romania, country of export:
Pfizer Europe MA EEIG
Boulevard de la Plaine 17
1050 Brussels
Belgium
Manufacturer:
Piramal Pharma Solutions (Dutch) B.V.
Level 7, Bargelaan 200
2333 CW, Leiden
The Netherlands
Parallel importer:
Medezin Sp. z o.o.
Zbąszyńska 3
91-342 Łódź
Poland
Repackaged in:
Medezin Sp. z o.o.
Zbąszyńska 3
91-342 Łódź
Poland
CEFEA Sp. z o.o. Sp. komandytowa
Działkowa 56
02-234 Warsaw
Poland
SHIRAZ PRODUCTIONS Sp. z o.o.
Tymiankowa 24/28
95-054 Ksawerów
Poland
Marketing Authorization numbers in Romania, country of export: 12398/2019/01
12398/2019/02
Parallel import authorization number: 249/23