Arthrotec

Package Leaflet: Information for the Patient

Warning! The leaflet should be kept. Information on the immediate packaging in a foreign language.

Arthrotec, 50 mg + 0.2 mg, tablets

Diclofenac sodium + Misoprostol

Before taking the medicine, the patient should carefully read the contents of the leaflet, as it contains important information for the patient.

• The leaflet should be kept so that it can be re-read if necessary.
• In case of any doubts, the patient should consult a doctor or pharmacist.
• This medicine has been prescribed specifically for this patient. It should not be given to others. The medicine may harm another person, even if the symptoms of their illness are the same.
• If the patient experiences any side effects, including any side effects not listed in this leaflet, they should tell their doctor, pharmacist, or nurse. See section 4.

Table of Contents of the Leaflet

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

Arthrotec is a nonsteroidal anti-inflammatory drug (NSAID).
Arthrotec is indicated for use in patients who require concomitant use of a nonsteroidal anti-inflammatory drug (diclofenac) and misoprostol.
Diclofenac in Arthrotec is indicated for the symptomatic treatment of osteoarthritis and rheumatoid arthritis. Misoprostol is indicated for the prevention of gastric and/or duodenal ulcers in patients who require NSAID therapy.

2. Important information before taking Arthrotec

When not to take Arthrotec

• if the patient is allergic to diclofenac, acetylsalicylic acid, nonsteroidal anti-inflammatory drugs (NSAIDs), misoprostol, or any other component of this medicine (listed in section 6). Hypersensitivity symptoms include, but are not limited to, chest pain;
• in case of active gastric and/or duodenal ulcer, perforation, or bleeding;
• in case of other active bleeding, such as cerebral hemorrhage;
• in pregnancy or in women planning to become pregnant;
• if the patient is of childbearing age and does not use effective contraception to prevent pregnancy (for additional information, see "Pregnancy");
• in patients with NSAID-induced asthma, urticaria, or acute rhinitis;
• for the treatment of postoperative pain in coronary artery bypass grafting;
• if the patient has heart disease and/or cerebrovascular disease, such as moderate or severe heart failure, myocardial infarction, stroke, transient ischemic attack (TIA), or cerebral vascular thrombosis, or after revascularization or coronary artery bypass grafting; Page 1 9
• if the patient has or has had circulatory disorders (peripheral vascular disease);
• in patients with severe renal or hepatic impairment.

Warnings and precautions

Before starting treatment with Arthrotec, the patient should discuss it with their doctor or pharmacist.
If the patient:

• is pregnant or plans to become pregnant (see "Pregnancy"); due to the risk to the fetus, Arthrotec should be discontinued immediately.
• is of childbearing age (see "Pregnancy"); due to the risk to the fetus, it is essential to use effective contraception during treatment with Arthrotec.

Special precautions when taking Arthrotec

• in patients with renal, hepatic, or severe heart disorders, as well as in the elderly. In case of severe hepatic impairment, significant dehydration, Arthrotec should only be used in exceptional cases and under close monitoring of the patient's condition (see "When not to take Arthrotec");
• when using high doses of diclofenac (150 mg per day) and long-term treatment, as this may be associated with an increased risk of serious thrombotic events (e.g., myocardial infarction or stroke). The doctor should inform the patient about the symptoms and/or signs of serious cardiovascular toxicity and the actions to be taken in case of such symptoms;
• in patients with a history of toxic effects on the gastrointestinal tract or gastric and/or duodenal ulcers. In particular, elderly patients should report any unusual abdominal symptoms (especially gastrointestinal bleeding) early in the treatment. In case of bleeding or ulcers in the gastrointestinal tract, the doctor will decide whether to discontinue the combined drug containing diclofenac and misoprostol;
• in patients with bleeding disorders or impaired coagulation, as well as in patients with a history of cerebral hemorrhage, as NSAIDs, including 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 the increased risk of gastrointestinal bleeding and other bleeding;
• in patients with ulcerative colitis or Crohn's disease, as Arthrotec may exacerbate the symptoms of these diseases;
• in patients with asthma or allergic disease - currently or in the past, as NSAIDs may cause bronchospasm in patients with asthma or allergic disease;
• in patients with hypertension and/or mild heart failure, as NSAIDs have been observed to cause fluid retention and edema in this patient population. The doctor will provide the patient with information on monitoring and other special recommendations.

Arthrotec should not be taken with other systemically administered NSAIDs, except for acetylsalicylic acid, including selective COX-2 inhibitors (e.g., rofecoxib, celecoxib), due to the increased frequency of ulcers and gastrointestinal bleeding.
Before taking Arthrotec, the patient should tell their doctor if they have recently undergone or are scheduled to undergo stomach or gastrointestinal surgery, as Arthrotec may sometimes cause impaired wound healing in the intestines after surgery.
Arthrotec may cause serious gastrointestinal side effects, including inflammation, bleeding, ulcers, and perforation of the stomach, small intestine, and large intestine, which can be fatal. In case of bleeding or ulcers in the gastrointestinal tract, the treatment should be discontinued. These events can occur at any time during treatment, with or without warning symptoms, or in patients with a history of serious gastrointestinal side effects.
The group at the highest risk of developing these gastrointestinal complications associated with Arthrotec includes patients receiving high doses of the drug, elderly patients, patients with cardiovascular disorders, patients taking acetylsalicylic acid, corticosteroids, selective serotonin reuptake inhibitors, patients consuming alcohol, or patients with a history of gastrointestinal diseases, active or inactive, such as ulcers, gastrointestinal bleeding, or inflammation of the gastrointestinal mucosa.
Therefore, Arthrotec should be used with caution in these patients, starting treatment with the lowest effective dose.
Arthrotec should not be used in premenopausal women unless they use effective birth control methods and have been informed about the risks associated with taking the drug during pregnancy. There is a warning on the packaging: "Do not use in women of childbearing age unless they use effective birth control methods".
Taking such drugs 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 of the drug. Higher doses and longer treatment than recommended should not be used.
Rarely, serious skin reactions have been observed with NSAIDs, including Arthrotec. The patient should immediately report any skin changes to their doctor. The doctor may decide to discontinue treatment with Arthrotec in case of the first occurrence of skin rash, mucosal lesions, or other symptoms of hypersensitivity.
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 pain and/or anti-inflammatory drugs, headache may occur, which should not be treated with 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 problems with becoming pregnant, they should inform their doctor.
Arthrotec may cause vision disturbances. In case of vision disturbances, the patient should contact an ophthalmologist.
Before taking the drug, the patient should inform their doctor:

• if they smoke
• if they have diabetes
• if they have angina pectoris, thrombosis, hypertension, high cholesterol, or high triglycerides.

The occurrence of side effects can be reduced by using the lowest effective dose and not for longer than necessary.

Arthrotec and other medicines

The patient should inform their doctor if they are taking any of the following medicines:

• diuretics (water pills): NSAIDs may reduce the effectiveness of diuretics. When taking diuretics that spare potassium, an increase in potassium levels in the blood may occur; Page 3 9
• cyclosporine (immunosuppressive drugs used, among others, in the treatment of transplant patients): diclofenac may increase the nephrotoxicity of cyclosporine; it is essential to start treatment with Arthrotec at the lowest dose and closely monitor the patient's condition for signs of toxic effects;
• tacrolimus (immunosuppressive drug used, among others, in the treatment of atopic dermatitis): when taking NSAIDs with tacrolimus, there is a possible increased risk of nephrotoxic effects;
• lithium preparations, digoxin, ketoconazole: Arthrotec may increase lithium and digoxin levels in the blood at steady state and decrease ketoconazole levels;
• antidiabetic drugs: NSAIDs may enhance the effect of oral antidiabetic drugs. When taken with antidiabetic drugs, there may be a risk of hypoglycemia or hyperglycemia;
• anticoagulant drugs, such as warfarin, and antiplatelet agents, such as acetylsalicylic acid. It is not recommended to take Arthrotec with acetylsalicylic acid;
• selective serotonin reuptake inhibitors (some antidepressant drugs): NSAIDs may enhance the effect of these drugs, thus increasing the risk of gastrointestinal bleeding;
• methotrexate: NSAIDs may increase methotrexate toxicity associated with its increased blood levels, especially in patients receiving high doses of methotrexate;
• other NSAIDs and corticosteroids: concomitant use of these drugs with Arthrotec may increase the frequency of ulcers or gastrointestinal bleeding and other side effects;
• antihypertensive drugs, including diuretics, ACE inhibitors, angiotensin II receptor antagonists (AIIA), and beta-blockers: NSAIDs may reduce their effectiveness. In patients with impaired renal function (e.g., dehydrated or elderly patients with impaired renal function), concomitant use of ACE inhibitors or AIIA and/or diuretics with cyclooxygenase inhibitors may lead to renal impairment, including acute renal failure, which is usually reversible;
• drugs that neutralize stomach acid: these drugs may delay the absorption of diclofenac. Drugs that neutralize stomach acid containing magnesium may enhance the diarrhea caused by misoprostol;
• quinolones: in patients taking NSAIDs and quinolones, there may be an increased risk of seizures;
• mifepristone (a non-marketed early abortion drug): NSAIDs may reduce its effect. NSAIDs should be taken 8 to 12 days after mifepristone administration;
• voriconazole (an antifungal drug);
• sulfinpyrazone (a drug used to treat gout).

The patient should tell their doctor or pharmacist about all the medicines they are currently taking or have recently taken, as well as any medicines they plan to take.

Arthrotec with food and drink

Tablets should be taken with food.

Pregnancy, breastfeeding, and fertility

Pregnancy
The patient should not take Arthrotec if they are pregnant, think they may be pregnant, or are trying to become pregnant. The patient should inform their doctor about planned pregnancy. Due to the possible risk to the fetus, the patient must ensure they are not pregnant before starting treatment with this drug. Women of childbearing age, during treatment with this drug, must use effective birth control methods.
The doctor must inform the patient about the risks associated with becoming pregnant while taking Arthrotec, as the drug may cause abortion, premature birth, or fetal malformation (birth defects). If the patient is pregnant, they should never take this drug, as it may have a serious impact on the child, particularly on their heart, lungs, and/or kidneys, up to causing death. If the patient has taken this drug during pregnancy, they should discuss it with their doctor. If the patient decides to continue the pregnancy, they should be closely monitored by ultrasound, with particular attention to the evaluation of the fetus's limbs and head.
Diclofenac may cause premature closure of the arterial duct.
NSAIDs, used in the second or third trimester of pregnancy, may cause renal impairment in the fetus, which may contribute to a decrease in the amount of amniotic fluid or, in severe cases, to oligohydramnios. These effects may occur soon after starting treatment and are usually reversible. The amount of amniotic fluid should be closely monitored in pregnant women taking NSAIDs.
Breastfeeding
If the patient is breastfeeding, they should consult their doctor or pharmacist before taking this drug. Arthrotec should not be used during breastfeeding. Misoprostol is metabolized to misoprostolic acid, which passes into breast milk and may cause side effects in breastfed infants, such as diarrhea.

Driving and using machines

Patients who experience dizziness or other central nervous system disorders while taking NSAIDs should not drive vehicles or operate machinery.

Arthrotec contains lactose monohydrate

If the patient has previously been diagnosed with intolerance to some sugars, they should consult their doctor before taking the drug.

Arthrotec contains sodium

The drug contains less than 1 mmol (23 mg) of sodium per tablet, which means the drug is considered "sodium-free".

Arthrotec contains hydrogenated castor oil

The drug contains hydrogenated castor oil, which may cause gastrointestinal upset and diarrhea.

3. How to take Arthrotec

This medicine should always be taken as directed by the doctor. In case of doubts, the patient should consult their doctor or pharmacist.
Tablets should be swallowed whole, not chewed.

Adults

The recommended dose is one tablet taken with food, one to three times a day.

Use in the elderly

No dose adjustment is necessary, but patients should be closely monitored.

Use in patients with renal impairment

No dose adjustment is necessary in patients with mild or moderate renal impairment, but they should be closely monitored.

Use in patients with hepatic impairment

No dose adjustment is necessary in patients with mild or moderate hepatic impairment, but they should be closely monitored.
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Use in children and adolescents

The safety and efficacy of Arthrotec have not been established in children and adolescents under 18 years of age.

Overdose of Arthrotec

In case of overdose, the patient should contact their doctor or pharmacist.
Treatment of acute NSAID overdose is based on supportive and symptomatic therapy. It is recommended to take measures to reduce the absorption of the recently taken drug, such as inducing vomiting, gastric lavage, or administering activated charcoal.
Clinical symptoms that may indicate misoprostol overdose include: sedation, tremors, seizures, dyspnea, abdominal pain, diarrhea, fever, tachycardia, hypotension, or bradycardia (slow heart rate). Inducing diuresis (urine production) may be beneficial, as Arthrotec metabolites are excreted in the urine.

Missed dose of Arthrotec

The patient should not take a double dose to make up for a missed dose.

Discontinuation of Arthrotec

The decision to discontinue treatment is made by the doctor. If the patient feels that the drug's effect is too strong or too weak, they should contact their doctor.
In case of any further doubts about taking this drug, the patient should consult their doctor or pharmacist.

4. Possible side effects

Like all medicines, Arthrotec can cause side effects, although not everybody gets them.
Very common (occurring in more than 1 in 10 patients)

• abdominal pain, diarrhea, nausea, dyspepsia

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

• insomnia
• headache, dizziness
• gastric and/or duodenal ulcer, gastritis, esophagitis, gastrointestinal inflammation, vomiting, constipation, flatulence, eructation
• rash, pruritus
• increased alanine aminotransferase activity, decreased hematocrit, increased alkaline phosphatase activity in the blood
• fetal malformation

Uncommon (occurring in more than 1 in 1000 and less than 1 in 100 patients)

• vaginitis
• thrombocytopenia (platelet deficiency)
• stroke
• blurred vision
• myocardial infarction, heart failure
• hypertension
• dyspnea
• gastrointestinal bleeding, oral mucosal inflammation
• urticaria, erythema multiforme

Rare (occurring in less than 1 in 1000 patients)

• anaphylactic reaction
• nightmares
• pancreatitis
• hepatitis
• bullous pemphigoid, angioedema
• chest pain, dysmenorrhea

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

• hemolytic anemia, agranulocytosis, platelet aggregation inhibition
• fluid retention
• mood changes
• aseptic meningitis (characterized 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 on the mucous membranes and genitals), erythema multiforme, exfoliative dermatitis, drug rash with eosinophilia and systemic symptoms (DRESS)
• renal failure, renal impairment, renal papillary necrosis, nephrotic syndrome, interstitial nephritis, membranous nephropathy, focal segmental glomerulosclerosis, nephropathy
• fetal death, amniotic fluid embolism, incomplete abortion, premature birth, abnormal uterine contractions, placental retention or fetal membrane retention
• uterine bleeding, uterine contractions, female infertility (reduced fertility)
• uterine rupture, uterine perforation

* Side effects reported after the drug was placed on the market.
The patient should immediately tell their doctor if they experience chest pain, which may be a symptom of a potentially serious allergic reaction called Kounis syndrome.
Side effects from controlled clinical trials, lasting up to 24 months, mainly concern the gastrointestinal system. Diarrhea and abdominal pain are usually mild or moderate in severity and are transient; these symptoms occur early in treatment and may last for several days. Diarrhea and abdominal pain usually resolve spontaneously during Arthrotec treatment.
When taking NSAIDs, including Arthrotec, very rare cases of exacerbation of infection-related inflammation have been observed.
After the drug was placed on the market, the most frequently reported side effects were gastrointestinal disorders (about 45% of all reported cases), followed by skin reactions and hypersensitivity, which is consistent with the side effect profile of NSAIDs.
Taking diclofenac, especially in high doses (150 mg per day) and long-term treatment, may be associated with a slightly increased risk of serious arterial thrombotic events (e.g., myocardial infarction or stroke).

Reporting side effects

If the patient experiences any side effects, including any side effects not listed in the leaflet, they should tell their doctor, pharmacist, or nurse. Side effects can be reported directly to the Department of Drug Safety Monitoring of the Office for Registration of Medicinal Products, Medical Devices, and Biocidal Products
Al. Jerozolimskie 181C
02-222 Warsaw
Phone: +48 22 49 21 301
Fax: +48 22 49 21 309
Website: https://smz.ezdrowie.gov.pl
By reporting side effects, more information can be collected on the safety of the drug.

5. How to store Arthrotec

The drug should be stored out of sight and reach of children.
Do not store above 25°C.
Store in the original packaging to protect from moisture.
Do not use this drug after the expiration date stated on the packaging. The expiration date refers to the last day of the specified month.
Medicines should not be disposed of via wastewater or household waste. The patient should ask their pharmacist how to dispose of unused medicines. This will help protect the environment.

6. Contents of the pack and other information

What Arthrotec contains

• The active substances of Arthrotec are diclofenac and misoprostol. Each tablet consists of a stomach acid-resistant core containing 50 mg of diclofenac sodium, coated with an outer layer containing 0.2 mg of misoprostol.

Other ingredients are: lactose monohydrate, microcrystalline cellulose, corn starch, povidone K 30, magnesium stearate, methacrylic acid copolymer (type C), sodium hydroxide (see "Arthrotec contains sodium"), triethyl citrate, crospovidone, silica colloidal anhydrous, hydrogenated castor oil (see "Arthrotec contains hydrogenated castor oil"), talc.

What Arthrotec looks like and contents of the pack

White, round, biconvex tablets, marked "A" on one side and "SEARLE 1411" on the other side.
The packaging contains: 10 tablets (1 blister), 20 tablets (2 blisters of 10 tablets), 30 tablets (3 blisters of 10 tablets), or 60 tablets (6 blisters of 10 tablets).
Outer packaging: cardboard box.
For more detailed information, the patient should contact the marketing authorization holder or the parallel importer.

Marketing authorization holder in Portugal, the country of export:

Laboratórios Pfizer, Lda., Lagoas Park, Edifício 10, 2740-271 Porto Salvo, Portugal
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Manufacturer:

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

Parallel importer:

Delfarma Sp. z o.o., ul. Św. Teresy od Dzieciątka Jezus 111, 91-222 Łódź

Repackaged by:

Delfarma Sp. z o.o., ul. Św. Teresy od Dzieciątka Jezus 111, 91-222 Łódź
Portuguese marketing authorization number: 8786210
4632881
8786202
4632782

Parallel import authorization number: 408/22 Date of leaflet approval: 18.11.2022

[Information about the trademark]
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